Progress in Polymer Science 39 (2014) 268307

Contents lists available at ScienceDirect

Progress in Polymer Science

journal homepage: www.elsevier.com/locate/ppolysci

Dendrimer as nanocarrier for drug delivery

Prashant Kesharwani, Keerti Jain, Narendra Kumar Jain
Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar (MP) 470
003, India

a r t i c l e

i n f o

Article history:
Received 13 December 2012
Received in revised form 5 July 2013
Accepted 12 July 2013
Available online 19 July 2013
Keywords:
Dendrimer
Toxicity
PAMAM
PPI
Drug delivery
Biocompatibility

a b s t r a c t
Dendrimers are novel three dimensional, hyperbranched globular nanopolymeric architectures. Attractive features like nanoscopic size, narrow polydispersity index, excellent
control over molecular structure, availability of multiple functional groups at the periphery
and cavities in the interior distinguish them amongst the available polymers. Applications
of dendrimers in a large variety of elds have been explored. Drug delivery scientists are
especially enthusiastic about possible utility of dendrimers as drug delivery tool. Terminal functionalities provide a platform for conjugation of the drug and targeting moieties. In
addition, these peripheral functional groups can be employed to tailor-make the properties
of dendrimers, enhancing their versatility. The present review highlights the contribution
of dendrimers in the eld of nanotechnology with intent to aid the researchers in exploring
dendrimers in the eld of drug delivery.
2013 Elsevier Ltd. All rights reserved.

Contents
1.
2.

History and introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Properties of dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Monodispersity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Nano-size and shape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Biocompatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

270
270
270
270
271

Abbreviations: AFM, atomic force microscopy; BHA, benzhydrylamine; BSA, bovine serum albumin; CE, capillary electrophoresis; CNTs, carbon
nanotubes; CPDs, cationic phosphorus-containing dendrimers; CZE, capillary zone electrophoresis; DMPC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine;
DOX, doxorubicin; DPA, 2,4-dichlorophenoxyacetic acid; DSC, differential scanning calorimetry; DTPA, diethylene triamine pentaacetic acid; EDTA,
ethylenediamine tetraacetic acid; ESI, electrospray ionization; ESI-MS, electrospray ionization-mass spectrometry; FA, folic acid; FAB-MS, fast-atom
bombardment-mass spectrometry; FITC, uorescein isothiocynate; FRET, uorescence resonance energy transfer; FT-ICR MS, fourier transform ion cyclotron
resonance mass spectrometry; FT-IR, fourier transform infrared spectroscopy; GFP, green uorescence protein; GOx, glucose oxidase; Hb, hemoglobin; HCT,
haematocrit; HEPES, (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid); HPLC, high performance liquid chromatography; HRP, horseradish peroxide;
HSV, herpes simplex virus; LC, liquid crystalline; LDH, lactate dehydrogenase; MALDI-TOF MS, matrix assisted laser desorption ionization-time of ight mass
spectrometry; MAP, multiple antigen peptides; MPEG, methoxy polyethylene glycol; MRI, magnetic resonance imaging; MS, mass spectrometry; MTD, maximum tolerated dose; MTX, methotrexate; NMR, nuclear magnetic resonances; NSAIDs, non steroidal anti-inammatory drugs; OS, organosilicon; PAGE,
polyacrylamide gel electrophoresis; PAMAM, polyamidoamine; PAMAMOS, PAMAM-organosilicon dendrimers; PAMAM-SAHs, PAMAM succinamic acid
dendrimers; PEI, polyethylenimine; PPI, poly (propylene imine); PSMA, prostate-specic membrane antigen; PTX, paclitaxel; PVP, polyvinyl-pyrrolidone;
RES, reticuloendothelial system; RNase, ribonuclease; RST, repetitive synthesis technique; SANS, small-angle neutron scattering; SAXS, small-angle Xray scattering; SEC, size exclusion chromatography; siRNA, small interfering RNA; TEER, transepithelial electrical resistance; TEM, transmission electron
microscopy; TGA, thermogravimetric analysis; TLR4, Toll-like receptor 4; UPLC, ultra performance liquid chromatography; WBCs, white blood corpuscles;
XRD, X-ray diffraction.
Corresponding author. Tel.: +91 (0)7582 265055; fax: +91 (0)7582 265055.
E-mail addresses: prashant pharmacy04@rediffmail.com (P. Kesharwani), keertijain02@gmail.com (K. Jain), jnarendr@yahoo.co.in (N.K. Jain).
0079-6700/$ see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.progpolymsci.2013.07.005

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

3.
4.

5.

6.

7.
8.

9.
10.

11.
12.
13.

2.4.
Periphery charge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.
Dendrimermembrane interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6.
End groups and toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7.
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Macromolecular architecture of dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Synthesis of dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Divergent approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
Convergent approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.
Other approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.1.
Hypercores and branched monomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.2.
Double exponential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.3.
Lego chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.4.
Click chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Types of dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.
PAMAM dendrimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
PPI dendrimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.
Liquid crystalline (LC) dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.
Core shell (tecto) dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5.
Chiral dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.
Peptide dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.7.
Glycodendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8.
Hybrid dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.9.
PAMAM-organosilicon (PAMAMOS) dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Characterization of dendrimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1.
IR spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.
NMR spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.
Electron microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4.
Size exclusion chromatography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5.
Mass spectrometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Toxicitiy of dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Applications of dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.
Therapeutic applications of dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.1.
Therapeutic activity of dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.2.
Solubilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.3.
Dendrimers in transdermal drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.4.
Dendrimers in oral drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.5.
Dendrimers in ocular delivery of bioactives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.6.
Dendrimers in pulmonary delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.7.
Dendrimers in targeted drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.8.
Reduction of toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.
Biomedical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.1.
Dendrimers in gene delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.2.
Dendrimers as nanoscale containers (nano-scaffolds) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.3.
Intracellular delivery of bioactives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.4.
Microvascular extravasation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.
Diagnostic applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.1.
X-ray contrast agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.2.
Molecular probes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.3.
MRI contrast agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Surface engineering of dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Dendrimer linked to other nanocarriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.1.
Dendrimer linked to liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.2.
Dendrimer linked to nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.3.
Dendrimer linked to CNTs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biofate of dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Regulatory considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion and future prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. History and introduction

Natural as well as synthetic polymers have always
fascinated the scientists in each and every area of
modern research. The synthetic polymers, particularly
the biodegradable polymers have further enhanced the
drug delivery applications of novel drug delivery systems. Nanobiopolymers are further rening the spectrum
of pharmaceutical and biomedical applications. In this
context dendrimers have emerged as one of the most
promising innovative polymeric nanocarriers for different
therapeutic categories of bioactives.
In the present context of architectural chemistry considerable efforts have been dedicated to development of
polymer systems. The 20th century has witnessed impressive innovations in polymer synthesis and advances in the
design of biodegradable polymeric macromolecules. The
dendrimers are the result of these advances and innovations in the eld of polymer science. Dendrimers were, for
the rst time, synthesized during 19701990 by two different groups; Buhleier et al. and Tomalia et al. In contrast
to linear polymers, dendrimers developed by these two
groups have precisely controlled architecture with tailormade surface groups, which could be nely tuned [1,2].
Initially very few laboratories got interested in developing synthetic routes to these aesthetically pleasing
macromolecules but in the later few years it was realized
that dendritic polymers have something very special to
offer. As a result, continual research efforts in this area have
mushroomed and at present a growing number of publications are available, which walk around the exploration of
dendrimers in the delivery of different bioactives i.e. drugs,
oligonucleotides, enzymes and vaccine etc. [36].
The potential of dendrimers as vessels or hosts for other
molecules as dendritic box was strikingly demonstrated
by Jansen et al. [7] followed by Zimmerman et al. who investigated the fabrication as well as drug delivery propensity
of benzyl ether dendrimers intervened by hydrogen bonds.
The scientists had prepared a wedge-like molecule with
dendritic tail and allowed six of these wedges to assemble
themselves into a pie like hydrogen bonded aggregate [8].
After a long journey of break through, the credit for discovering the Dendrimer Technology i.e. the accurate and
validated method to design a complete dendrimer goes to
the pioneer chemist in the eld of dendrimer i.e. Professor
Donald A. Tomalia [210].
The expression dendrimer is derived from a Greek term
dendron that means tree, which is logical in view of
their typical structure with a number of branching units.
Dendrimers are dened as synthetic macromolecules characterized by high branching points, three dimensional
globular shape, monodispersity and nanometric size range.
In literature, these are also popularly described as Cascade
molecules, Arborols, Dendritic molecules; or as nanometric architectures because of their nanoscopic size and
monodispersity [9,10]. The characteristic architecture of
dendrimers provides a well-dened branched structure
with globular shape, which renders a large number of surface groups that can be tailored to provide a template for
drug delivery [10]. Dendrimers are globular, nano-sized
(1100 nm) macromolecules with a particular architecture

constituted of three distinct domains: (i) a core at the center

of dendrimer consisting of an atom or a molecule having at
least two identical chemical functions; (ii) branches, emanating from the core, constituted of repeat units having at
least one branch junction, whose repetition is organized in
a geometrical progression that results in a series of radially concentric layers called generations; and (iii) many
terminal functional groups, generally located at the surface of dendritic architecture. These surface groups are vital
in determining the properties of dendritic macromolecules
[11] (Fig. 1).
2. Properties of dendrimers
Dendritic architecture holds immense potential over
the other carrier systems, particularly in the eld of drug
delivery, because of their unique properties. As compared
to traditional linear polymers, dendrimers exhibit signicantly improved physical and chemical properties. Salient
properties of dendrimers are discussed below.
2.1. Monodispersity
Dendrimers are the class of dendritic polymers that can
be constructed with a well-dened molecular structure,
i.e. monodisperse unlike linear polymers. Monodispersity
offers researchers the possibility to work with a tool for
well-dened and reproducible scalable size [12]. Monodispersity of dendrimer has been conrmed widely by
mass spectroscopy, size exclusion chromatography (SEC),
gel electrophoresis and transmission electron microscopy
(TEM). Due to the purication at each step of synthesis
the convergent methods generally produce the most nearly
isomolecular dendrimers [1114]. Mass spectroscopy data
have well established that PAMAM dendrimers produced
by the divergent method are extremely monodisperse for
earlier generation (1.05.0 G). Factors such as dendrimer
bridging and incomplete removal of ethylenediamine at
each of the generation sequences may affect the degree of
monodispersity [2]. This latter factor, at any point in dendrimer growth, will function as an initiator core to produce
0.5 G and subsequent generation dendrimers that leads to
polydispersity [15].
2.2. Nano-size and shape
Dendrimers with uniform and well-dened size and
shape are of prominent interest in biomedical applications
because of their ability to cross cell membranes as well as
reduce the risk of premature clearance from the body. The
high level of control over the dendritic architecture makes
them an ideal carrier. The size of dendrimers increases systematically, as does the generation number, ranging from
several to tens of nanometers in diameter. Dendrimers are
similar in size to a number of biological structures, for
example, 5.0 G PAMAM dendrimers is approximately the
same size and shape as hemoglobin (Hb) (5.5 nm diameter)
[16]. Several classes of dendrimers have been synthesized
with a variety of core materials, branching units and surface modications. Dendrimer size will also be relevant to
the three dimensional shape; lower generation dendrimers

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

271

Fig. 1. Schematic representation of general structure of dendrimer.

tend to be open and amorphous structures whereas higher

generations can adopt a spherical conformation, capable
of incorporating drug molecules. X-ray analysis on dendrimer aggregates suggested that the molecular shape of
the lower to higher generations becomes increasingly globular (i.e. more spherical compared to linear shape), in order
to spread out the larger molecular structure with a minimal
repulsion between the segments [17].

end groups or conversion of end groups of dendrimers

to neutral or anionic groups have resulted in dendrimers
with decreased toxicity or even non-toxic dendrimers in
both in vitro and in vivo studies as observed in case of
neutral dendrimers like polyester, polyether and surface
engineered dendrimers, for example glycosylated, PEGylated dendrimers etc. [21,26,27].

2.4. Periphery charge

2.3. Biocompatibility
Regardless of their toxicity dendrimers have been
considered as smart carrier owing to their ability as intracellular drug delivery vehicle, to cross biological barriers,
to circulate in the body during time needed to exert a
clinical effect, and to target specic structures. Toxicity of
dendrimers is ascribed mainly to the end group present
on its periphery. Generally amine-terminated PAMAM and
PPI dendrimers display concentration-dependent toxicity
and hemolysis [1820] whereas neutral or anionic groups
terminated dendrimers have shown comparatively less
toxicity and hemolysis [18,2124]. Fortunately the toxicity of cationic dendrimers can be overcome by partial
or complete modication of their periphery with negatively charged or neutral groups [18,20,25]. Although both
PAMAM and PPI dendrimers have terminal amino groups
yet they display different pattern of toxicity. In case of
cationic PAMAM dendrimers, toxicity increases with each
generation but unpredictably cationic PPI dendrimers do
not follow this pattern of toxicity [18,19]. The cytotoxicity behavior of cationic dendrimers is widely explained by
the favored interactions between negatively charged cell
membranes and the positively charged dendrimers surface,
enabling these dendrimers to adhere to and damage the cell
membrane, causing cell lysis. Whereas masking of cationic

Dendrimers consist of three structural units i.e. core,

branching units and a number of terminal end groups. End
groups may possess positive, negative or neutral charges,
which are vital in the exploration of dendrimers as drug
delivery vehicles. This polyvalency can be exploited to
play an important role in the application of dendrimers as
gene carrier because cationic dendrimers like poly-l-lysine,
PPI and PAMAM, etc. can form complexes with negatively
charged DNA. Also the positive charges of dendrimers
facilitate its interaction with negatively charged biological membranes leading to applicability of dendrimers for
intracellular drug delivery. Challenging these advantages,
the polyvalency of dendrimers also leads to the toxicities
including cytotoxicity, hemolysis etc. [18,28]. Fortunately
these toxicities can be overcome by surface modication (engineering) of dendrimers with different agents
like carbohydrates, PEG, acetate etc. Thus polyvalency has
important implication on the properties of dendrimers and
provides a potential arena for scientists working in the eld
of dendrimers-mediated drug delivery [25,29], the focal
theme of this review.
Sadekar and Ghandehari, reviewed the role of PAMAM
dendrimers in oral delivery with effect of surface charge
and generation on the toxicity as well as transepithelial
transport and cellular uptake. In studies with Caco-2 cell

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lines that these dendrimers were found to be transported

by both routes; paracellular via opening of tight junction
as well as transcellular mediated by endocytosis. The surface engineering of PAMAM dendrimers resulted in both
reduced toxicity as well as enhanced transepithelial transport. In addition to this, authors also performed the critical
in vivo evaluation of PAMAM dendrimers-based conjugates
to elucidate their efcacy, toxicity and stability [30].

subphysiologic surface pressure in liquid crystalline state,

particularly evident in case of rapidly dividing cells [38].
Lower generation cationic dendrimers interact electrostatically with biological membrane without affecting its
integrity but the higher generation dendrimers with large
density of cationic charges interact with membrane to
induce formation of nanoholes and may lead to cell death
followed by toxicity.

2.5. Dendrimermembrane interactions

2.6. End groups and toxicity

Interaction of higher generation dendrimers having

positively charged surface groups with negatively charged
biological membrane results in formation of nanoscale
holes and cell lysis. Two most widely used models
to understand this mechanism include biological membranes as well as living cell membranes [3134]. The
interaction of cationic phosphorus-containing dendrimers
(CPDs) (3.0 G and 4.0 G) with model lipid membranes
has been investigated. Model lipid bilayers consisting
of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)
and dispersed in aqueous HEPES buffer solution (10 mM,
pH 7.4) were used and then interactions were studied with differential scanning calorimetry (DSC) and
zeta-potential techniques. Result of calorimetric analysis
displayed generation-dependent interaction. Presence of
dendrimers attributed signicant changes in the main transition enthalpy and phase transition temperature values.
Rate of alteration of thermotropic behavior was found
to be concentration-dependent. The uidity rate of the
lipiddendrimer complexes was proportional to the dendrimer/lipid molar ratios [35].
The effect of PAMAM dendrimers on paracellular permeability, integrity, and viability of Caco-2 cell monolayers
was investigated by measuring the mannitol permeability, transepithelial electrical resistance (TEER) and lactate
dehydrogenase (LDH) enzyme leakage, respectively. The
concentration of dendrimers, incubation time and generation increase were found to be directly proportional to
LDH leakage [36]. Mecke et al. suggested that in the uid
phase of a membrane, cationic PAMAM dendrimers leads to
hole formation however the existence of a gel phase in the
plasma membrane is unaffected by the presence of these
dendrimers [37].
Tiriveedhi et al. studied the interaction of 1.0 G and
4.0 G PAMAM dendrimers with model lipid membranes
using the uorescence spectroscopy and surface tensiometry techniques. As examined with uorescence anisotropy,
electrostatic interaction was found to mediate the binding between dendrimers and membrane owing to positive
surface charge and negative charge of dendrimers and
membranes, respectively. Finally authors concluded that
the PAMAM dendrimers of low generation penetrate into
lipid monolayer at low surface pressure (<30 mN/m) and
high uidity as elucidated with surface tensiometry. From
this study it was inferred that lower generation PAMAM
dendrimers interact electrostatistically with membrane by
inducing aggregation of lipid vesicles without affecting
integrity of membrane signicantly. Further, this interaction was affected by two parameters; membrane uidity
and surface pressure with preferential interaction at

Dendrimers being nanometric size can non-specically,

interact with a variety of cells and cellular components
menifesting toxic consequences. It has been reported
that in case of dendrimers the cell toxicity is associated with the number of end groups and surface charges.
Cationic dendrimers like PAMAM, PPI and poly-l-lysine
have shown toxicity in a dose-dependent manner however negatively charged dendrimers such as sulfonated,
carboxylated, phosphonated; or neutral dendrimers, such
as dendrimers with poly(ethylene oxide), acetyl, carboxyl,
mannose, galactose end groups; revealed less toxicity compared to positively charged dendrimers. In light of these
reports, modication of surface groups of cationic dendrimers with neutral molecules is preferred to possibly
prevent toxicity of dendrimers [28,3538] (Fig. 2). As discussed in the previous section dendrimer having positively
charged endgroups may interact with negatively charged
membrane and may increase the permeability that facilitates the intracellular delivery of bioactives. But in case
of higher generation dendrimers, dendrimermembrane
interaction may result in disruption of membrane integrity
followed by leakage of important intracellular components, which nally leads to cell death and toxicity. This
toxicity is attributed to high charge density inherently
associated with larger generations of positively charged
dendrimers.
2.7. Pharmacokinetics
Pharmacokinetics of macromolecules depends primarily upon the anatomical and physiological characteristics,
the physicochemical properties of macromolecules and
their interactions with biological components [39]. In
case of intravenous administration, macromolecules are
instantly introduced into the blood circulation with
restricted diffusion to the extravascular space. Subsequent elimination of these circulating macromolecules
occurs followed by distribution to particular organs for
disposition, which reects the plasma clearance by these
organs or tissues. Factors that play a major role in
the specic tissue-macromolecules uptake are capillary
permeability, organ blood ow and nature of the macromolecules.
In case of dendrimers, parenteral administration has
been utilized mostly suggesting the potential for dendrimer absorption across various epithelial barriers,
including the intestine and the skin [40]. Ideally, dendrimers are developed to deliver drugs to target tissues
to obtain adequate therapeutic efcacy, avoiding toxic
effects on the healthy bystander cells, which are associated

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

273

Fig. 2. Biological interaction of cell with cationic, anionic, neutral and surface modied dendrimer.

with the potential organ-specic toxicity of the free drugs.

Surface decorated dendrimers are reported to exhibit
improved pharmacokinetic proles than plain PPI dendrimers [21,41].
Pharmacokinetics of intravenously administered tritiated poly-l-lysine dendrimers has been reported. Very
rapid initial clearance and unpredictably high initial
volumes of distribution were observed in case of amineterminated 3.0 G and 4.0 G dendrimers [42]. In another
study, effect of surface charge on excretion prole of nonbiodegradable 5.0 G PAMAM dendrimers was compared. As
compared to cationic dendrimer, about twice as much of
the uncharged dendrimer was excreted via the urine and
feces over 7 days; suggesting enhanced cellular uptake of
the cationic dendrimers [43].
Rapid vascular binding of dendrimers with surface
amino groups may reduce on conjugation with anionic
capping groups, which conceals the surface amine group.
Subsequently the systemic disposition is governed by the
renal and reticuloendothelial system (RES) clearance. It was
found to be dependent on the nature of the anionic group
[18,44]. Nigavekar et al. evaluated the biodistribution of
3 H-labeled 5.0 G PAMAM dendrimers (positively charged)
and acetylated dendrimers in B16 melanoma and DU145
prostate tumor models and concluded greater tissue
deposition in case of positively charged PAMAM [43].
Although, enough reports are available on the pharmacokinetics of dendrimers yet systematic investigation on
the in vivo fate of dendrimers is urgently needed to
this myriad drug delivery system to certify its clinical
utility.

3. Macromolecular architecture of dendrimers

The dendritic architecture has been stated as the fourth
major class in the family of macromolecular polymeric
architecture after linear, cross linked and branched molecular architecture. According to Tomalia [45], this fourth
class of macromolecular architecture could be further subdivided into four dendritic or cascade molecule subclasses
namely random hyperbranched polymer, dendrigraft polymers, dendrons, and dendrimers (Fig. 3).
During the production of dendrimer each step is controlled throughout the chemical synthesis that results
in monodisperse, macromolecular, globular polymeric
architecture. This globular macromolecular architecture
of dendrimers has a large number of surface groups,
which can be easily tailored to achieve various objects
[46] (Fig. 4). Dendritic architecture is synthesized either
by divergent or convergent approaches [47]. In divergent method dendrimer is grown away from a central
focal point i.e. core extending radially to the periphery; whereas in convergent method, synthesis starts from
the surface and proceeds towards the interior prior to
the attachment of pre-synthesized dendrons to the core.
Since dendrimers are synthesized by step-by-step growth
method, the branching elements are depicted by generation number. The core molecule is demonstrated by
generation 0 (G0 ) whereas successive addition of branching units leads to higher generations G1, G2, G3. . .. . .. . . and
so on. Fig. 5 portrays the different generations of ethylene
diamine cored poly (propylene imine) (PPI) dendrimers.
Both of these methods result in exponential increase in the

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P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

Fig. 3. Schematic representation of various classes of polymeric architecture.

number of functional groups with each successive generation. This exponential increase in functional groups leads
to steric crowding, which nally results in geometrical
changes. Initially diameter of dendrimer increases linearly
however in later stage dendritic polymer adopts more
globular shape with increase in dendrimer generation due
to steric hindrance [13,45,47,48]. These unique structural
features ascribe the dendrimers ideal architectural properties including monodispersity, hyperbranched polymeric
architecture, denite nanometric size, shape, molecular
weight and stability. In this way, dendrimer has widely

been explored as a new platform for delivery of bioactives owing to unique biological properties such as high
drug pay load, lipid bilayer interactions, targeting potential, blood plasma retention time, ltration, intracellular
internalization, biodistribution, transfection, good colloidal and biological stability (Fig. 6). A variety of dendritic
molecules have been explored thoroughly for drug delivery
including polyamidoamine (PAMAM), PPI, poly-l-lysine,
triazine, melamine, PEG and carbohydrate-based citric
acid, poly(glycerol-co-succinic acid), poly(glycerol), and
poly[2,2-bis(hydroxymethyl)propionic acid] dendrimers

Table 1
Theoretical details of different generation of PAMAM and PPI dendrimers.
Dendrimer type

PAMAM

Generation

Surface groups

Molecular formula

Molecular weight

PPI
Surface groups

Molecular formula

Molecular weight

0
1
2
3
4
5

4
8
16
32
64
128

C22 H48 N10 O4

C62 H128 N26 O12
C142 H288 N58 O88
C302 H608 N122 O60
C622 H1248 N250 O124
C1282 H2528 N508 O252

517
1430
3256
6909
14,215
28,826

4
8
16
32
64
128

C14 H36 N6
C38 H92 N14
C86 H204 N30
C182 H428 N62
C374 H876 N126
C758 H1772 N254

288
746
1658
3486
7140
14,436

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

275

[46,49,50] (Fig. 7). For sake of clarity theoretical details of

molecular weight, molecular formula and surface groups
of two most explored dendrimers, PPI and PAMAM dendrimers are summarized in the Table 1.

4. Synthesis of dendrimers

Fig. 4. Dendrimer as platform for multiple ligands as a tool for various

applications.

Dendrimers are symmetric, highly branched polymers

with a compact spherical structure (diameter ranging from
1.1 nm for 1.0 G PAMAM to 9 nm for 8.0 G PAMAM dendrimer) [51]. They are normally synthesized from a central
polyfunctional core by repetitive addition of monomers.
The core is characterized by a number of functional groups.
Addition of monomers to each functional group results
into next dendrimer generation as well as expression of
end groups for further reaction [52,53]. Size of dendrimer
increases as the generation number increases; a stage will
soon reach when dendrimer attains its maximum size and
becomes tightly packed looking like a ball. Divergent and
convergent methods are most frequently used for dendrimer synthesis [48]. In addition other approaches like
hypercores and branched monomers growth, double

Fig. 5. Depiction of various generations of PPI dendrimers.

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P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

Fig. 6. Key features derived from well-dened structure and controlled synthesis of dendrimers.

exponential growth, lego chemistry and click chemistry

are also used (Fig. 8).
4.1. Divergent approach
Divergent approach comprises of two steps, rst is
the activation of functional surface groups, and second
is the addition of branching monomer units [47]. In this
approach, the core is reacted with two or more moles of
reagent containing at least two protecting/branching sites,
followed by removal of the protecting groups. This will lead
to the formation of rst generation dendrimer. This process
is repeated several times until the dendrimer of the desired
size is formed. PAMAM starburst dendrimers are prepared
by this method. As compared to others method, divergent
approach has some over riding advantages such as ability
to modify the surface of dendrimer molecules by changing
the end groups at the outermost layer. Another advantage
is that the overall chemical and physical properties of dendrimer can be congured to specic need [5456].
4.2. Convergent approach
This is an alternative method of dendrimer synthesis rstly proposed by Hawker and Frechet in 1990.
Only one kind of functional group on the outermost
generation is the main constraint of divergent growth
method. Convergent growth would overcome such a weakness. Convergent method involves two stages, rstly a

reiterative coupling of protected/deprotected branch to

produce a focal point functionalized dendron; and secondly, divergent core anchoring step to produce various
multidendron dendrimers. Precise control over molecular
weight and production of dendrimers having functionalities in precise positions and number are some outstanding
dividends of this method [13].
However difculty to synthesize the dendrimer in large
quantities, because of repeated reaction occurring during convergent approach that necessitates the protection
of active site, is a signicant limitation of these methods. Presently dendrimers are commercially manufactured
by companies like Dentritech (Midland, US), Dutch State
Mines (DSM), Netherlands, Dow Chemicals (Michigan, US),
Aldrich Chemical Company (Milwaukee, WI) and Weihai
CY Dendrimer Technology (China).
4.3. Other approaches
4.3.1. Hypercores and branched monomers
This method involves the pre-assembly of oligomeric
species to hasten up the rate of dendrimer synthesis. In this
method oligomeric species are linked together to yield dendrimers in fewer steps and/or higher yields. Essentially a
hypercore having multiple attaching groups is grown from
core molecule and the surface units are linked to branched
monomer with focal point activation leading to synthesis
of blocks, which are then attached to hypercore to generate
a higher generation dendrimers [57].

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

277

Fig. 7. Different types of dendrimers.

4.3.2. Double exponential

This approach allows the preparation of monomers for
both divergent and convergent growth from a single starting material, which is similar to a rapid growth technique
for linear polymer. The resultant two products are then
reacted to give an orthogonally protected trimer, which
can be used to repeat the growth again. Advantage of double exponential growth approach is rapid synthesis and
applicability to either divergent or convergent method.
4.3.3. Lego chemistry
In order to simplify the synthetic procedure for dendrimers, in terms of cost as well as duration of synthesis,
various approaches have been explored by scientists; Lego
chemistry is one of the outcomes of these explorations.
Lego chemistry is based on the application of highly functionalized cores and branched monomers and has been
utilized in the synthesis of phosphorus dendrimers. The
basic synthetic scheme has undergone several modications and has resulted in a rened scheme wherein a

single step can amplify the number of terminal surface

groups from 48 to 250. Apart from higher growth in the
number of terminal surface groups in few reactions, this
method also encompasses the advantage of utilizing minimum volume of solvent, allowing simplied purication
procedure with eco-friendly by-products like water and
nitrogen [58].
4.3.4. Click chemistry
Another approach for fast and reliable synthesis of dendrimers is based on click chemistry where in small units
are joined together. High chemical yield with innocuous
by-product is the main characteristic of click chemistry
reaction. Use of simple reaction conditions, easily available reagents, and benign solvent are the additional prots
of click chemistry. Following the click chemistry strategy
dendrimers with various surface groups can be obtained
in high purity and excellent yield. 2.0 G and 3.0 G triazole
dendrimers were synthesized using Cu (I)-catalyzed click
chemisty reactions and obtained dendrimers were isolated

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P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

Fig. 8. Methods of dendrimers synthesis.

as pure, solid sample with only sodium chloride as the

major by-product using chromatographic procedure [58].

positive charge on the surface, PAMAM dendrimers have

the ability for condensation of DNA followed by transfection [61].

5. Types of dendrimers
5.2. PPI dendrimer
A rapid development of dendritic novel carrier has been
possible due to recent advances in synthetic chemistry and
characterization techniques. Also a range of dendritic scaffolds has become available with dened nanoscopic size
and ample numbers of functional end groups [59]. Some of
the dendrimers having different functionalities along with
their applications are described in Fig. 7.
5.1. PAMAM dendrimer
The rst dendritic structures that have been exhaustively investigated and have received widespread attention
were Tomalias PAMAM dendrimer. PAMAM dendrimers
are synthesized by the divergent method starting from
ammonia or ethylenediamine initiator core reagents. Products up to generation 10 (a molecular weight of over
930,000 g/mol) have been obtained. The polydispersity
index of 5.010.0 G PAMAM dendrimers is less than 1.08,
which means that the particle size distribution is very
uniform for each generation [60]. Due to the presence of

PPI dendrimers are amine-terminated hyperbranched

macromolecules, which are mainly synthesized by divergent method [62]. PPI dendrimer contains two types of
nitrogen atoms; nitrogen of primary amine and nitrogen of tertiary amine. As compared to tertiary nitrogen
atoms, which are more acidic having a pKa around 69,
primary nitrogen atoms are more basic having a pKa
around 10. PPI dendrimers are synthesized by divergent
approach, in a sequence of repetition of double Micheal
addition of acrylonitrile to primary amines followed by
heterogeneously catalyzed hydrogenation of nitriles. This
repeated reaction results in a doubling of the number of
primary amines. During the synthesis of PPI dendrimer 1,4diaminobutane is utilized as dendrimer core. A variety of
molecules with primary or secondary amine groups can
also be used as core in dendrimer synthesis [63]. These PPI
dendrimers are commercially available from Dutch State
Mines (DSM), Netherlands and Aldrich Chemical Company
(Milwaukee, WI).

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

5.3. Liquid crystalline (LC) dendrimers

LC dendrimers consist of mesogenic LC monomers
e.g. mesogen functionalized carbosilane dendrimers. Thermotropic LC phases or mesophases are usually formed by
rod-like (calamitic) or disk-like (discotic) molecules [59].
Dendrimers with AB mesogens in the branches were rst
reported by Percec et al. in 1995 [64]. Frey and coworkers
also attached several mesogenic units to carbosilane dendrimers, such as cyanobiphenyl [65] and cholesteryl [66].
In a reported study, mesogenic 3,4-bis-(decyloxy)benzoyl
groups functionalized PPI dendrimers of different generations (1.05.0 G) were investigated for mesogenic activity.
It was found that apart from fth generation dendrimer,
all other lower generations dendrimers displayed a hexagonal columnar mesophase in which the dendrimers had
a cylindrical conformation [67,68]. The lack of mesomorphism for the fth generation dendrimer was due to its
inability to reorganize into a cylindrical shape. In 2001,
Boiko et al. reported the debut synthesis of photosensitive LC dendrimer with terminal cinnamoyl groups [69].
These LC dendrimers are being investigated by scientists
for biomedical applications. Recently Pedziwiatr-Werbicka
and coworkers suggested that amino terminated carbosilane dendrimers have potential to deliver short chain siRNA
and anti-HIV oligodeoxynucleotide to HIV-infected blood
cells. Although these dendrimers had limited application
in the delivery of long-chain double stranded nucleic acids,
yet the dendriplexes of carbosilane dendrimers and antiHIV nucleic acid were stable and less cytotoxic to blood
cells than the plain dendrimers suggesting their utility in
the delivery of bioactives [70].
5.4. Core shell (tecto) dendrimers
Coreshell or tecto-dendrimers represent a polymeric
architecture with highly ordered structure obtained as
a result of controlled covalent attachment of dendrimer
building blocks [71,72]. Tecto-dendrimers are composed
of a core dendrimer, which may or may not contain the
therapeutic agent, surrounded by dendrimers. Synthesis
of tecto-dendrimers has been reported with uorescein
in the core reagent for detection and folate as the targeting moiety [59,73]. Such conjugates solved the solubility
problems encountered in previous studies with aromatic
uorescein isothiocynate (FITC) moieties on dendrimeric
surfaces. This conjugate was found to be overwhelmingly superior to those dendrimeric conjugates containing
both FITC and folic acid attached to the surface [74].
In contrast to simple dendrimers, synthesis procedure
for tecto-dendrimers is complaratively simple and hence
expected to inate the application of dendrimers. Schilrreff et al. investigated the cytotoxicity of tecto-dendrimers
to point out their application in biomedical eld. In this
study tecto-dendrimers having amine-terminated 5.0 G
PAMAM dendrimers as core, surrounded by shell composed of 2.5 G PAMAM dendrimers with surface carboxyl
groups, were investigate for cytotoxicity towards SK-Mel28 human melanoma cells. These tecto-dendrimers were
found to inhibit growth of melanoma cells at a concentration which is safe to healthy keratinocytes epithelial cells

279

[71]. Thus tecto-dendrimers could be explored for application in the eld of nanomedicine including drug delivery.
5.5. Chiral dendrimers
Dendrimer based upon the construction of constitutionally different but chemically similar branches to
chiral core is referred to as chiral dendrimers. Chiral,
non-racemic dendrimer with well-dened stereochemistry is particularly interesting subclass with potential
applications in asymmetric catalysis and chiral molecular
recognition [75]. Ghorai et al. described the rst molecules
of anthracene capped chiral dendrimers derived from a
1,3,5-trisubstituted aromatic core and carbohydrate units
in the interior and periphery. These are claimed to be suitable for anchoring other useful functionalities aimed at
applications as drug delivery system and light harvesting materials [76]. Evidence supporting the above claim is
keenly awaited, particularly in the eld of drug delivery
application of chiral dendrimers.
5.6. Peptide dendrimers
Peptide dendrimers are radically branched macromolecules that contain a peptidyl branching core and/or
peripheral peptide chains [77], and can be divided into
three categories. First category having peptides only as
surface functionalities is referred to as grafted peptide
dendrimers, the second category composed entirely of
amino acids is known as peptide dendrimers, while the
third one utilizes amino acids in the branching core and surface functional groups but having non-peptide branching
units. Divergent and convergent methods are frequently
used for the synthesis of peptide dendrimers, and the availability of solid-phase combinatorial methods facilitates
large libraries of peptide dendrimers to be produced and
screened for desired properties. Peptide dendrimers have
been used in industry as surfactants, and in biomedical
eld as multiple antigen peptides (MAP) [77], protein mimics [78] and vehicles for drug and gene delivery [77,78].
Additionally, Darbre and Reymond have utilized peptide
dendrimers as esterase catalysts [79].
5.7. Glycodendrimers
Dendrimers that encompass sugar moieties such as glucose, mannose, galactose [80] and/or disaccharide [81] into
their structure are referred to as glycodendrimers. The vast
majority of glycodendrimers have saccharide residues on
their outer surface, but glycodendrimers containing a sugar
unit as the central core, from which all branches emanate,
have also been described. Generally, glycodendrimers can
be divided into three categories (i) carbohydrate-centered,
(ii) carbohydrate-based, and (iii) carbohydrate-coated dendrimers [59,82]. One anticipated application of these
dendrimers is site-specic drug delivery to the lectin-rich
organs. These dendrimers were anticipiated to display better association with lectins anchored systems as compared
to mono-carbohydrate anchored systems [83,84].

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5.8. Hybrid dendrimers

Hybrid dendrimers are combination of dendritic and linear polymers in hybrid block or graft copolymer forms. The
spherical shape and a large number of surface functional
groups of dendrimers made the formation of dendritic
hybrids possible. The small dendrimer segment coupled to
multiple reactive chain ends provides an opportunity to use
them as surface active agents, compatibilizers or adhesives,
or hybrid dendritic linear polymers [85]. The dendritic
hybrids obtained from various polymers with dendrimers
generated the compact, rigid, uniformly shaped globular
dendritic hybrids, which have been explored for various
aspects in the eld of drug delivery [85,86].
5.9. PAMAM-organosilicon (PAMAMOS) dendrimers
Inverted unimolecular micelles that consist of
hydrophilic, nucleophilic PAMAM interiors and hydrophobic organosilicon (OS) exteriors are known as radially
layered PAMAMOS dendrimers (PAMAMOS). PAMAMOS
dendrimers offer unique potential for novel application in
electronics, chemical catalysis, nano-lithography and photonics etc., due to its unique properties such as constancy
of structure and ability to form complex and encapsulate various guest species with nanoscopic topological
precision [87].
Continuous urge for optimum therapeutic delivery
system for various medicaments used in treatment of infectious and non-infectious diseases leads to development and
investigation of various types of dendrimers like polyether
dendrimers, polyester dendrimers, triazine dendrimers,
melamine dendrimers, citric acid dendrimers etc. using different core and branching units. The arena of dendrimers
is everexpanding and applications of this versatile carrier
system in the drug delivery are inating day by day.
6. Characterization of dendrimer
The well-dened nanometric architecture of dendrimers is the result of controlled synthesis of these
moieties at each step by chemical reaction. Characterization of dendrimers is therefore a vital step in the
designing and engineering of these versatile nanoscopic
carriers [88,89] (Fig. 9, Table 2). The different generations
of dendrimers having different surface groups ( OH, NH2 ,
COCH3 , COOH, CN) as well as surface modied dendrimers (folate conjugated, PEGylated, glycosylated etc.)
have been separated and identied by analytical methods like high performance liquid chromatography (HPLC),
ultra performance liquid chromatography (UPLC), NMR,
UVvisible spectroscopy, X-ray diffraction etc. Titration
and chemical reactions with chemical agents like ninhydrin
reagent, reaction with CuSO4 are also used to characterize number of amino groups in dendrimers [8892].
The presence of tailor-made surface groups facilitates
surface modication of dendrimers, which could be further conrmed by reliable analytical methods including
infrared spectroscopy (IR), NMR, AFM, X-ray photoelectron
spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), matrix-associated

laser desorption ionization-time of ight (MALDI-TOF)

mass spectrometry, size exclusion chromatography, electrospray ionization-mass spectrometry (ESI-MS), vapor
phase osmometry (VPO), laser light scattering (LLS)
and sodium dodecyl sulfate-poly acrylamide gel electrophoresis (SDS-PAGE) etc. [9298]. Various methods of
characterization of dendrimers along with description of
respective parameters are summarized in Table 2. The
principle methods widely used by scientists for characterization of dendrimers are discussed in detail in the following
sections.
6.1. IR spectroscopy
Different groups present on dendrimer surface as
well as end groups generated by surface engineering
can be characterized through infrared (IR) spectroscopy.
Jain and coworkers characterized the synthesis of 0.5 G
PPI dendrimer [EDAdendr(CN)4 ] by the presence of
strong peak of nitrile at 2248.2 cm1 . The conversion
of nitrile terminals of 0.5 G PPI dendrimer into amino
groups of 1.0 G PPI [EDA(NH2 )4 ] dendrimer was conrmed by the presence of major peaks at 3373.9 cm1 ,
3294.3 cm1 attributed to the presence of primary
amine groups. Synthesis of 5.0 G PPI dendrimer was
further conrmed by IR peaks of NH stretch of primary amine (3396.9 cm1 ), NH bend (1597 cm1 ), CH
stretch (2824.2, 2957.5 cm1 ), CH bend (1466.3 cm1 ,
1531 cm1 ), CN stretch (1033.2 cm1 , 1081.6 cm1 ) [99].
In another study, Jain and coworkers characterized 4.0 G
PAMAM through IR spectroscopy by some characteristic peaks such as NH asym stretch (3473.9 cm1 ), NH
sym stretch (3440 cm1 ), CH stretch (2975.9 cm1 ), C O
stretch (1731.5 cm1 , 1692.5 cm1 ) NH in plane bending
(1599.9 cm1 ), CN stretch (1285.5 cm1 ), OCN deformation (630.1 cm1 ), CC bend (1109.6 cm1 , 1052.7 cm1 )
[5].
Jain and coworkers synthesized poly-l-lysine dendrimers using sequential protection and deprotection of
amino groups of lysine with di-tertiary butyl pyrocarbonate (di-t-BOC). Again the protection and deprotection
were monitored by IR. Di-t-BOC protected 4.0 G lysine dendrimers showed the characteristic peaks of OH stretch
(3428.1 cm1 ), symmetric CH stretching (2934.8 cm1 ),
aliphatic CH stretch (2829.9 cm1 , 2722.2 cm1 ), C O
stretch due to ester linkage (1595.8 cm1 ), asymmetric and symmetric CH bending (1360 cm1 ), CO stretch
(1169.1 cm1 ), CH bending (1113.1 cm1 ), CC stretching
(773.4 cm1 ), CH rocking (619.5 cm1 ) [90]. The detection
of functional groups via infrared spectroscopy assists in
evaluating the formation of different generation of dendrimers as well conjugation of a variety of targeting or
imaging ligands at the periphery of dendrimers for targeted
drug delivery, or diagnosis of disease, respectively.
6.2. NMR spectroscopy
NMR spectroscopy provides another mean to characterize different groups present on plain as well as
engineered dendrimers. Gajbhiye and Jain characterized
5.0 G PPI dendrimer by 1 H NMR spectroscopy using

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

281

Fig. 9. Methods of characterization of dendrimers.

multiplets between 0.9 ppm and 1.2 ppm and 2.22.3 ppm
corresponding to methylene ( CH2 ) groups of EDA and
multiplets between 2.5 ppm and 2.8 ppm corresponding
to N(CH3 ) [100]. Jain and coworkers has also characterized 4.0 G PAMAM dendrimers by 1 H NMR spectroscopy.
Characteristic multiplets at 2.362.39 ppm (triplet) corresponding to R2 CH2 , 2.642.69 ppm (triplet) corresponding
to CH2 CO , 2.7702.815 ppm (triplet) corresponding to

>N CH2 CH2 CO NH, and 3.0263.067 ppm (triplet) corresponding to CH2 NH2 were observed [5].
6.3. Electron microscopy
Transmission as well as scanning electron microscopy
(TEM and SEM) both have been explored to investigate the
size, shape, surface morphology of dendrimers. Dendrimer

Table 2
Methods of characterization of dendrimers.
Analytical methods

Characterization parameter

Nuclear magnetic resonance (NMR)

It helps in determining chemical transformation undergone by end groups and hence applicable to
structural analysis of dendrimers and step-by-step characterization of synthesis
It ascertains the chemical transformation taking place during the synthesis or surface engineering
of dendrimers
It helps in determining the change in chemical structure and synthesis method by detecting
chromophores and auxochromes. Also used to test the purity of dendrimers
It is used to characterize the structure and synthesis of dendrimers having photochemical groups
and to quantify defects occurred during the synthesis
Characterization of structure of dendrimers having optical activity
Size, shape and structure

Infrared spectroscopy and Raman spectroscopy

UVvisible spectroscopy
Fluorescence
Circular dichroism
Atomic force microscopy
Transmission electron microscopy
Electron paramagnetic resonance
X-ray diffraction
X-ray photoelectron spectroscopy
Electrochemistry
Electrophoresis
Small-angle X-ray scattering (SAXS)
Small-angle neutron scattering (SANS)
Laser light scattering (LLS)
Mass spectrometry (FAB-MS, ESI-MS, FT-ICR MS,
MALDI-TOF MS)
Size exclusion (or Gel permeation)
chromatography (SEC) (GPC)
Intrinsic viscosity
Differential scanning calorimetry (DSC)
Dielectric spectroscopy

Surface structure
Chemical composition, size and shape
Chemical composition and size
It gives information about the structure of dendrimers
Purity and homogeneity of water-soluble dendrimers
It gives average radius of gyration (Rg) in solution hence used for determination of average
particle size, shape, distribution, and surface-to-volume ratio
It gives average radius of gyration (Rg) in solution as well as detailed information about the
internal structure of entire dendrimer
Hydrodynamic radius of dendrimers
Determination of molecular mass and some structure information
Molecular weight and size
Physical characterization and morphological structure
Glass transition temperature (Tg), which is affected by the molecular weight, entanglement and
chain-end composition of polymers
Study of molecular dynamics

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Fig. 10. Different approaches of surface engineering of dendrimers.

surface can be assessed by SEM as Jain and coworkers found

a smooth surface of dendrosomes by SEM image [5]. TEM
was mainly performed to conrm the size of the synthesized dendrimers [97]. In TEM analysis dendrimers have
been found to elicit nanometric size range as evident from
various TEM photographs [99,101].
6.4. Size exclusion chromatography
Size exclusion chromatography (SEC) is used to determine absolute molar mass of the substance to be examined
and it is also the case with dendrimers. Jain and coworkers determined the absolute molar mass of the PEGylated
5.0 G PPI dendrimers using SEC. The molecular weight was
found to be 48,125 indicating that 20 PEG chains were conjugated to one molecule of 5.0 G PPI dendrimers molecule
[102]. Hence SEC could be employed to determine not only
the molar mass of dendrimers but also the extent of surface
conjugation.
6.5. Mass spectrometry
Mass spectrometry has been explored to determine
mass of dendrimers, which could help conrming not
only the synthesis of dendrimers but also engineering in
the dendrimeric architecture. Different methods of mass
spectrometry have been explored for characterization of
dendrimers. One of these methods is MALDI-TOF mass
spectrometry (MALDI-TOF MS). The average mass of the

systems is determined from the peaks of parent molecular ion. This method is applicable to higher molecular
weight dendrimers, molecular weight is no constraint for
this type of mass spectrometry [88,89]. Jain and coworkers
determined the molecular weight of EDA-5.0 G PPIglycine
conjugate by MALDI-TOF and the molecular weight of
the conjugate was found to be 11663.0 D (4535.0 D more
than EDA-5.0 G PPI dendrimer), which helped the scientists in exploring that the increase in molecular weight
of conjugate, in comparison to plain dendrimer, corresponded to an average of 60.4666 molecules of glycine
conjugated per molecule of EDA-5.0 G PPI dendrimers
[103]. In another study, the MALDI-TOF mass spectrum of
tuftsin-5.0 G PPI (TuPPI) showed that the tuftsin conjugated
PPI dendrimers has a molecular mass of 19,544 D conrming the conjugation of average 24.83 terminal amino
groups of PPI dendrimers with tuftsin [104]. In addition
to the above discussed methods for the determination of
molecular mass; ESI-MS, Fast-atom bombardment-mass
spectrometry (FAB-MS), Fourier transform ion cyclotron
resonance mass spectrometry (FT-ICR MS), and liquid
chromatographymass spectrometry (LCMS) have also
been employed for determining the molecular weight of
different generation of dendrimers, separation and purication of dendrimers [88,89].
Apart from the characterization methods described in
this section various other analytical techniques including atomic force microscopy (AFM), confocal microscopy,
small-angle X-ray scattering (SAXS), small-angle neutron

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Fig. 11. An overview of dendrimers applications.

Fig. 12. Hostguest entrapment of a bioactive in the cavities of dendrimer.

283

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P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

scattering (SANS), dynamic light scattering, X-ray photoelectron spectroscopy and X-ray diffraction have been
also employed to characterize dendrimers in terms of
size, shape, surface structure and chemical composition
[89,105]. The surface structure and surface modication
of dendrimer could be assessed by electrophoresis as
well as polyacrylamide gel electrophoresis (PAGE), agarose
gel electrophoresis, capillary zone electrophoresis (CZE).
In addition to the surface structure, electrophoresis is
also helpful in determining the purity and electrophoretic
mobility [88,106]. Other electrical methods such as potentiometric acid-base titration have also been reported
for determining the surface modication of dendrimers
[89]. The physical parameters of dendrimers like viscosity, glass transition temperature, sedimentation, density
etc. have been studied by various methods including
viscometer, DSC, absorption spectroscopy, pH and turbidity measurements [88,89,106,107]. Measurement of zeta
potential and zeta size has been explored for characterization of dendrimers and dendrimer based formulation
like dendrimerDNA complexes [5,108]. Another method,
circular dichroism, has also been adopted to conrm complexation between dendrimers and oligonucleotides as
well as alterations in the secondary structure of DNA
[5]. DSC has been used to conrm encapsulation of drug
molecules into dendrimers via analyzing thermal stability
and crystalline transformation over a temperature range
[102]. In conclusion, dendrimers have been well characterized for their synthesis, surface modications, conjugation,
physical encapsulation and complexation as well as for various applications in the eld of drug delivery via a wide
range of analytical techniques. However it is essential that
the researcher should clearly delineate the purpose, merits
and limitations of various analytical tools.
7. Toxicitiy of dendrimers
The elds of medicine and drug delivery have particularly witnessed immense progress after the emergence of
nanomaterials such as dendrimers. The well-dened structure, large number of surface groups and nanometric size
of dendrimers lead to tremendous advances in intracellular and targeted delivery of drugs. PAMAM dendrimers
surface modied with lauryl chains and conjugated with
paclitaxel has been found to increase permeability of drug
across the cellular barriers and to show the higher cytotoxic potential against human colon adenocarcinoma cell
line (Caco-2) [109]. This increase in permeability and cytotoxicity is advantageous in the treatment of diseases like
cancer. However dendrimers have been found to exhibhit
toxic effects due to their size in the range of nanometers (1100 nm) and presence of positively charged surface
groups in case of cationic dendrimers. The nanometric size
and cationic surface groups lead to non-specic interaction of dendrimers with cellular components including cell
membrane, nucleus, mitochondria, enzymes, endosomes
etc. Although, nanomaterials have brought advances in
drug delivery yet the biological and toxicological potential of nanocarriers like nanoparticles, dendrimers, carbon
nanotubes is one of the main concern of nanotoxicology
[18,28,110].

Toxicity of dendrimers has been primarily explored ex

vivo with cancer cell lines barring a few reports available on the in vivo toxicity potential of dendrimers. The
existence of surface NH2 groups and associated cationic
charge on dendrimers connes their applications in drug
delivery due to toxicity (Fig. 2). The toxicity of dendrimers
is affected by concentration, surface charge, generation,
size as revealed through hemolytic toxicity, haematological
toxicity, cytotoxicity, immunogenicity and in vivo toxicity [18,28]. Cancino et al. evaluated the toxicity of single
walled carbon nanotubes (SWCNT), PAMAM dendrimers
and PAMAMSWCNT complexes in mouse myoblast cell
line (C2C12). In the results these nanomaterials were found
to damage DNA and signicantly toxic towards C2C12 cell.
Finally the authors concluded that the toxicity of nanomaterials is strongly correlated to their surface charge [110].
Surface charge of dendrimers plays important role in in vivo
exploration of dendrimers with regards to safety.
Thiagarajan et al. assessed oral drug delivery aptitude of
6.5 G PAMAM dendrimers via in vivo oral translocation in
CD-1 mice with evaluation of acute oral toxicity and physicochemical disposition and concluded that dendrimers
have the potential to permeate gut epithelial barrier [111].
Later, Thiagarajan et al. evaluated the in vivo toxicity of
PAMAM dendrimers including effect of surface charge and
size of dendrimers on the permeability through epithelial
barrier and acute toxicity, on oral administration in CD-1
mice. The scientists investigated the positively charged as
well as anionic dendrimers for toxicity and determined the
maximum tolerated dose (MTD). The MTD for anionic dendrimers was found to be 10 folds higher than for cationic
dendrimers. For cationic dendrimers MTD was found to be
in the range of 10200 mg/kg, while anionic dendrimers
were found to be tolerable at doses as high 500 mg/kg [112].
Toxicological issues pose most vital limitation in clinical
application of dendrimers due to the presence and number of surface amine groups. Recent research has focused
on the development of biocompatible dendrimers, which
will hasten the era of dendrimer-mediated drug delivery.
Apart from designing biocompatible dendrimers, surface
engineering presents yet another attractive approach to
diminish toxicity of dendrimers; in addition to other benecial aspects like drug targeting, reduced drug leakage,
increased stability, improved pharmacokinetic prole and
biodistribution pattern etc. Surface engineering masks the
cationic charge of dendrimer surface either by neutralization of charge, for example PEGylation, acetylation,
carbohydrate and peptide conjugation; or by introducing
negative charge such as half generations of dendrimers
(Fig. 10). The modication of PAMAM dendrimers with 4carbomethoxypyrrolidone groups reduced the toxicity to a
signicant level. These pyrrolidone modied dendrimers
were found to elicit negligible toxicity against Chinese
hamster broblasts (B14), embryonic mouse hippocampal
cells (mHippoE-18) and rat liver derived cells (BRL-3A). The
last two decades have witnessed signicant development
of biodegradable and/or biocompatible, and surface engineered dendrimers resulting into improved therapeutic
index. All these efforts resulted into a new class of dendrimer family comprising of biocompatible, biodegradable
and surface engineered dendrimers [28,113]. The issues

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

related to toxicity of dendrimers and the strategies to

resolve these toxicities have been discussed in detail by
various scientists including our group [28], which could be
referred for a deeper insight.

285

Owing to the exclusive monodispersity, nanometric size

range, permeability across the biological membrane and
container properties dendrimers serve as appropriate host
for the guest molecules either in the interior cavities or on
the periphery of the dendrimers (Fig. 12).

8.1.2. Solubilization
The poor solubility vis a vis hydrophobicity of most of
the drug molecules limits their applications. It is the major
constraint in the development of a safe, effective and stable
formulation. Various conventional as well as novel methods have been employed to overcome solubility problems.
Dendrimers have been explored by various scientists as a
promising candidate for solubilization of bioactives having
different therapeutic activity like anticancer, antimalarial,
antiviral, antitubercular, antimicrobials, NSAIDs and antihypertensive etc. [50]. Dendrimer-mediated solubilization
is affected by various factors including generation size,
concentration of dendrimers, pH, core, internal branching
units, surface groups as well as temperature. Micellar solubilization, ionic interactions, hydrophobic interactions as
well as hydrogen bonding are the main mechanisms, which
are sought to be accountable in dendrimer-mediated solubility enhancement. Solubilization efciency of dendrimers
can be easily modied by tailoring core, branching unit
and surface functionalities or engineering surface of dendrimers with hydrophilic moieties [118120]. In a study
with polypropylene oxide cored PAMAM dendrimers it was
observed that the solubilization efcacy of dendrimers is
proportional to their generation and concentration. The
study was performed with NSAIDs including Ketoprofen,
Ibuprofen and Diunisal and authors concluded that dendrimers are effective solubility enhancer for NSAIDs [121].
Dendrimers emerge out as outstanding carrier in respect of
bioavailability enhancement of chemical entities.

8.1.1. Therapeutic activity of dendrimers

Dendrimers are being evolved as topical antimicrobial
agents following exploration of effectiveness of polylysine
dendrimers against herpes simplex virus (HSV), currently under Phase II clinical trials for its efcacy against
vaginal infection. SPL7013 Gel (VivaGel ) developed by
Starpharma Pty Ltd (Melbourne, Australia) is a vaginal
microbicide for the prevention of HIV and HSV infections
[114]. The active ingredient of this Carbopol-based aqueous
gel is a dendrimer comprising a divalent benzhydrylamine
(BHA) core, four generations of lysine branches with the
outermost branches capped with a total of 32 naphthalene
disulfonic acid groups that impart hydrophobicity, and a
high anionic charge to the dendrimer surface [115]. Success of VivaGel (Starpharma) gave a philip to the other
possible applications of dendrimers.
Wang et al. assessed mechanism of antimicrobial activity of PAMAM dendrimers in guinea pig model of chorioamnionitis against Escherichia coli induced ascending uterine
infection. The authors attributed the antimicrobial activity
to the interaction of polycationic dendrimers with polyanionic lipopolysaccharide present in E. coli [116]. Later it
was observed that 3.5 G PAMAM dendrimers glycosylated
with glucosamine exhibited anti-inammatory activity by
inhibiting complex of lipopolysaccharide, Toll-like receptor
4 (TLR4) and MD-2, which mediates the proinammatory
cytokine responses [117]. This activity of partially glycosylated dendrimers could provide a platform for exploration
of dendrimers in the treatment of malignancies, inammatory diseases as well as infectious diseases.

8.1.3. Dendrimers in transdermal drug delivery

Recently dendrimers have been investigated for transdermal delivery of drugs due to the two facts: (i) the
presence of hydrophobic moieties in most of the drugs
resulting in poor water solubility, which restricts the entry
of drugs in the biological compartments, and (ii) high
water solubility and biocompatibility of most of the premeditated dendrimers.
Dendrimers have been found effective in efcient transdermal delivery of drugs with improved pharmacokinetic
prole [59]. Dendrimers have been investigated with different non steroidal anti-inammatory drugs (NSAIDs)
for transdermal delivery. Jain and coworkers investigated the 4.0 G PAMAM dendrimers with amino and
hydroxyl terminal and 4.5 G PAMAM dendrimers for transdermal delivery of a model drug, indomethacin. In the
in vivo pharmacokinetic and pharmacodynamic studies
with Wistar rats, a signicant increase in concentration of indomethacin in blood was observed in case of
PAMAM dendrimers-mediated delivery of indomethacin,
in comparison to that observed with pure drug suspension [122]. Later, Cheng and coworkers developed the
conjugate of ketoprofen and diunisal with 5.0 G PAMAM
dendrimers. In the in vitro permeation studies with excised
rat skin, ketoprofendendrimer and diunisaldendrimer
complex displayed the 3.4 and 3.2 times higher permeation rate compared to ketoprofen and diunisal dispersion
in saline, respectively. In the anti-nociception effect studies on mice, reduction in the writhing activity was
observed during 18 h, on transdermal administration of
ketoprofendendrimer complex, while with ketoprofen

8. Applications of dendrimers
In view of the fact that all the three architectural
components; namely the core, internal branching units
and the surface groups of dendrimers can be tailored to
meet unique properties. These unique properties including unparalleled molecular uniformity, multifunctional
end groups and occurrence of numerous internal cavities
render dendrimers apposite for potential pharmaceutical
applications including various therapeutic and biomedical applications. Applications of dendrimers have been
reviewed exhaustively by many scientists [58,91]. Specic
applications of dendrimers in drug delivery are summarized in Table 3 and schematically presented in Fig. 11.

8.1. Therapeutic applications of dendrimers

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Table 3
Therapeutic applications of dendrimers.
Application

Dendrimers

Bioactive(s)

Outcome

References

Solubilization

PPI dendrimers

Dendrimers can enhance solubility of acidic, basic as well as amphoteric drugs

(increase in solubility clearly depends on chemical nature of drug and pH)

[50]

Enhanced cellular uptake

Mannosylated PPI
dendrimers

Amphotericin B
Famotidine
Indomethacin
Efavirenz

[153]

Biocompatible drug carrier

Mannosylated PPI
dendrimers
Mannosylated PPI
dendrimers
PPI (5.0 G),
mannosylated and
lactosylated PPI
dendrimers
Dextran conjugated PPI
dendrimers
Folate conjugated
dendrimers

Rifampicin

12 and 5.5 times increase in cellullar uptake of efavirenz was obtained with
mannosylated PPI dendrimers after 48 h in comparison to free drug and
t-Bocglycine conjugated PPI dendrimers, respectively
A biocompatible formulation was obtained

Rifampicin

Site-specic delivery to the alveolar macrophages was achieved

[196]

Radioactive
technetium (sodium
pertechnetate;
99
mTcO4 )
Doxorubicin HCl

In biodistribution studies in female Balb/c mice, all formulations were found to

accumulate in liver but dendrimers with mannose and lactose terminal
retained for longer time in liver. Concluded that carbohydrate-coated
dendrimers can selectively deliver the bioactives to liver
Enhanced uptake by A549 cancer cell lines was observed

[87]

Methotrexate

Folate conjugated dendrimers enter the cancer cell by receptor-mediated

endocytosis

[136]

Lamivudine

Mannosylated dendrimers prolonged the release rate up to 144 h

[148]

Doxorubicin HCl

Developed formulation showed sustained release prole compared to free

drug

[93]

Chloroquine phosphate

Galactosylated dendrimers showed the negligible hemolytic toxicity with

reduction in toxicity of chloroquine phosphate

[90]

Efavirenz

Mannose conjugated dendrimers showed negligible cytotoxicity in human

hepatoma (HepG2) cell lines and very little hemolytic toxicity, respectively i.e.
2.8 0.04% and 5.3 0.03% at a concentration of 1 mg/ml
16.7% hemolysis was observed with drug (0.1 M) whereas 12.3% hemolysis
was observed with drug loaded dextran conjugated PPI dendrimers

[197]

MRI agent for kidney/bladder in Nude Copenhagen rats

[198]

MRI agent for kidney in Nude mice

MRI agent for breast cancer in Nude mice

[199]
[200]

MRI agent for breast cancer in mice

MRI and uorescein imaging agent for sentinel (mammary) lymph nodes in
mice
MRI agent for sentinel (mammary) lymph nodes in mice
MRI agent for sentinel (mammary) lymph nodes in mice

[201]
[202]

Carrier

[145,203]

Drug targeting

Reduction in toxicity

Mannosylated PPI
dendrimers
Dextran conjugated PPI
dendrimers
Galactose conjugated
poly-l-lysine
dendrimers
Mannosylated PPI
dendrimers
Dextran conjugated PPI
dendrimers

MRI contrast agents (contrast or imaging agent)

Immunotherapy (antibody conjugate)

Doxorubicin HCl

99m
Poly(2,2Tc
bis[hydroxymethyl]propanoic
acid) (5.07.0 G)
PAMAM (4.0 G)
(1B4M-Gd)64
GD-DO3A
PAMAM-cystamine
(6.0 G)
PAMAM (6.0 G)
(1B4M-Gd) 256
G6-Cy(5.5)1.25(1B4PAMAM (6.0 G)
Gd)145
PAMAM (8.0 G)
(1B4M-Gd)1024
PAMAM (6.0 G)
(1B4M-Gd)256

PAMAM dendrimers
(5.0 G)
PAMAM
PAMAM

60bca and J591

Antibody
Monoclonal sheep
antibody

TM

Binding (Anthrax detection) [Alert Ticket (by US army)]

Carrier [Stratus CS Acute CareTM Anti-proBNP (pBNP) (Siemens Healthcare)]

[93]

[93]

[155]
[155]

[204]
[205]

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

Sustained release

[196]

Gene transfection

PPI-DAB dendrimers
PAMAM dendrimers
PAMAM-Arginine
dendrimers
PAMAM dendrimers
Priostar-PAMAM
PAMAM (4.0 G)
4.0 G PAMAM

As a sensor in liquid media

As a uorescent sensor

1.0 G PPI

Intracellular drug targeting delivery

Mannosylated PPI
dendrimers
PAMAM (0.03.0 G)
Mannosylated PPI
dendrimers (5.0 G)
Folate conjugated
PAMAM dendrimers

Complexes

Complexation

Carrier
Complexation

[206]
[207209]
[210]

Oligonucleotides
(linear and anionic)
DNA/SiRNA
Oligo-DNA
siRNA and DOX

Physical mixing (commercially available as SuperFect )

[58]

Complex
Complex
Effective intracellular accumulation of siRNA with co-delivery of drug was
obtained with developed system

[132]
[210]
[211]

Developed system displayed chemical sensor activity for heavy metal in liquid
media

[212]

Developed biosensor was successfully applied for the glucose analysis in

beverages
Synthesize new dendrimer [blue uorescent poly(propyleneamine) dendrimer
whose periphery is modied with a
4-(N,N-dimethylaminoethyloxy)-1,8-naphthalimide] allows development of a
new selective uorescent sensor for Fe3+

[213]

Rifampicin

Delivery of rifampicin to alveolar macrophage

[215]

Furosemide
Lamivudine

Complexation

[216]
[148]

Azithromycin

PAMAM (4.0 G)

Erythromycin

PAMAM

Encapsulating agents

Delivery of anticancer bioactives

Delivery of anti-HIV drug

[217]

Indomethacin

PAMAM (4.0 G)

[214]

PAMAMAzithromycin complex delivered azithromycin effectively for

treatment of chlamydia infection
PAMAMErythromycin conjugates showed high drug loading, improved
solubility and reduced local periprosthetic inammation in a sustained manner
Manganese complexes of polystyrene-supported PAMAM dendrimer were
found to be efcient and reusable catalysts for the oxidation of secondary
alcohols to ketones under mild reaction conditions
Synthesize dendrimer (2.0 G and 3.0 G PPI) capped NiFe nanoalloy exhibited
photoluminescence properties

[218]
[151]
[219]

2.0 G and 3.0 G PPI

NiFe nanoalloy

Core PAMAM
dendrimers
caprolactone
polyethylene glycol
PEG-mesylate
PAMAM

Etoposide

Micelles

[218]

Indomethacin
Methotrexate

Liposomes

[221]
[6]

PPI

Paclitaxel

4.0 G PAMAM

DOX

4.0 G PPI

Zidovudine

[220]

Conjugation of surface amino groups of PPI dendrimers with folate, galactose

and dextran
Synthesis of collagen peptide-modied dendrimer attached doxorubicin DOX
via a pH-degradable linkage as a polymer prodrug

[92]

Sialic acid conjugated-Mannosylated PPI (SMPPI) dual ligand dendritic system

showed enhanced biocompatibility and site-specic delivery of Zidovudine

[141]

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

Glucose biosensor

Thiol 3.0 G PPI

dendrimer coated with
CdSe quantum dots
4.0 G PAMAM

DNA and Cucurbituril

DNA

[222]

287

[225]

[223]

[224]

References

4.06.0 G PAMAM-OH
and PAMAM-NH2
3.0 G PAMAM
Reduction of 4-nitrophenol

Photodynamic therapy

4.0 G PAMAM
Cardiac function

siRNA

Dendrimers
Application

Table 3 (Continued)

Bioactive(s)

Developed oligo-arginine-conjugated tadpole dendrimer found to be

non-cytotoxic and efcient non-viral delivery system for siRNA in cardiac
tissue, and the delivery of siRNA against AT1R by the dendrimer was able to
preserve cardiac function after ischemia-reperfusion injury in rats
Cu, Ag and Au dendrimer-encapsulated NPs exhibited good activity for
reduction of 4-nitrophenol to 4-aminophenol
3.0 G PAMAM dendrimer-grafted porous hollow silica NPs have been
successfully fabricated as photosensitive drug carriers for PDT

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

Outcome

288

dispersion writhing was reduced during 46 h post

transdermal administration. The authors concluded that
dendrimer based transdermal delivery system of NSAIDs
could be explored as an attractive approach for treating
various ailments [123]. Overall, dendrimers hold promise
in transdermal drug delivery although available reports are
inadequate.
8.1.4. Dendrimers in oral drug delivery
Oral route for administration of anticancer agents is
preferred because this route is convenient to patients,
requires reduced cost of administration and also facilitates the use of more chronic treatment regimens. But
the problems like low aqueous solubility and poor permeability across the biological membrane associated with
drugs limit the application of oral route [124,125]. Dendrimers have been investigated for the oral delivery of
various drugs with promising results. Plain as well as surface modied dendrimers have been found to increase the
transepithelial permeability. Jevprasesphant et al. studied
the permeation of PAMAM dendrimers and surface modied PAMAM dendrimers across the Caco-2 cell monolayers
by measuring the TEER and [14 C] mannitol apparent permeability coefcient at 4 C and 37 C in both directions
i.e. apical to basolateral and basolateral to apical directions in the presence and absence of ethylenediamine
tetraacetic acid (EDTA) and colchicines. The researchers
concluded that PAMAM dendrimers and surface modied
dendrimers with lauroyl groups could efciently traverse
epithelial monolayers via paracellular and transcellular
pathways [126]. Later, propranololPAMAM dendrimer
conjugate was investigated for transport across Caco-2
cell monolayers and it was observed that the conjugate
could reduce the effect of P-glycoprotein on intestinal
absorption of propranolol. Hence it could be concluded
that dendrimers can bypass P-glycoprotein efux transporter and can facilitate the oral administration of drugs
[127]. Najlah et al. investigated the oral delivery potential of prodrug of naproxen based on PAMAM dendrimers.
The low aqueous solubility of naproxen hinders its oral
bioavailability. In this study authors investigated the transepithelial permeability of naproxendendrimer conjugates
and stability of these conjugate in 50% liver homogenate
and 80% human plasma. Two different linkers i.e. lactate ester and diethylene glycol were used to link drug
to dendrimers and these linkages showed considerable
inuence on the stability of conjugate. Conjugates with
lactate ester linker were more stable in plasma and illustrate the slow hydrolysis in liver homogenate whereas
diethylene glycol linker based conjugate demonstrated
the high chemical stability with quick release of drug in
plasma and liver homogenate. Finally authors concluded
that (i) dendrimer based conjugate of naproxen could
enhance the oral bioavailability, and (ii) conjugate based
on lactate ester linker may serve as promising candidate for controlled release [128]. Conjugate of anticancer
drug 7-ethyl-10-hydroxy-campothecin (SN38) with 3.5 G
PAMAM dendrimers showed improved oral bioavailability with reduced toxicity [129]. Sweet et al. investigated
the effect of PEGylation on the anionic PAMAM dendrimers with respect to toxicity as well as transepithelial

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

transport and cellular uptake. Two generations of PAMAM

dendrimers 3.5 G and 4.5 G were PEGylated and it was
observed PEGylation of 3.5 G PAMAM dendrimers resulted
in decreased cellular uptake and transepithelial transport
whereas PEGylated 4.5 G dendrimers showed increased
uptake with decreased transport. This was thought to be
due to the reduction in the opening of tight junction
by PEGylated dendrimers. Finally authors concluded that
PEGylated dendrimers could be explored in oral delivery
when drug conjugation and drug release dictate increased
surface functional groups [130].
8.1.5. Dendrimers in ocular delivery of bioactives
The treatment of ocular disorders necessitates the
topical application of bioactives nevertheless intraocular delivery suffers from poor bioavailability problems
due to elimination of formulation by (i) tear turnover,
and (ii) nasolacrimal duct-mediated drainage of uid in
excess. Thus the development of formulation, which can
overcome these limitations of ocular route, emerges as
an arena for extensive research. In addition to this, formulation intended to be applied by ocular route should
be non-sensitizing, non-irritating, isotonic, biodegradable
and biocompatible with good retention within the eye
[59,131,132]. Dendrimers have been explored for the ocular delivery of bioactives. Vandamme and Brobeck, found
the PAMAM dendrimers with carboxyl or hydroxyl end
functionalities, to increase the retention of pilocarpine
within the eyes. Thus this study supports the applicability
of dendrimers via ocular route [133].
8.1.6. Dendrimers in pulmonary delivery
Dendrimers have been evaluated as a carrier for pulmonary delivery of a low molecular weight heparin,
enoxaparin. In this study 2.0 G, 2.5 G and 3.0 G of PAMAM
dendrimers were assessed for pulmonary absorption of
enoxaparin, which was estimated indirectly by determining the anti-factor Xa activity and analyzing the deep vein
thrombosis preclusion efcacy in a rodent model. In these
studies, cationic charged 2.0 G and 3.0 G dendrimers were
found to increase the relative bioavailability of enoxaparin
by about 40% without any adverse effect on mucocilliary
transport rate, and without producing the severe damage
to lung tissues, whereas negatively charged dendrimers
with carboxyl end groups (2.5 G) did not inuence the
bioavailability. So dendrimer with surface cationic charge
can serve as promising vehicle for pulmonary delivery of
bioactives [59,134]. Applications of various dendrimers via
different routes are briey summarized in Table 4. Mignani
et al. have recently reviewed various routes including oral,
transdermal, ocular and transmucosal for exploration of
dendrimers as drug delivery system [135].
8.1.7. Dendrimers in targeted drug delivery
Currently treatment of ailments is aimed at increasing
the therapeutic efcacy of bioactives by selective delivery
to target site. This tactic increases the therapeutic index
of drug by increasing its efcacy and reducing its adverse
effects. Dendrimers can easily provide the targeted delivery of medicaments by passive as well as active targeting,
which is achieved by engineering the branching units and

289

surface groups of dendrimers. This approach is particularly effective in treating the fatal disorders like cancer
and diseases caused by parasitic infection. The target site is
well-dened in these ailments and hence efciently engineered, site-specic carriers can be designed.
Dendrimers have emerged as versatile carrier in
this regard because of their well-dened architecture,
monodispersity, tailor-made surface groups. These properties make dendrimers useful in targeted delivery of
bioactives. One of the most explored examples in this
context is folate conjugated dendrimers for targeting anticancer bioactives to tumor. Since the folate receptors are
over-expressed on the surface of different types of cancer
cells such as ovarian cancer, breast cancer etc., hence folate
conjugated dendrimers can efciently target anticancer
bioactives to cancer cells [136,137]. In a study, folic acid was
conjugated to PAMAM dendrimers followed by coupling
with anticancer drug methotrexate (MTX) and evaluated by
biodistribution studies and confocal microscopy in immunodecient mice enduring human KB carcinoma. In the
biodistribution studies folic acid conjugated dendrimers
showed three times higher accumulation in the tumor
cells after 24 h compared to those conjugated without folic
acid. Confocal microscopy and ow cytometric analysis
further conrmed the results of biodistribution studies
[138]. Thomas et al. conjugated the CD14 and prostatespecic membrane antigen (PSMA) antibodies to 5.0 G
PAMAM dendrimers with uorescein imaging tag. In the
ow cytometry and confocal microscopy studies the conjugate was found to bind specically to antigen-expressing
cells in an afnity comparable to free antibody. The binding afnity was time- and dose dependent [139]. Choi
et al. designed folic acid and FITC conjugated PAMAM
dendrimers for tumor targeting and imaging, respectively,
followed by linking of complementary oligonucleotides for
cell specic binding and internalization. Hence dendrimers
provide a template with which it is possible to conjugate
more than one ligand for different purposes [140].
The well-dened structure of dendrimers provides
the opportunity for multifunctional engineering. Jain and
coworkers successfully designed dual ligand-conjugated
PPI dendrimers i.e. sialic acid conjugated mannosylated
dendrimers for dual targeting of anti-HIV drug Zidovudine. This dual conjugated system was found efcient in
increasing the biocompatibility as well as targeted delivery
of antiviral drug [141].
8.1.8. Reduction of toxicity
Although dendrimers with cationic surface groups
cause cytotoxicity and hemolytic toxicity yet their toxicity can be alleviated by modication of surface groups
with biocompatible ligands such as PEG, acetyl group, carbohydrates, amino acids and peptides etc. The surface
engineering of dendrimers results in biocompatible dendrimers as well as reduces the toxicity of some cytotoxic
and hemolytic bioactives [28,131].
Dendrimers show the surface charge-, concentrationand generation-dependent cytotoxicity. The permeability
prole of dendrimers is also related to its surface charge.
Cationic dendrimers have been found to be more toxic
(hemolytic as well as cytotoxic) and more permeable than

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P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

Table 4
Summary of applications of dendrimers via different routes.
Route of drug
delivery

Dendrimer

Limitations of
conventional
formulations

Bioactive

Advantages of dendritic
formulation

References

Parenteral

PAMAM (4.0 G)
Poly-l-lysine (PEG
1000) (3.0 G and 4.0 G)

N-acetyl cysteine
Chloroquine phosphate

Carrier
Encapsulating agent

[226]
[90]

Transdermal

PAMAM dendrimers

1. Gastrointestinal side
effects including
dyspepsia,
gastrointestinal
bleeding (on oral
administration)
2. Renal side effects (on
oral administration)
3. Poor rates of
transcutaneous
delivery due to barrier
posed by skin

NSAIDs (Ketoprofen,
Diunisal)

1. Complex of NSAIDs (Ketoprofen,

Diunisal) with dendrimers
resulted in improvement of drug
permeation through skin
2. 3.4 and 3.2 times higher
permeation observed for
Ketoprofen and Diunisal
complexed with dendrimers,
respectively

[123]

NSAIDs (Indomethacin)

Higher concentration of
Indomethacin was observed in the
blood of Wistar rats after
application of dendrimer based
transdermal formulation to
abdominal skin

[122]

1. Dendrimers can cross epithelial

monolayers by pathways,
paracellular and transcellular
2. Drug dendrimer conjugate can
reduce the effect of P-gp on
intestinal absorption of drug
administered orally
3. Dendrimer based drug conjugate
can signicantly enhance the oral
bioavailability

[126]

PAMAM dendrimers
with amino and
hydroxyl terminals

Oral

PAMAM dendrimers

Low solubility and/or

poor permeation
across the biological
membrane hinders the
oral absorption.
Removal of drug by
P-gp efux transporter

Propranolol
Naproxen
Pulmonary

PAMAM dendrimers

Ocular

PAMAM dendrimers
with hydroxyl/carboxyl
peripheral groups

Colon delivery
Topical
delivery

3.0 G PAMAM
5.0 G PAMAM
2.06.0 G PAMAM
4.0 G Lysine based
dendrimers

[127]
[128]

Pulmonary
administration of some
drugs results in
adverse effect on
mucocilliary transport
rate and extensive
damage of lungs
Ocular administration
of drugs is limited by
two factors (i) poor
retention of dosage
form for the ocular
region, and (ii) patient
inconvenience

Enoxaparin (low
molecular weight
heparin)

Considerable increase in rate and

extent of absorption observed with
dendrimers having cationic surface
groups

[134]

Pilocarpine

Increased retention of pilocarpine

within the eyes

[131,133]

5-Amino salicylic acid

Nifedipine

[227]
[118]

5-Fluorouracil
SPL7013
[Poly(l-lysine)-based
dendrimer with
naphthalene disulfonic
acid surface groups]

Carrier
Solubility and permeation
enhancer
Permeation enhancer
Therapeutic agent (anti-HIV agent)

the anionic and neutral dendrimers (Fig. 2). Designing of

biocompatible and biodegradable dendrimers either by
synthesizing dendrimers from biocompatible units (peptides, amino acids, carbohydrates etc.), or modifying the
surface of cationic dendrimers with biocompatible ligands
(PEGylation, acetylation, glycosylation etc.), will facilitate
reduction in toxicity [28,91].

[228]
[229,230]

8.2. Biomedical applications

Owing to well-dened size and structure, dendrimers
attracted attention of researchers for biomedical applications like controlled delivery of bioactives, gene
transfection, and as imaging and diagnostic agents.
The nanometric size, extensive branching, tailor-made

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

291

endocytosis, and consequently endosomal destabilization

of electrostatically assembled dendrimerDNA complex
takes place, which is followed by release of DNA. Then
this DNA is taken up by nucleus where it replicates with
host DNA. Subsequently transcription takes place, and as
a result, mRNA is released as biosignal, which is followed
by translation of target protein [147]. All these steps are
depicted in the Fig. 13.

Fig. 13. Dendrimer-mediated gene transfection.

surface groups, monodispersity and excellent stability are

some unique features, which make dendrimers particularly
nest candidate for application in biomedical eld. Various
scientists have reviewed different biomedical applications
of dendrimers including gene delivery, diagnostic agent,
vaccines etc. [58,142].
8.2.1. Dendrimers in gene delivery
Plethora of research is now available on the applicability of dendrimers in gene transfection, particularly
amino terminated dendrimers like PPI, PAMAM, arginine
and ornithine conjugated dendrimers. These amino terminated dendrimers enhance the transfection efciency
into nucleus by endocytosis [58,143145]. Dendriplexes i.e.
complexes of dendrimers and nucleic acids showed good
transfection efciency and hence explored for the delivery of genetic materials including oligonucleotides, genes,
aptamers, siRNA etc [146]. Dendrimers with structural
exibility and hyperbranched architectures are suitable
candidates for gene delivery operations owing to formation of more compact complexes with DNA, attributed
to enhanced exibility of dendrimers. The mechanism of
genetic materials delivery to the nucleus and translation
assistance is depicted in the Fig. 13. Basically in the rst
step dendrimerDNA complex is taken up by cells by

8.2.2. Dendrimers as nanoscale containers

(nano-scaffolds)
The tailor-made surface groups, interior branching and
core epitomize three components of dendrimers, which
can function as carrier for bioactives. Particularly the interior cavities of dendrimers are procient at encapsulation
of drugs as guest molecules, while dendrimers serve as
host (Fig. 12). The surface groups of dendrimers, which
are exposed to exterior, are predominantly imperative for
targeted delivery [45]. PPI dendrimers have been modied
at surface via amino acids to design dendritic boxes. Dendritic boxes are characterized by the formation of dense,
hydrogen bonded surface shells with solid state character
with excellent entrapment properties. It was observed that
encapsulation efciency of these molecules depends on the
two factors; rst one being the amount, shape as well as
size of internal cavities accessible in the dendrimers, and
second is the shape and size of the molecule to be encapsulated in the dendrimers. For example, it was observed that
a PPI dendrimer with 12 small cavities and four large cavities can encapsulate 810 molecules of bioactive with small
size like p-nitrobenzoic acid, which were incapable of leaking out. In contrast, only four molecules of large bioactives
(e.g. Rose Bengal dye) can be accommodated into these
dendrimers [7,58].
8.2.3. Intracellular delivery of bioactives
One of the most promising applications of dendrimers is
their ability to deliver the molecular cargo at intracellular
level. They have been successfully utilized by various scientists for intracellular delivery of medicaments to achieve
intracellular level targeting. Targeting of antiviral drugs
to the macrophages has been achieved with dendrimers
surface engineered with mannose to accomplish mannose
receptor-mediated endocytosis (Fig. 14) [148]. Enhanced
uptake of dendrimers with consequent release of anticancer agent into cancer cells has been reported by many
scientists [92,93].
To achieve intracellular delivery of bioactives it is
necessary to minimize extracellular leakages by preventing the non-specic interaction of dendrimers with
systemic circulation as well as ensuring that the drug
loaded nanometric dendritic system will not be cleared
off very rapidly from the systemic compartment. Conjugation of PAMAM dendrimers with methylprednisolone
resulted into improved uptake by human lung carcinoma
epithelial cell line. In this study, the activity of dendritic complex was found to be comparable to free drug
[149]. In case of some dendrimeric complexes of drug,
it has been also observed that the drugdendrimer complex is rapidly internalized by the target cells, although
drug was released slowly over a prolonged period of

292

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

Fig. 14. Schematic representations of pH-responsive bioactive release from targeted dendrimeric conjugate possessing pH sensitive linker: (a) receptor
association of ligand-conjugated bioactive-loaded dendrimers, (b) endosomal uptake of conjugates, (c) rupture of acid-sensitive linkage between dendrimer
and bioactive ensuring selective endosomal release (at pH < 7), (d) release of drug at targeted site, (e) formation of recycling vesicles, and (f) receptor
regeneration.

time. Kolhe et al. observed that while ibuprofen complexed PAMAM dendrimers was rapidly taken up by A549
cells. The covalently linked ibuprofen showed the sustained release. It was concluded that dendrimers as well
as surface engineered dendritic nano-architectures could
be successfully exploited for intracellular level of targeting
of medicinal substances [150]. Bosnjakovic et al. developed erythromycin conjugated PAMAM dendrimers for
treatment of periprosthetic inammation via targeted and
sustained intracellular delivery to macrophages exploiting
inammation inhibitory potential of erythromycin and targeting ability of dendrimers. Antibiotic erythromycin was
conjugated to dendrimers by way of ester bond and activity was evaluated in RAW 264.7 macrophage cell lines.
The conjugate was found to improve activity of erythromycin against periprosthetic inammation with high
drug payload, improved solubility and sustained release
[151]. Similarly, PAMAM dendrimerazithromycin conjugate was found to be efcient in intracellular delivery
of azithromycin to treat Chlamydia trachomatis infection
[152].
8.2.4. Microvascular extravasation
Owing to the nanometric size and lower molecular
weight, dendrimers show the extravasation propensity,
which is dened as the movement of molecules from the
blood circulatory system across the endothelial lining of
capillary walls into the neighboring interstitial tissues [91].
Extravasation is essential for effective targeted delivery of
medicinal substances. Kitchens et al. inspected the extravasation of different generations of PAMAM dendrimers
through the microvascular endothelium and concluded

that the extravasation time is exponentially proportional to

the size and molecular weight of dendrimers in following
order 0.0 G < 1.0 G < 2.0 G < 3.0 G < 4.0 G. Time for extravasation was in the range of 143.9422.7 s [153]. Microvascular
extravasation is particularly important for passive tumor
localization of anticancer bioactives and diagnosis of cancer
via MRI contrast agent etc. [154,155].
8.3. Diagnostic applications
The unique morphology and distinct characters of dendrimers makes them promising candidate for diagnostic
applications. Dendrimers have been used efciently as
imaging agent, in radiotherapy, as X-ray and MRI contrast
agent as well as molecular probes [84,156].
Dendrimers linked to various ligands have been used
for molecular detection, separation, radiotherapy and as
imaging agent. Wu et al. exploited the antibody linked
metalchelatedendrimers for radioimmunotherapy and
imaging purposes [157]. Similarly FITC tagged PAMAM
dendrimers has been investigated for determining the
cellular uptake [158]. The spectrum of the diagnostic applications of dendrimers is likely to broaden in near future.
8.3.1. X-ray contrast agent
Substances of high molecular weight are preferred over
low molecular weight as X-ray contrast agent as the low
molecular weight substances equilibrate readily within
the extracellular uid and intravascular compartments of
the body. Hence high molecular weight contrast agents
are used to achieve X-ray image with high resolution
to detect disease lesions or view organs; for example

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

kidneys, bones, fracture, arteriosclerotic vasculature,

tumors and infarcts etc. Various groups of scientists are
exploring dendritic polymers as X-ray contrast agent, by
designing organometallic (Bi and Sn) complexes of dendrimers, dendritic nanoparticles with heavy isotopes of
iodine, dendrimers with PEG cores etc., for microvascular
quantication of various diseases as well as in angiography and computed tomography imaging [157,159,160]. In
most of the studies, the dendrimers-based contrast agent
was found to be advantageous on account of one or more
of the following characteristics; high iodine content, prolonged intravascular enhancement, high X-ray attenuation,
osmolality, good chemical stability, high water solubility
and hydrophilicity [161].
8.3.2. Molecular probes
The unique properties and architectural specicity of
dendrimers makes them interesting candidate as molecular probes. To exploit dendrimers as molecular probe,
one of the strategies is generation of an integrated dendrimer based molecular probe by immobilizing the sensor
units on the surface of dendrimers. One example of this
strategy is the designing of a dendrimer with Pt coordination complexes as end groups having high sensitivity
to sulfur dioxide (SO2 ). On exposure to SO2 , due to electronic absorption, the square-planar Pt II complex changes
to ve-coordinate SO2 adduct [162]. Dendrimers have also
been modied or surface functionalized to design molecular probe for avidin, DNA, amino alcohols and pH etc.
[163167].
8.3.3. MRI contrast agent
X-ray imaging contrast agents are also essential for
Magnetic Resonance Imaging (MRI). MRI is a distinguished
non-invasive technique for the diagnosis of various diseases, which is based on different relaxation time of
protons in different tissues. Low toxicity, biocompatibility
and high relaxivity are the desirable qualities for MRI contrast agents. The most widely used contrast agent in MRI
for clinical application is Gd (III) ions, which unfortunately
are highly toxic due to strong afnity for serum protein.
Hence a chelate, which is the complex of diethylene triamine pentaacetic acid (DTPA), is also being used clinically
as contrast agent [156,168]. However as discussed under
X-ray contrast agent, high molecular weight MRI contrast
agents are preferred over low molecular weight contrast
agents because the later diffuse readily from blood vessels
into interstitial space followed by rapid clearance from the
body. To combat this problem several complexes of Gd with
high molecular weight compounds like albumin, dextran,
polylysine and dendrimers are being explored [169171].
Dendrimer based DTPA complexes have shown the potential to improve upon all the limitations of previously used
MRI contrast agents [155,156].
9. Surface engineering of dendrimers
The major constraints to the biological and biomedical
applications of dendrimers are related to hemolytic toxicity, immunogenicity, RES uptake, stability, hydrophobicity,
drug leakage etc. Dendrimers may also interact effectively

293

with the components of cell such as plasma membranes,

cell organelles, and proteins such as enzyme etc., due to
their nanometric size. Most commonly used dendrimers
like PPI, PAMAM and PLL exert considerable in vitro cytotoxicity due to their surface cationic groups [29,172]. Only
if these problems are resolved then dendrimers may be
one of the better, if not best, options among the others
nanocarriers. There are various strategies available for surface engineering of dendrimers, such as PEGylation, coating
with other carriers, attachment of ligands etc. [131] which
can generally overcome these limitations (Fig. 10).
PEGylation, conjugation or linking with the dendritic
system with PEG additionally increase the solubility of
hydrophobic drugs. PEG enjoys various advantages like
non-toxic, non-antigenic, non-immunogenic, high solubility in water and FDA approval (Fig. 15). The PEGdrug conjugates have several advantages such as decreased degradation by metabolic enzymes, prolonged residence in body,
and a reduction or elimination of protein immunogenicity [173]. PEG contains two equivalent hydroxyl groups,
which makes it a potential cross-linking agent for many
systems to which it is attached. These hydroxyl groups
also provide the possibility for the attachment of bioactives by covalent coupling. Various PEG derivatives such
as bromo, amino, carboxymethyl, succinimido succinate,
tosylate, mesylate, aldehyde, octadesylamine, monopalmitate, and stearyloxy, or methoxy PEG (MPEG) have been
conjugated with dendrimers to form PEGylated dendrimers
[174]. MPEG is the derivative of choice in derivatization
reactions having one hydroxyl group blocked [175]. The
cytotoxicity of cationic melamine dendrimers having surface groups like amine, guanidine, carboxylate, sulphonate
or phosphonate has been found to be much higher as compared to anionic or PEGylated dendrimers [25].
In present scenario, surface engineering with different
ligands is most frequently used concept in drug delivery,
projecting incredible advantages in nanotechnology. Dendrimers like PAMAM, PPI and PLL can be easily decorated
with various ligands due to the presence of many surface cationic groups. The attachment of various ligands
such as carbohydrates, amino acids, peptides, antibodies, tuftsin, folate, surfactants etc [92,104,139,176178]
not only enhances the targeting potential of conjugates
but also enhances their biocompatibility. In reported
studies surface of PPI dendrimers were modied with
three different ligands including folate, dextran and galactose. As compared to plain PPI, developed conjugates
not only exhibited better targeting potential but also
drastically decreased hemolytic toxicity than plain PPI
[92]. Many available reports clearly support the benets
of dendrimer surface modication with various ligands
[99,100,103,137,179,180]. Dendrimer has also been used
with various other carriers such as liposomes [6,181],
nanoparticles [182186] and carbon nanotubes (CNTs)
[187189] etc. The developed hybrid systems may have
some path-breaking advantages in the eld of drug delivery. Various ligands have been used for surface engineering
of dendrimers and a detailed report on principle ligands
used for engineering and effect of surface engineering on
the drug release, toxicity and efcacy of formulation are
summerized in Table 5.

Dendrimer

Ligand

Bioactive

PAMAM

Peptide

PPI

Folate, dextran, galactose

PTX

PPI

Polysorbate 80

PPI

294

Table 5
Summary of surface engineering of dendrimers with various ligands.
Toxicity

IC50

Drug
release

Rationale

Reference

Decreased

[231]

Decreased

Decreased

Sustained

DTX

Decreased

Increased

Sustained

Folate

MTX+ATRA

Decreased

Sustained

PPI

Dextran

DOX

Decreased

Decreased

Sustained

PPI

Decreased

Decreased

PAMAM

t-BOC-protected
glycine-coated dendrimer
(DBG), t-BOC-protected
phenylal-anine-coated
dendrimer (DBPA),
mannose-coated
dendrimer (M-PPI) and
lactose-coated dendrimer
(L-PPI)
PEG

Novel peptidedendrimer conjugates as drug carriers for targeting

nonsmall cell lung cancer
Cancer targeting potential of some ligand-anchored poly
(propylene imine) dendrimers: a comparison
The treatment of Glioblastoma xenografts by surfactant
conjugated dendritic nanoconjugates
Surface engineered dendrimers for dual drug delivery: a receptor
up-regulation and enhanced cancer targeting strategy
Dextran conjugated dendritic nanoconstructs as potential vectors
for anticancer agent
Investigations on the toxicological prole of functionalized 5.0 G
PPI dendrimer

Decreased

Sustained

PEGylated dendritic nanoparticulate carrier of uorouracil

[232]

PPI

Galactose

Sustained

Mannose

PPI

Tuftsin

Efavirenz

Decreased

PPI

Mannose

Rifampicin

Decreased

Sustained

PPI

PEG

Rifampicin

Decreased

Sustained

PAMAM

Galactose

Decreased

Sustained

PPI

PEG

Chloroquine
phosphate
Famotidine

Decreased

Sustained

PAMAM

PEG

Decreased

Decreased

PAMAM

Iron oxide NPs (IONPs)

Doxorubicin

Sustained

PAMAM

PEG

Indomethacin

Increased

PAMAM

PEG

DOX

Decreased

Increase

Increased

PPI

Sialic acid and mannose

Zidovudine

Decreased

Decreased

Sustained

4.0 G
PAMAM

Arginine

siRNA

Glycodendrimeric nanoparticulate carriers of primaquine

phosphate for liver targeting
Targeting potential and anti-HIV activity of lamivudine loaded
mannosylated PPI dendrimer
Targeting of efavirenz loaded tuftsin conjugated PPI dendrimers to
HIV-infected macrophages in vitro
Intracellular macrophage uptake of rifampicin loaded
mannosylated dendrimers
PEGylated dendritic architecture for development of a prolonged
drug delivery system for an antitubercular drug
Glycoconjugated peptide dendrimers-based nanoparticulate
system for the delivery of chloroquine phosphate
PEGylated PPI dendritic architectures for sustained delivery of H2
receptor antagonist
PEGPAMAM dendrimers conjugate-mediated efcient
intramuscular gene expression
Novel water-soluble and pH-responsive anticancer drug
nanocarriers: DoxorubicinPAMAM dendrimer conjugates
attached to superparamagnetic iron oxide NPs (IONPs)
PEGylated thermo-sensitive PAMAM dendritic drug delivery
systems
Partly PEGylated PAMAM dendrimer for tumor-selective targeting
of doxorubicin, the effects of PEGylation degree and drug
conjugation style
Sialic acid conjugated-Mannosylated PPI (SMPPI) dual ligand
dendritic system for site-specic delivery of anti-HIV drug
Functionalized dendrimer based delivery of angiotensin type 1
receptor siRNA for preserving cardiac function following infarction

[3]

PPI

Fluorouracil
(5-FU)
Primaquine
phosphate
Lamivudine

Sustained
Decreased

Sustained

[100]
[103]
[99]
[29]

[148]
[104]
[196]
[215]
[90]
[102]
[233]
[234]

[235]
[236]

[141]
[223]

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

Decreased

[92]

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

295

Fig. 15. Approaches to dendrimer PEGylation. (a) Dendrimers with surface PEGylation, (b) PEG cored dendrimers, (c) dendrimers having PEG as branching
unit, (d) PEGylated dendrimers conjugated with drug, and (e) PEGylated dendrimers conjugated to multiple ligands for various applications.

10. Dendrimer linked to other nanocarriers

Dendrimers have been linked to different carriers
for different pharmaceutical and biomedical purposes
(Fig. 16). The conjugates or complexes of dendrimers with
different novel drug carriers such as liposomes, CNTs and
nanoparticles have resulted in some long term advantages,
which have been enlisted in Tables 68.
10.1. Dendrimer linked to liposomes
In a study by Jain & Coworkers the encapsulation of
MTX in liposomes (acidic drug) was increased through
PAMAM dendrimer. Liposmes were prepared by lm
hydration method using hydrogenated soy phosphatidylcholine, cholesterol and dicetylphosphate in 1.5:1:1 molar
ratio, with or without PAMAM dendrimer. Encapsulation of
MTX was increased in the presence of dendrimer possibly
due to the entrapment of dendrimer by charge interaction that creates pH and solubility gradient across the
bilayer and lead to an inux of MTX. The entrapment
behavior of drug was proportional to the dendrimer generation. Liposomes containing 4.0 G dendrimer were capable
to encapsulate drug approximately two- and four times
greater than 3.0 G and 2.0 G dendrimer containing liposomes, respectively, which is ascribed to less solubility of
MTX in 3.0 G and 2.0 G dendrimer. Another possibility may
be the proportion of these dendrimers attached with the

surface phosphate groups that was unable to encapsulate

drug due to their open structure [6].
Papagiannaros et al. developed two liposomal
formulations, composed of HePC:Egg phosphatidylcholine:Stearylamine 10:10:0.1 (molar ratio) (formulation
1) and Egg phosphatidylcholine:Stearylamine 10:0.1
(molar ratio) (formulation 2) incorporating a doxorubicin
(DOX)PAMAM (3:1 molar ratio) (formulation 3) complex.
Lipid bilayers of liposomes composed of hydrogenated
soy phospatidyl-choline, cholesterol and dicetylphosphate
were attached to PAMAM dendrimers [182]. DOXPAMAM
complex into liposomes displayed low release pattern
for DOX as well as high incorporation efciency, which
is essential for the activity of DOX. As compared to formulations 2 and 3, a better in vitro cytotoxic activity
as well as a delayed release of DOX was observed by
the DOXPAMAM complex attached to formulation 1;
tested against various cell lines i.e. lung (DMS114, NCIH460), colon (HT29, HCT116), breast (MB435, MCF7),
prostate (DU145) and CNS (SF268). The two colon cancer
cell lines HT29 and HCT116 were found to be somewhat more sensitive in the treatment with formulation
2 than other cell lines suggesting a selective action
of DOX.
In nal conclusion, the hybrid of dendrimers with liposomes may result in improved therapeutic response due to
high drug pay load as well as selective drug delivery to the
target site (see Table 6).

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P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

Fig. 16. Dendrimers as co-carriers.

10.2. Dendrimer linked to nanoparticles

An addition of a hydrosilane unit (SiH) to a double bond
is known as hydrosilylation reaction, widely employed
in the preparation of silane coupling agents and silicon
polymers [190]. Using the principle of this hydrosilylation
reaction Li et al. developed platinum nanoparticles wherein
carbosilane dendrimer served as capping agent and stabilizer. The surface of Pt nanoparticles was capped by excess

hydrosilane, and then stabilized by the dendrimers. The

result of X-ray photoelectron spectroscopy conrmed that
the Pt surface was directly capped by dendrimers due to the
presence of PtC bonds because the carbon atom in the PtC
bonds belongs to the dendrimer. It was concluded that the
developed nanoparticles have a good dispersibility under
the protection of dendrimers [186].
Nakanishi and Imae evaluated the photocatalytic activity of PAMAM dendrimer-protected TiO2 nanoparticles

Table 6
Dendrimer linked to liposomes.
Liposomes

Dendrimer

Bioactives

Result

Rationale

References

DSPC:CHOL:PG

Lipidic peptide
partial dendrimers

Interaction of cationic partial

dendrimers with charged and
neutral liposomes

[237]

HePC:EPC:SA

PAMAM

Doxorubicin

Cytotoxicity studies of
DoxorubicinPAMAM
dendrimer complex attached
to liposomes against human
cancer cell lines

[182]

HSPC-CH-DCP-GD

PAMAM

Methotrexate

Adsorption is inversely
proportional to the head size of
the partial dendrimer
molecules and the extent of
adsorption was similar on both
positively and negatively
charged liposomes
Modulatory liposomal
controlled release system
(MLCRS) seems to be possible
for drug delivery and can
modulate the release of drugs
from dendrimeric liposomal
formulations
The encapsulation increases
with dendrimer generation

Effect of dendrimer on
entrapment and release of
bioactive from liposomes

[6]

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

297

Table 7
Dendrimer linked to nanoparticles.
Nanoparticles

Dendrimer

Result

Rationale

References

Pt NPs

4.0 G of carbosilane
dendrimer

Formed Pt NPs have good

dispersibility under the
protection of dendrimers

[185]

Pd NPs

Frchet type 1.0 G

dendrimer

Developed NP catalysts capable

of catalyzing several reactions

Au NPs

1.05.0 G PPI

Au NPs

4.0 G PAMAM

TiO2 NPs

4.0 G PAMAM, 4.5 G

PAMAM-COONa

The resistivity of the lms

increased exponentially with
increasing dendrimer
generation
Oxygen permeability occurs
easily for up to three bilayers
of PAMAM-Au, with little extra
benet being obtained from
using thicker lms with more
than three bilayers
Dendrimer acts as a reservoir of
photoreacting reagents besides
acting as a protector of NPs

Synthesis of Platinum NPs in

the hydrosillylation reaction
using dendrimer as capping
agent and stabilizer
Synthesis of Palladium
NP-cored Frchet type
G1-dendrimer (Pd-G1)
stabilized by Pdcarbon bonds
Gold NP/PPI-dendrimer based
chemiresistors vapor-sensing
properties as a function of the
dendrimer size
Oxygen reduction and
diffusion in electroactive
nanostructured membranes
(ENM) using a layer-by-layer
dendrimer-gold NP approach

[183]

Au NPs

4.0 G PAMAM

The PAMAM-Au played an

essential role in not only
binding the target proteins but
also assisting the electron
transfer process

CdS and Au NPs

4.0 G and 7.0 G and

PAMAM

Au NPs

2.05.0 G PAMAM

Au NPs

3.0 G PPI

Ag NPs

1.5 G PAMAM

PVP and 1.5 G PAMAM

dendrimer co-mediated
synthesis of silver NPs

[186]

Magnetite NPs

5.0 G PAMAM

Synthesis of
dendrimer-modied magnetite
NPs for protein immobilization

[184]

PdRh bimetallic
NPs

4.0 G PAMAM-OH

Partial hydrogenation of
1,3-cyclooctadiene using
dendrimer-encapsulated
PdRh bimetallic NPs

[244]

Au NPs

Glycodendrimers,
2.05.0 G PPI
dendrimers with
dense maltose shell

Stabilization of polydisperse
NPs by both PAMAMNH2 and
PAMAM/PEG dendrimers
Size of self-assembled cluster
decreased with increasing
dendrimer generation
The dendrimer-protected gold
NPs were prepared, size of
which can be controlled by
molar ratio of dendrimer to
gold
PVP and G1.5 PAMAM
dendrimer co-mediated Ag NPs
were synthesized, reaction rate
of which was strongly
inuenced by the molar ratios
of PVP and G1.5 PAMAM
dendrimer and the reaction
temperature
The dendrimer-modied
magnetite NPs were used to
carry out magnetic
immobilization of BSA. BSA
immobilizing efciency
increased with increasing
generation from one to ve
Resulting
dendrimer-encapsulated
PdRh bimetallic NPs show a
promising catalytic activity in
partial hydrogenation of
1,3-cyclooctadiene
The particle size and size
distribution of resulting NPs
can be controlled directly as a
function of dendrimers
generation with formation of
smaller particles at higher
dendrimer generations

Determination of
photocatalytic activity of
dendrimer-protected TiO2 NPs
in water and comparison with
TiO2 NPs
Development of
electrochemical
immunosensor for -synuclein
based on dual signal
amplication using PAMAM
dendrimer-encapsulated Au
and enhanced gold NP labels
Templating of inorganic NPs by
PAMAM/PEG dendrimerstar
polymers
Dendrimer-mediated strategy
for the self-assembly of gold
NPs into structured ensembles
Size-controlled synthesis of
dendrimer-protected gold NPs
by microwave radiation

Oligosaccharide-modied
dendrimers for templating gold
NPs

[245]

[238]

[239]

[240]

[241]

[242]

[184]

[243]

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P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

Table 7 (Continued)
Nanoparticles

Dendrimer

Result

Rationale

References

AuAg alloy NPs

5.0 G PAMAM

Tunable synthesis and acetylation of

dendrimer-entrapped or
dendrimer-stabilized goldsilver alloy NPs

[246]

FeS NPs

4.0 G PAMAM

Synthesis, characterization, and

manipulation of dendrimer-stabilized iron
sulde NPs

[247]

Chitosan NPs

1.0 G and 2.0 G

PAMAM

Synthesis and characterization of

quaternized carboxymethyl
chitosan/poly(amidoamine) dendrimer
coreshell NPs

[248]

Porous hollow
silica NPs

3.0 G PAMAM

PAMAM-grafted porous hollow silica NPs

for enhanced intracellular photodynamic
therapy

[225]

AuNps

5.0 G PAMAM

Multifunctional dendrimer-entrapped gold

NPs for dual mode computed tomography
(CT)/magnetic resonance (MR) imaging
applications

[249]

AuNps

4.0 G PAMAM

Developed
dendrimer-entrapped or
dendrimer-stabilized AuAg
alloy NPs should have a
promising potential for CT
imaging and other biomedical
applications
Synthesis and manipulation of
FeS NPs onto mesoporous silica
microparticles provide
versatile platforms for their
environmental remediation
applications
Quaternized carboxymethyl
chitosan (CM-HTCC)/PAMAM
dendrimer NPs displayed
higher antibacterial activity
against Gram-negative bacteria
Escherichia coli, whereas they
showed much less efciency
against Gram-positive bacteria
Staphylococcus aureus;
compared to quaternized
chitosan (HTCC)
3.0 G PAMAM
dendrimer-grafted porous
hollow silica NPs have been
successfully fabricated as
photosensitive drug carriers
for PDT
Developed gadolium-loaded
dendrimer-entrapped gold NPs
provided multifunctional
nanoplatform for targeted
CT/MR dual mode imaging of
various biological systems with
high accuracy and high
sensitivity
Developed biosensor was
successfully applied for the
glucose analysis in beverages

Modied gold surfaces by

6-(ferrocenyl)hexanethiol/dendrimer/gold
NPs as a platform for the mediated
biosensing applications

[213]

in water and compared with necked TiO2 nanoparticles. 2,4-dichlorophenoxyacetic acid (DPA) was used as a
photodegradation reagent for the determination of photocatalyzed degradation mechanism [183]. As compared to
TiO2 nanoparticle without protector, dendrimer-protected
TiO2 nanoparticle was more procient as a photocatalyst.
This was due to the fact that dendrimer works as a reservoir of 2,4-DPA that is trapped in the interior of a dendrimer
before oxidation.
The magnetite particles are generally of coreshell
type, the biological cells, nucleic acids, and proteins are
connected to the magnetite core through an organic or
polymeric shell. Pan et al. reported the direct formation of
a cascading PAMAM dendrimer on the surface of aminosilane modied magnetite nanoparticles for bovine serum
albumin (BSA) immobilization. Thermogravimetric analysis (TGA) has been used for the evaluation of coating formed
on the magnetite nanoparticle surface. Authors concluded
that the number of surface amines on magnetite nanoparticles was directly proportional to dendrimer generations
one through ve. It was observed that from generation one
to four the amine group becomes double, however in case of

generation ve the amine groups increased less than twice

due to the steric interference between dendrimers [184].
Silver nanoparticles stabilized by polymer can be
synthesized by several reported physical and chemical
methods [191]. Factors such as selection of the reductant
as well as its reducing ability and selection of a suitable
protecting agent during the course of reduction of relevant metal salts are important during chemical synthesis
approach. Earlier reported method in which polyvinylpyrrolidone (PVP) was used as protecting agent has some
disadvantages like the particles prepared by this method
were usually irregular in shape and the size would be
larger than 100 nm [192]. To overcome these disadvantages, Li et al. developed dendrimer templating synthesis
of metallic nanoparticles. Nanoparticles were prepared by
reducing silver nitrate with H2 in the presence of PVP and
1.5 G PAMAM dendrimer as a co-protective agent. These
nanoparticles were found to be stable for very long time in
appropriately selected solvent systems [186]. The stability as well drug delivery potential is found to be improved
by complexation of dendrimers with nanoparticles (see
Table 7).

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

299

Table 8
Dendrimer linked to carbon nanotubes (CNTs).
CNT

Dendrimer

Result

Rationale

References

MWCNT

G4-PAMAM

Development of novel functionalized carbon

nanotube CNTPAMAM hybrid by covalently
linking PAMAM onto CNTs

[187]

SWCNT

Fluorinated
dendrimer

Synthesis and applications of novel uorinated

dendrimer-type copolymers by the use of
uoroalkanoyl peroxide as a key intermediate

[250]

MWCNT

PAMAM

An enhanced biosensor for glutamate based on

self-assembled carbon nanotubes and
dendrimer-encapsulated platinum
nanobiocomposites-doped polypyrrole lm

[188]

SWCNT

DABdendrimer[NH2 ]8

Dendrimer based cobalt (Co32 ) nanocluster:

synthesis and application in
diameter-controlled growth of single-walled
carbon nanotubes

[251]

MWCNT

PAMAM

Dendrimer-encapsulated Pd NPs anchored on

carbon nanotubes for electro-catalytic
hydrazine oxidation

[181]

MWCNT

PAMAM

PPI

Improved gene intracellular transporting (GFP)

gene transfection mediated by PAMAM
dendrimer-functionalized MWCNTs with high
biocompatibility
Effective functionalization of MWCNTs with
amphiphilic PPI dendrimer carrying silver NPs
for better dispersability and antimicrobial
activity

[189]

MWCNT

MWCNT

2.0 G and 3.0 G

PPI

The dispersed solution of the hybrid

possesses excellent stability in water
due to the plenty amino groups on the
surface of the CNTPAMAM
Developed polymeric aggregates had
an extremely higher dispersion ability
of not only SW-CNT and fullerene but
also magnetic NPs into water,
compared to that of the corresponding
two uoroalkyl end-capped
dimethylacrylamide oligomers
Developed biosensor was used to
detect glutamate as substrate with
high sensitivity, low detection limit,
fast response and nearly free of
interference
Developed nanocluster molecules
possess uniform size and well-dened
molecular structure; they are
fundamentally different from cobalt
colloids or other NPs formed from
decomposition of a salt precursor
Prepared Pd/4.0 G-NH2 /MWNTs
exhibited high electro-catalytic activity
towards hydrazine oxidation,
suggesting that the nanocomposites
have good potential application in fuel
cells
The MWCNTPAMAM hybrid
improved the transfection efciency
and simultaneously decreased the
cellular toxicity
The antimicrobial activity of
MWCNTs-APPI and
MWCNTs-APPI-AgNPs against Bacillus
subtilis, Staphylococcus aureus, and
Escherichia coli was achieved. The order
of activity in terms of percentage of kill
was MWCNTs-APPI-AgNPs > MWCNTSAPPI > MWCNTS-COOH
MWCNT-APPI (3.0 G)-PdNPs was more
efcient among the four types of
MWCNT nanohybrid catalysts

Synthesis, characterization, and catalytic

activity for hybrids of MWCNT and
amphiphilic PPI dendrimer immobilized with
silver and palladium NP

[253]

10.3. Dendrimer linked to CNTs

Due to excellent electrical functions of CNTPAMAM,
it has been evaluated as a potential carrier for biosensor design by Zeng et al. A bi-enzymatic CNTPAMAM
was prepared by immobilizing glucose oxidase (GOx) and
horseradish peroxide (HRP) on the CNTP-AMAM matrix.
In water, CNTPAMAM possesses good dispersability with
plenty of functional groups on the surface. The presence
of amino groups on the CNTPAMAM surface allows it
to be functionalized by different generations of PAMAM.
These developed hybrids were found to be capable of carrying biologic macromolecules for different purposes. Thus
the functionalized CNTs are very effective when they are
used for constructing the platform of biosensors [187]. In
another study an enhanced biosensor for glutamate based
on self-assembled CNTs and dendrimer-encapsulated platinum nanobiocomposites-doped polypyrrole lm was
developed. The biosensor was claimed to show performance characteristics with rapid response, high sensitivity,

[252]

low level of interference, low detection limit and excellent

reproducibility and stability [188].
A facile method for the advancement of amineterminated PAMAM dendrimer (4.0 G-NH2 )-encapsulated
palladium nanocatalysts with CNTs as a support (Pd/4.0 GNH2 /MWNTs) was reported by Shen et al. Developed
system characterized by UVvis spectroscopy, X-ray
diffraction (XRD), TEM conrmed them to be in nanometric range. High electro-catalytic activity towards
hydrazine oxidation of nanocomposites proved their
potential application in fuel cells [181]. Using covalent linkage approach, Qin et al. successfully prepared
PAMAM dendrimer-functionalized MWCNTs for green uorescence protein (GFP) gene delivery into HeLa cells.
As compared to mixed acid-treated MWCNTs (MWCNTCOOH) and pure PAMAM dendrimers, the transfection
efciency of MWCNTPAMAM hybrid was improved 2.4
and 0.9 times, respectively. Based on this, authors concluded that the transfection efciency of MWCNTs could be
improved through modication with PAMAM dendrimers

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P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

and this hybrid could provide a good option for delivering

biomolecules into mammalian cells [189].
All these studies suggest that the hybrids of two most
recent nanocarriers i.e. dendrimers and CNTs can provide
a new vista in the eld of medicine (see Table 8).
11. Biofate of dendrimers
Very few reports are available on the fate of dendrimer in the biological system. Jain & coworkers studied
the biofate of dendrimers by investigating the biodistribution of plain as well as glycosylated (mannosylated
and lactosylated) PPI dendrimers labeled with radioactive
technetium (sodium pertechnetate; 99m TcO4 ) in female
Balb/c mice. In this study the authors assessed the various pharmacokinetic parameters such as clearance, plasma
drug concentration prole, distribution and uptake of these
dendrimers. In the result it was found that both surface
modied and unmodied PPI dendrimers were excreted
through kidney and were preferentially taken up and
retained by liver although the retention was remarkably
high for glycosylated dendrimers. It was observed that
the dendrimers showed the clearance pattern that was
concentration-dependent and biphasic. Also the clearance
of surface modied dendrimers was faster than the plain
dendrimers [87].
Kaminskas et al. examined the factors affecting the
in vivo deposition of dendrimers and found that size
and surface charge played a crucial role after parenteral,
non-parenteral and interstitial administration. However
lipophilicity and hydrophilicity are yet another aspects,
which affect in vivo deposition of dendrimers after parenteral and interstitial administration, respectively. Size of
the dendrimer may inuence the clearance mechanisms
of dendrimers, for example small uncharged dendrimers
(<25 kDa) cleared rapidly from blood via urinary excretion
however in case of large uncharged dendrimers, clearance
mechanisms typically shift to non-renal clearance processes [40].
Dendrimers have been designed to be administered by
different routes, which result in different rates of drug
absorption. For example, after oral absorption the order of
increasing permeability of PAMAM dendrimer for Caco-2
cells was cationic > anionic > uncharged or PEGylated; however in case of percutaneous absorption the order was
cationic > uncharged > anionic [40]. From the above mentioned account it may be concluded that in view of grossly
inadequate studies available on the biofate of dendrimers
there remains need for more intense research on the interaction of dendrimers and biological environment so as to
have clear picture on the exploration of dendrimers for
clinical applications.
12. Regulatory considerations
The objective of regulatory affairs is to protect public
health. It is mandatory to control the safety and efcacy
of products, which are intended to be used clinically such
as pharmaceuticals, medical devices, veterinary medicines,
agrochemicals and cosmetics. Regulatory affairs are particularly important in case of health-care industries like

pharmaceuticals, foods, in vitro diagnostics, biologicals,

nutritional products, cosmetics and medical devices. The
continuously emerging new concepts in the eld of drug
delivery like nanocarriers (nanoparticles, dendrimers, carbon nano tubes etc.), diagnostic agents, bioactives etc. have
increased the importance of regulations for new pharmaceutical products. It would be protable for dendrimeric
formulation based market, if dendrimers attains the status
of generally referred as safe (GRAS). Recently, Starpharma
has started the phase 3 clinical trials of VivaGel (SPL7013),
which is a dendrimer based formulation for treatment of
bacterial vaginosis. The advantages of VivaGel over conventional antibiotics for treatment of bacterial vaginosis
are depicted in Fig. 17. It is a major milestone in the eld
of dendrimer-mediated therapeutics and will possibly lead
to new vistas in the eld of medicine [193].
13. Conclusion and future prognosis
Accurate selection of the delivery system is a key factor
in the arena of drug delivery. The application of nanotechnology in drug delivery has witnessed exponential growth
in the past few years. It is a technological breakthrough,
which is being realized very fast, from concept to reality. In the eld of nanotechnology, dendrimers emerge as
a potential macromolecule for biomedical, pharmaceutical and biopharmaceutical applications in the 21st century.
Dendrimers popularity has increased almost exponentially,
for example the number of manuscripts published on dendrimers each year has increased from approximately 40
in 1999 to over 520 in 2012 (PubMed database) (Fig. 18)
[194]. Dendrimers establish an electrifying opportunity for
scientists to fabricate macromolecular structures with a
specically tailored function. In particular, the advantage
of dendrimers over other macromolecular constructs lies
in ne tuning the potential to generate highly monodisperse systems with good control over nal size and surface
functionality. This precisely controlled architecture allows
modication of dendrimers as per the requirements, which
makes these compounds ideal (possibly?) carrier in the
eld of medicine. Additionally, the irritating behavior of
polycationic dendrimers toward biomembranes creates
transient nanoholes, which provide another option in the
exchange of payload across the biomembrane. The tailormade surface of dendrimers provides opportunities for
designing and tuning properties that are not possible with
other types of nanocarriers and have shown that they may
have a bright future as a new generation of drug delivery.
Menjoge et al. investigated the transfer of PAMAM dendrimers across the human placenta and observed that drug
conjugated dendrimers were inable to cross human placenta in ex vivo studies suggesting utility of dendrimers for
controlled delivery of bioactives in pregnant women. But it
would be premature to stack any claim in absence of conclusive proof of dendrimer safety and their deposition in
human body [195].
Finally, we can conclude that dendrimers have shown
signicant potential as a versatile delivery system for drugs,
gene, DNA, oligonucleotides, proteins, peptides; as well
as diagnostic agent, solubilizing agent etc. However the
story of dendrimer from bench of chemist to formulation

P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

Fig. 17. Advantages of VivaGel over conventional bacterial vaginosis.

Fig. 18. Yearwise number of dendrimer publications [Pubmed].

301

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P. Kesharwani et al. / Progress in Polymer Science 39 (2014) 268307

desk is still far from complete. Lot of vistas remains to be

unfolded. Still dendrimer applications to drug delivery are
in infancy and scientists are exploring different aspects
of dendrimers as drug delivery vehicle. Interdisciplinary
vision on dendrimer hybrids with other nano delivery systems may emerge as a rewarding strategy. However the
toxicity of the constituents of hybrid nanosystems vis a vis
the hybrid itself will have to be explored and established,
if not ruled out.
Acknowledgments
Author Prashant Kesharwani and Keerti Jain are grateful
to Indian Council of Medical Research (ICMR), and Council
of Scientic & Industrial Research (CSIR), New Delhi, India,
respectively for nancial support in the form of Senior
Research Fellowship.
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