Research J. Pharm. and Tech.

14(1): January 2021

ISSN 0974-3618 (Print) www.rjptonline.org

0974-360X (Online)

REVIEW ARTICLE

A Review on Enzyme Activated Drug Delivery System

Hindustan Abdul Ahad1*, Chinthaginjala Haranath1, Srikantham Sai Vikas2,
Naga Jyothi Varam1, Tarun Ksheerasagare1, Surya Prakash Reddy Gorantla1
1
Department of Industrial Pharmacy, Raghavendra Institute of Pharmaceutical Education and Research (RIPER)-
Autonomous, Ananthapuramu – 515721, Andhra Pradesh, India.
2
Department of Pharmaceutics, Raghavendra Institute of Pharmaceutical Education and Research (RIPER)-
Autonomous, Ananthapuramu – 515721, Andhra Pradesh, India.
*Corresponding Author E-mail: abdulhindustan@gmail.com
ABSTRACT:
Enzymes are the bio-molecules that are present in the various sites of the body and are specific in the organs.
The recent trend of drug delivery as nanoparticles has a handful of uses. The designing of the systems in small-
sized particles like nanoparticles have merits as they can easily diffuse into the membrane through the
intracellular pores of very small size. Such a kind of delivery system has its applications in various treatments,
one of which is in cancer therapy. Even though the anti-neoplastic drugs are much potent, they may also act on
the normal cells and thus inhibiting the normal physiological process leading to serious adverse effects. Such a
kind of problem can be overcome by the enzyme activated drug delivery system (EADDS). An enzyme activated
system, the discharge of drugs from the system is activated by the enzymatic process. Various approaches for
enzymatic drug delivery include liposomes, nanoparticles, prodrug, microparticles, etc. The main components in
this system are drug, nanocarrier, promoiety, coating polymer, ligand, etc. The present review is about to provide
some ideology on how the drug can be delivered to a particular type of organ or site based on the presence of
respective enzyme.

KEYWORDS: Enzyme, Bio-catalysts, Nanocarriers, Targeted delivery, Ligand.

INTRODUCTION: Some of the enzymes are specific in particular organs

Enzymes are the bio-molecules present in the body (E.g., Renin in kidneys, rennin, pepsin and chymotrypsin
performing a variety of functions. Enzymes consist of from Gut, Ptyalin in mouth oral cavity and others having
the non-protein part (co-factor), which is responsible for significant functions are carbonic anhydrase, hexokinase,
binding to a substrate and catalyze the reaction. An glycogen phosphorylase and protease in a certain type of
enzyme without co-factor (apo-enzyme) is a protein, specialised cells.
whereas an enzyme with all necessary components
(holoenzyme). Enzymes hasten the rate of a biochemical Proteases regulate most of the biological and
reaction and consists of active sites on their surface to pathological processes by proteolysis2. Proteolysis, a
which substrate binds. The main functions of enzymes type of irreversible regulatory mechanism, is
viz., bio-catalysts, synthesizing the molecules, etc. accountable for discerning cleavage of certain
substrates3. The levels of proteases can act as biomarkers
in the finding and prediction of tumors4. Proteases are
involved in controlling various pathways viz., DNA
replication and transcription, cell proliferation and
differentiation, cell mobilization, inflammation,
immunity, necrosis, apoptosis, hemostasis and blood
coagulation5. Therefore, abnormalities in proteolytic
actions result in cancer, cardiovascular and
Received on 05.12.2019 Modified on 08.02.2020
Accepted on 29.03.2020 © RJPT All right reserved
neurodegenerative disorders.
Research J. Pharm. and Tech. 2021; 14(1):516-522.
DOI: 10.5958/0974-360X.2021.00094.9

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 Research J. Pharm. and Tech. 14(1): January 2021

Another class of enzymes called matrix Now the current article gives a clear idea of how the
metalloproteinases (MMPs) are mainly involved in the drug can be delivered to a particular type of organ or site
cancer initiation and act as biomarkers and therapeutic based on the enzyme present at that respective site. The
targets. Recent emerging trends deal with the ideal drug is supplied to the particular site, showing action on
expansion of MMP receptive drug delivery thereby that site thus avoiding the unsolicited side effects on
targeting the tumour cells6. It was established that the other types of tissues or organs. Before studying the
diseases befalling by the dysfunctioning of enzymes laid EADDS, it is necessary to have a brief idea on rate-
the foundation for drug development to act in such sites controlled drug delivery systems (RCDDS), it refers to
or conditions of the physiological status. the delivery of the drug to a particular site of which the
rate can be determined by the various factors. The
Now a day, nanoscience is an emerging technology RCDDS can be classified as illustrated in chart 1.
including EADDS finds its significance in drug delivery
to various sites to the enzymes present in that region.
The designing of the systems as small-sized entities like
nanoparticles (NP) have advantages that they can easily
diffuse into the membrane through the intracellular pores
of very small in size.

It was a known fact that certain type of drug molecules

shows rather an enhanced action when their size gets
reduced to the nanometer level. Hence the NP are
described as the good carriers of drug delivery owing to
their small size, shape and surface characteristics. It also
offers the prolonged release of entrapped drug by the aid
of an external or internal impact7.

Another type of well-known strategy is the prodrug

mechanism, which is described as the inactive form of
drug molecules. Upon the action of certain enzymes,
chemical or environment stimuli, prodrugs transform to
release the active drug in-vivo. With this approach, the
features of the drug-like solubility, stability,
permeability, and distribution can also be enhanced8. It
includes the chemical conjugation of the drug with a
suitable moiety, can be described as the prodrug9.
Because of these significant aspects, the prodrug
approach has been in practice in developing various Chart 1: Classification of rate-regulated drug delivery systems
novel formulations. Approximately 5-7% of currently
approved drugs as a prodrug. The designing of prodrug MATERIAL AND METHODS:
should be such that the promoiety should get removed Enzyme activated drug delivery system (EADDS):
after the respective enzymatic action. It provides an idea In this article, the authors highlighted EADDS, which is
that the prodrug gets transformed into its active form a bio-chemical activated type of rate-controlled system.
only when the enzyme of interest, having the promoiety This type of drug delivery is utilized for the treatment of
as substrate, cleaves it. So, the drug will be released at a various ailments including cancer. However, the
specific site where the enzyme is in overexpressed traditional system of cancer treatment called
condition. There are so many difficulties arising that chemotherapy was in practice, it shows rapid toxicity to
even though the anti-neoplastic drugs are much potent, other types of cells because of its non-specificity. In
they may also act on the normal cells and thus inhibiting ESDDS, the discharge of drugs from the system is
the normal physiological process like cell division activated by the enzymatic process11. Here the drug is
leading to serious adverse effects. Due to the drug initially dissolved in a suitable medium to form the drug
resistance developed by the patients, it leads to the let- reservoir and can be enclosed physically as microspheres
down of treatment. Such a kind of problem can be or by chemical means which includes the using of
overcome by the aid of several approaches of which one biopolymers like albumins or polypeptides to which the
of them is EADDS10. drug is bounded to their polymer chains. The chief
procedure involved in the hydrolysis of biopolymers by
the distinguishing type of enzyme present in the target
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site. E.g., Albumin microspheres of 5-Fluorouracil can Yildiz et al., 2018,14 came with another work using
be made targeted to the cancer cells based on the enzyme Doxorubicin prepared by polymeric NP for the treatment
called protease present in the cancer cells, that act of cancer. Here, the system gets activated by the enzyme
specifically on the proteins like albumin. In this system, called protease that acts on proteins. They have
the degradation of albumin microspheres occurs by the employed poly (lactic-co-glycolic acid)-b-poly-l-lysine
action of the protease enzyme. and poly (lactic acid)-b-poly (ethylene glycol), among
which the first polymer with Poly-l-lysine covalently
Past successful attempts on EADDS: adapted with near-IR 750 molecules. Doxorubicin
The scientific report by Dzamukova et.al. 2015,12 delivery primed by the nanoprecipitation of copolymer
revealed the successful delivery of brilliant green (an blends were called as Theraneustic nanomedicines with a
anti-neoplastic and anti-septic agent) delivered into the mean size of 60-80nm and was shown a controlled
human cells by using the halloysite nanotube (HNT) release of drug for 30 days. The discharge of NP to
carriers of 50nm size. They have used dextrin end breast cancer cells was studied by fluorescence
stoppers, which are physically adsorbed for regulating microscopy and was concluded that they were seemly as
the discharge of brilliant green. The interpenetration of controlled release systems and contrast agents in the
the carrier particles can be achieved and their uptake by areas of imaging of cancer cells.
the cells is reliant on upon the cellular growth rate and
creation. Glycosyl hydrolase is the enzyme present in the Sun et al., 2019,15 worked on the improvement of the
cells that act on the system and causes the dextrin tube anti-tumour competence of Gemcitabine as a prodrug by
end stoppers to undergo decay to release the loaded- FAPα-mediated activation. Gemcitabine agonizes with
brilliant green to act upon the human lung carcinoma low uptake by tumor cells and low competence. So, the
cells rather than on the hepatoma cells thus the hepatic 4-amino group of Gemcitabine was modified to form Z-
damage can be evaded. In this study, they have gone GP- Gemcitabine that advances the specificity and
through the assortment of two kinds of cells i.e., cleavage via FAPα-enzyme activation in tumor
Adenocarcinomic human alveolar basal epithelial cells environment. In contrast, the prodrug form was found to
and human hepatoma cells (Hep3b) that are explored for have an improved uptake of tumor cells and enhanced
the cellular uptake as a purpose as they display diverse inhibition effect on both growths of the 4T1 tumor cells
rates of proliferation. These cells were cultured in a and pulmonary metastasis in mice bearing orthotopic
manner of increasing concentrations of halloysite type of 4T1 breast tumors along with a reduction of
formulation of DX-HNTs (25-100μg/1, 00,000 cells, tumor-associated fibroblast (TAF) was observed during
BG-free) for incubation up to 24 h. The cells were animal testing. Therefore, it was established as an
analysed microscopically by using the enhanced dark- anticipated tactic for the treatment of cancer treatment by
field (EDF) microscopy and was found characteristic the route of intravenous administration.
uptake nature of A549 cells and Hep3b, such that A549
cells appeared as obviously evident aggregates, while Phillips and Pombeiro 2016,16 described the transition
Hep3b cells have random delivery. The results obtained metal-based prodrugs for anticancer drug delivery by
from TEM images revealed that A549 is arbitrarily taking Cisplatin as a model. The adverse effects of
dispersed in lysosomes, defining the enzymatic Cisplatin can be overcome by converting them into
breakdown of dextrin tube-end stoppers with an prodrug that gets activated and released by the
improved discharge. The results were drawn from differences in oxygen concentration or pH, by the action
various other investigations and prophesied that the of overexpressed enzymes, by differences in metabolic
dextrin stoppers substantially reduced the toxicity of the rates, etc., through which the cancer cells can be easily
formulation towards Hep3b and an improved release at differentiated from normal ones. By this technique, the
the A549 cells. Their study has proven that the discharge pharmacological activity of the Cisplatin will be
of brilliant green by using the dextrin-coated halloysite enhanced and becomes more inert.
nanotubes (HNT) is one of the most appropriate methods
for handling cancer. Qing et al., 2018,17 provided the novel idea of MMP
(Matrix Metallo Proteinases) responsive smart drug
Bernardos et al., 2010,13 designed a system with delivery and tumor targeting systems. These are the
Doxorubicin, entailing of hydrocarbon molecules which extracellular enzymes that become overexpressed in the
are covalently attached to the silences. Doxorubicin neoplastic conditions. However, under normal
release from mesoporous silica NP that are capped with physiologic conditions, MMPs get regulated by the
saccharides, occurs by the enzyme called glycoside tissue inhibitors of metalloproteinases and they will be in
hydrolase. This system upon coming into the cancer cells limited quantity. Three types of MMPs are described in
comprising the enzyme glycoside hydrolase undergoes which MMP-2, MMP-7, and MMP-9 are found in cancer
putrefaction to discharge the drug into the cells thus conditions. This concept can be utilized in developing
producing the effect. the MMP inhibitors for targeting as nanocarriers of size
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<200nm. The nanocarriers can be covalently linked to Delivery carriers:

drug and coated with PEG (PEGylation). The These are the substances used to deliver the drug, in
mechanism is such that this system will reduce the which the drug molecule gets entrapped/linked to its
apprehending of the Mono Nuclear Phagocytic (MNP) polymer chains. Nanotubes of carbon molecules are the
system, thereby promotes circulation and improved effectual carriers of the drug because they get easily
permeability and retention effect. internalized by mammalian cells and acts as the room for
drugs until they reach the target cell. They are less
Paul et al., 2007,18 described the role of polymer preferable owing to its toxic effects20.
hydrogel particles in the case of bio-responsive polymer
hydro gel for prolonged discharge. As per the view, the Strategies:
major advantage is that the active ingredient was Polymer type nanoparticles:
protected from premature degradation using polymeric One of the methods for preparing the NP is by using the
carrier. In this study, they described the carriers as polymers of concerned physicochemical properties. The
“smart” materials because of their nature of altering their extensively used polymers as nanocarriers are
physical possessions in rejoinder to the applied stimuli, polyethylene glycol (PEG), dextran, hydroxypropyl
involving enzyme activity. The main components he methyl acrylamide (HPMA)21-23. Various types of
used in emerging the system are enzyme cleavable polymers can be used for preparing the NP that offers a
linkers and hydrogels which are chemically cross-linked targeted drug delivery especially in the case of cancer
and are sensitive to a disease state enzyme. Upon the conditions. They not only meant for site targeting but
enzymatic action, these gels undergo a macroscopic also provides an enhanced and retention type of effect.
change and get disintegrate to release the drug molecules During the time of designing, there is a need to
that are entangled in it. For this work, he used PEGA- incorporate a molecule that can be identified and acted
800 (copolymers of polyethylene glycol and acrylamide, by the respective enzyme to satisfy enzyme-based drug
800). These PEGA particles were then modified using release24. Moreover, the polymer should have its
diglycine or dialanine as ECL (Enzyme Cleavable properties, non-toxic, no influence on drug action and a
Linkers). They were found to respond for three types of chemical modification can be done25. This technique of
enzymes thermolysin, chymotrypsin, and elastase. Later, combining healing and diagnostic drugs within a single
they were evaluated for size characteristics, swelling nanoscale “theranostic” offers significant potential for
nature of the hydrogel in response to the enzymatic personalized nanomedicine to cancer patients26.
action, and release physiognomies upon hydrolysis of the Theranostic type of NP employed in various conditions
hydrogel by the enzymes. The enzymatic response of the including cancer treatment, diabetes27, neural disorders28,
PEGA particles was determined by three complementary cardiovascular29, inflammatory or autoimmune disease30
methods. and pulmonary31 afflictions.
• Analysis of the hydrogel accessibility to a
fluorescently labeled dextran marker by two-photon Over 10 years, several types of NP 32
have been established
microscopy for imaging and treating cancer , based on organic and
• Analysis of cleaved peptide fragments by HPLC inorganic materials including quantum dots, carbon
nanotubes, gold, silica, iron oxide, and polymers. NP
• Optical microscopy for particle diameters
approach for enzymatic drug delivery was shown in
Rationale: figure 1.
The basis in the development of EADDS is the
activation of the delivery system by the physiological
enzymes present at respective sites to which the drug is
envisioned to be delivered. Usually, in certain disease
conditions like cancer, intracellular enzymes become
overexpressed to uphold the rapid cell proliferation and
obtaining more nutrients for cellular growth. Such an
altered cellular enzymatic expression can be made as the
target for drug delivery by which the system gets
activated at the respective site or organ. Abnormal
functioning of enzymes leads to the severe diseases that
laid the basis for drug development that act in such sites
or conditions of the physiological status19.

Fig 1: Nanoparticulate approach for enzymatic drug delivery

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Liposomes:
Liposomes are the combination of phospholipids in
water, by which many types of drugs can be delivered
and offers the most efficient targeting of drugs to the
particular site33. The drugs need to contain both
lipophilicity and hydrophilicity for effective absorption
as well as dissolution in the biological membrane. It was
conversant that the cell membranes of most of the organs
covering the lipid layers and followed by the hydrophilic
layers due to which the permeability of drugs get limited
and accounting a lot of difficulties to permeate into the
membrane. This can be easily overcome by drug
delivery through liposomes in which both hydrophilic
and lipophilic drugs can be incorporated and delivered 34.
Due to their bio-compatibility and feasibility, liposomes Fig. 2. Representation of mechanism of Enzyme activated drug
are used in drug delivery35. delivery system

Mesoporous Silica Nanoparticles: Prodrug:

They have a variety of applications in the delivery of Another type of well-known strategy is the prodrug
drugs due to their large surface area, pore volume and mechanism, which is described as the inactive form of
high stability36. An organo-silane precursor was used for drug molecules. Upon the action of certain enzymes,
their preparation and the drug is incorporated through the chemical or environment stimuli, prodrugs transform to
pores. Along with these, the enzyme responsive discharge of the active parent drug in-vivo42. With this
materials should also be present which include lipase approach, the pharmaceutical properties. It includes the
responsive, hydrolase responsive, and protease chemical conjugation of the drug with a suitable moiety,
responsive NP etc.37 can be described as the prodrug. Because of these
significant aspects, the prodrug approach has been in
Another type of nanocarriers is clay nanotubes where the practice in developing various novel formulations.
drug gets encumbered into the lumen of tubule and also Approximately 5-7% of currently approved drugs as a
provides surface modification38. An example of clay prodrug. The designing of prodrug should be such that
nanotubes is halloysite which is an aluminosilicate clay the pro moiety should get removed after the respective
tubule having its external diameter of 50–60nm. At a enzymatic action. It provides an idea that the prodrug
neutral pH, the surface of silicon dioxide has a negative gets transformed into its active form only when the
charge and the aluminium oxide inner lumen has positive enzyme of interest, having the pro moiety as substrate,
charge39. It has good bio-compatibility. Another example cleaves it. So, the drug will be released at a specific site
of the polymer used for surface modification is PEG and where the enzyme is in overexpressed condition. The
thereby increase the aqueous solubility. Another type of Prodrug approach for EADDS was illustrated in figure 3.
polymer which is in the clinical study at present is
HPMA (n- hydroxypropylmethacrylamide)40

Microspheres:
Here the drug is initially dissolved in a suitable medium
to form the drug reservoir and can be enclosed
physically as microspheres or by chemical means which
includes the using of biopolymers like albumins or
polypeptides to which the drug is bounded to their
polymer chains. The main process involved in the
hydrolysis of biopolymers by the characteristic type of
enzyme present in the target site. Here, is an example
that albumin microspheres of 5-Fluorouracil can be
made targeted drug delivery to the cancer cells based on
the enzyme called protease present in the cancer cells,
that act specifically on the proteins like albumin. In this
system, the degradation of albumin microspheres occurs
by the action of the protease enzyme41. Representation of
the mechanism of EADDS is represented in figure 2.
Fig. 3. Pro-drug approach for Enzyme activated DDS
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