We studied the anisotropy of the influence of plasmonic fields, arising from the optical excitati... more We studied the anisotropy of the influence of plasmonic fields, arising from the optical excitation of a gold nanoshell plasmon absorption at 770 nm, on the lifetime of the bandgap state of the CdTe core in vertically aligned CdTe-Au core-shell nanorods. The previously observed decrease in the lifetime was studied as a function of the tilt angle between the long axis of the nanorod and the electric field polarization direction of the plasmon inducing exciting light. It is observed that the strongest enhancement to the exciton relaxation rate occurs when the two axes are parallel to one another. These results are discussed in terms of the coupling between the exciton transition moment of the CdTe rod and the electric field polarization direction of the gold nanoshell plasmon at 770 nm, which was determined from theoretical modeling based on the discrete dipole approximation.
The dependence of the plasmon field enhancement of the nonradiative relaxation rate of the band g... more The dependence of the plasmon field enhancement of the nonradiative relaxation rate of the band gap electrons in vertically aligned CdTe-Au core-shell nanorods on the plasmonic gold nanoshell thickness is examined. Increasing the thickness of the gold nanoshell from 15 to 26 nm is found to change the decay curve from being nonexponential and anisotropic to one that is fully exponential and isotropic (i.e., independent of the nanorod orientation with respect to the exciting light polarization direction). Analysis of the kinetics of the possible electronic relaxation enhancement mechanisms is carried out, and DDA simulated properties of the induced plasmonic field of the thin and thick gold nanoshells are determined. On the basis of the conclusions of these treatments and the experimental results, it is concluded that by increasing the nanoshell thickness the relaxation processes evolve from multiple enhancement mechanisms, dominated by highly anisotropic Auger processes, to mechanism(s) involving first-order excited electron ejection process(es). The former is shown to give rise to nonexponential anisotropic decays in the dipolar plasmon field of the thin nanoshell, while the latter exhibits an exponential isotropic decay in the unpolarized plasmonic field of the thick nanoshell.
ABSTRACT Gold nanoparticles are rapidly emerging platforms for multifunctional diagnostic and the... more ABSTRACT Gold nanoparticles are rapidly emerging platforms for multifunctional diagnostic and therapeutic nanotechnologies. Tumor-specific cellular delivery of a gold nanoparticle however, is a complex, multistep process involving systemic circulation, transvascular flux, intratumoral penetration, and intracellular delivery. Each of these steps present unique constrains which determine the optimal architecture for gold nanoparticle construct including at its most fundamental level, size, shape, and surface chemistry. Gold nanoparticles, given their highly well-defined chemical synthesis and surface chemistry, represent one of the most versatile and reliable platforms for designing and understanding tumor-targeting nanotechnologies. Here, we review a recent body of work examining the effects of gold nanoparticle size, shape, and surface chemistry on circulation kinetics, tumor extravasation, interstitial tumor transport, and cellular uptake with the aim of delineating optimal design parameters for each of these processes. Discussions here focus primarily on poly(ethylene glycol)-functionalized gold nanoparticles with an emphasis on practical design considerations for new researchers in the field.
Infections associated with orthopedic implants cause increased morbidity and significant healthca... more Infections associated with orthopedic implants cause increased morbidity and significant healthcare cost. A prolonged and expensive two-stage procedure requiring two surgical steps and a 6-8 week period of joint immobilization exists as today's gold standard for the revision arthroplasty of an infected prosthesis. Because infection is much more common in implant replacement surgeries, these issues greatly impact long-term patient care for a continually growing part of the population. Here, we demonstrate that a single-stage revision using prostheses coated with self-assembled, hydrolytically degradable multilayers that sequentially deliver the antibiotic (gentamicin) and the osteoinductive growth factor (BMP-2) in a time-staggered manner enables both eradication of established biofilms and complete and rapid bone tissue repair around the implant in rats with induced osteomyelitis. The nanolayered construct allows precise independent control of release kinetics and loading for ea...
Layer-by-layer (LbL) based self-assembly of nanoparticles is an emerging and powerful method to d... more Layer-by-layer (LbL) based self-assembly of nanoparticles is an emerging and powerful method to develop multifunctional and tissue responsive nanomedicines for a broad range of diseases. This unique assembly technique is able to confer a high degree of modularity, versatility, and compositional heterogeneity to nanoparticles via the sequential deposition of alternately charged polyelectrolytes onto a colloidal template. LbL assembly can provide added functionality by directly incorporating a range of functional materials within the multilayers including nucleic acids, synthetic polymers, polypeptides, polysaccharides, and functional proteins. These materials can be used to generate hierarchically complex, heterogeneous thin films on an extensive range of both traditional and novel nanoscale colloidal templates, providing the opportunity to engineer highly precise systems capable of performing the numerous tasks required for systemic drug delivery. In this review, we will discuss the recent advancements towards the development of LbL nanoparticles for drug delivery and diagnostic applications, with a special emphasis on the incorporation of biostability, active targeting, desirable drug release kinetics, and combination therapies into LbL nanomaterials. In addition to these topics, we will touch upon the next steps for the translation of these systems towards the clinic.
Layer-by-layer (LbL) self-assembly is a versatile technique from which multicomponent and stimuli... more Layer-by-layer (LbL) self-assembly is a versatile technique from which multicomponent and stimuli-responsive nanoscale drug carriers can be constructed. Despite the benefits of LbL assembly, the conventional synthetic approach for fabricating LbL nanoparticles requires numerous purification steps that limit scale, yield, efficiency, and potential for clinical translation. In this report, we describe a generalizable method for increasing throughput with LbL assembly by using highly scalable, closed-loop diafiltration to manage intermediate purification steps. This method facilitates highly controlled fabrication of diverse nanoscale LbL formulations smaller than 150 nm composed from solid-polymer, mesoporous silica, and liposomal vesicles. The technique allows for the deposition of a broad range of polyelectrolytes that included native polysaccharides, linear polypeptides, and synthetic polymers. We also explore the cytotoxicity, shelf life and long-term storage of LbL nanoparticles produced using this approach. We find that LbL coated systems can be reliably and rapidly produced: specifically, LbL-modified liposomes could be lyophilized, stored at room temperature, and reconstituted without compromising drug encapsulation or particle stability, thereby facilitating large scale applications. Overall, this report describes an accessible approach that significantly improves the throughput of nanoscale LbL drug-carriers that show low toxicity and are amenable to clinically relevant storage conditions.
Large dsRNA molecules can cause potent cytotoxic and immunostimulatory effects through the activa... more Large dsRNA molecules can cause potent cytotoxic and immunostimulatory effects through the activation of pattern recognition receptors; however, synthetic versions of these molecules are mostly limited to simple sequences like poly-I:C and poly-A:U. Here we show that large RNA molecules generated by rolling circle transcription fold into periodic-shRNA (p-shRNA) structures and cause potent cytotoxicity and gene silencing when delivered to cancer cells. We determined structural requirements for the dumbbell templates used to synthesize p-shRNA, and showed that these molecules likely adopt a co-transcriptionally folded structure. The cytotoxicity of p-shRNA was robustly observed across four different cancer cell lines using two different delivery systems. Despite having a considerably different folded structure than conventional dsRNA, the cytotoxicity of p-shRNA was either equal to or substantially greater than that of poly-I:C depending on the delivery vehicle. Furthermore, p-shRNA caused greater NF-κB activation in SKOV3 cells compared to poly-I:C, indicating that it is a powerful activator of innate immunity. The tuneable sequence and combined gene silencing, immunostimulatory and cytotoxic capacity of p-shRNA make it an attractive platform for cancer immunotherapy.
Angewandte Chemie (International ed. in English), Jan 22, 2015
Packaging multiple small interfering RNA (siRNA) molecules into nanostructures at precisely defin... more Packaging multiple small interfering RNA (siRNA) molecules into nanostructures at precisely defined ratios is a powerful delivery strategy for effective RNA interference (RNAi) therapy. We present a novel RNA nanotechnology based approach to produce multiple components of polymerized siRNA molecules that are simultaneously self-assembled and densely packaged into composite sponge-like porous microstructures (Multi-RNAi-MSs) by rolling circle transcription. The Multi-RNAi-MSs were designed to contain a combination of multiple polymeric siRNA molecules with precisely controlled stoichiometry within a singular microstructure by manipulating the types and ratios of the circular DNA templates. The Multi-RNAi-MSs were converted into nanosized complexes by polyelectrolyte condensation to manipulate their physicochemical properties (size, shape, and surface charge) for favorable delivery, while maintaining the multifunctional properties of the siRNAs for combined therapeutic effects. These ...
ABSTRACT Global incidence and mortality from cancer is projected to more than double between 2008... more ABSTRACT Global incidence and mortality from cancer is projected to more than double between 2008 and 2030, resulting in an additional 8.7 million new cases and 5.6 million deaths annually (United Nations, 2009). Head and neck cancers (HNCs) account for approximately 12 percent of current incidence and mortality worldwide. HNC is more prevalent in less developed regions than in economically developed countries (8 versus 15 percent) and most arise from the squamous cell lining of the upper aerodigestive tract. Despite advances in diagnostic imaging and treatment, there has been little change in survival rates over the past 50 years. There is a dire need to improve early detection of HNC and therapeutic outcomes. Nanoscience refers to the study and application of structures ranging from 1 to 100 nm in size. Materials of these dimensions differ dramatically from their atomic, molecular, or bulk counterparts. At the nanoscale, new physical properties emerge as interfacial properties dominate and electrons become restricted. The equally matched size between nanoparticles and cellular organelles and biomolecules allows potential interactions of these materials within cells. This chapter discusses several promising diagnostic/therapeutic nanotechnologies with special emphasis on rational design, photonic properties/applications, and relevance to head and neck cancer.
Plasmonic photothermal therapy (PPTT) is a minimally-invasive oncological treatment strategy in w... more Plasmonic photothermal therapy (PPTT) is a minimally-invasive oncological treatment strategy in which photon energy is selectively administered and converted into heat sufficient to induce cellular hyperthermia. The present work demonstrates the feasibility of in vivo PPTT treatment of deep-tissue malignancies using easily-prepared plasmonic gold nanorods and a small, portable, inexpensive near-infrared (NIR) laser. Dramatic size decreases in squamous cell carcinoma xenografts were observed for direct (P < 0.0001) and intravenous (P < 0.0008) administration of pegylated gold nanorods in nu/nu mice. Inhibition of average tumor growth for both delivery methods was observed over a 13-day period, with resorption of >57% of the directly-injected tumors and 25% of the intravenously-treated tumors. Published by Elsevier Ltd.
Layer-by-Layer (LbL) assembly is a highly tunable, modular approach to surface-limited functional... more Layer-by-Layer (LbL) assembly is a highly tunable, modular approach to surface-limited functionalization of materials with nanoscale precision over the composition and properties of the film components. This high level of control affords the capability to design systems that are multi-functional in nature, with temporal and spatial control over the release of a diverse range of materials and therapeutics of interest. Surface-mediated interactions are of particular interest in biological settings where this interface between delivery systems and cells/biological environment govern binding and internalization on a cellular level and the pharmacokinetic properties of the system at a higher level in vivo. Application of this approach to nanomedicine has been successful in designing hydrated, protein-resistive long-circulating nanoparticles, as well as systems that shed a hydrated shell used for enhanced persistence in the bloodstream and EPR-based accumulation in the hypoxic tumor micro...
Nanoscale drug delivery is a power full tool for the treatment of solid tumors. Although a range ... more Nanoscale drug delivery is a power full tool for the treatment of solid tumors. Although a range of approaches have been described over the past several years, the vast majority seek to improve cytotoxic chemotherapies that have been in use for decades. Nanoscale delivery strategies integrating rational drug combinations, synthetic lethal RNA interference, stimuli-responsive drugs, or so-called molecularly targeted cancer therapeutics are and remain underexplored. Here, we present work from our laboratory describing the development of a range of such nanoscale platforms for drug delivery to solid tumors. These include: (i) self-assembled peptide co-polymer nanoparticles for synthetic lethal RNA interference of DNA damage response in ovarian and lung cancers, (ii) multivalent anti-androgen and anti-estrogen gold nanoparticles for the treatment of hormone-refractory breast and prostate cancers, (iii) photo-responsive nanoparticles that deliver drugs or achieve photothermal ablation in...
Synergistic and synthetic lethal drug delivery to solid tumors can be difficult to achieve using ... more Synergistic and synthetic lethal drug delivery to solid tumors can be difficult to achieve using traditional pharmaceutical excipients and nanotechnologies. Ideally, these strategies not only require that drug compounds with vastly differing size, charge, and hydrophobicity be co-delivered to tumor cells, but also that delivery (i) targets multiple cell populations within a heterogeneous tumor, (ii) is non-toxic to healthy tissues, and (iii) circumvents known mechanisms of resistance. Here, we describe recent progress in our laboratory utilizing self-assembled polymer drug carriers to address these difficult challenges. (i) We report the development of a nanoscale drug carrier based on Layer-by-Layer (LbL) polymer self-assembly that is capable of simultaneously targeting both cancer stem cells and the hypoxic tumor microenvironment in vitro and in vivo. (ii) We also describe the discovery of a novel DNA damage signal effector whose loss is synthetic lethal in ovarian cancer cells th...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2015
Crosstalk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is c... more Crosstalk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is critical for tumor initiation, maintenance, and adaptive resistance to targeted therapy in a variety of solid tumors. Combined blockade of these pathways - horizontal blockade - is a promising therapeutic strategy; however, compounded dose-limiting toxicity of free small molecule inhibitor combinations is a significant barrier to its clinical application. AZD6244 (selumetinib), an allosteric inhibitor of Mek1/2, and PX-866, a covalent inhibitor of PI3K, were co-encapsulated in a tumor-targeting nanoscale drug formulation - Layer-by-Layer (LbL) nanoparticles. Structure, size, and surface charge of the nanoscale formulations were characterized, in addition to in vitro cell entry, synergistic cell killing, and combined signal blockade. In vivo tumor-targeting and therapy was investigated in breast tumor xenograft-bearing NCR nude mice by live animal fluorescence/bioluminescence imaging, west...
The journal of physical chemistry. B, Jan 10, 2015
Poly-L-Lysine (PLL) adsorption onto various materials has been widely applied as a surface modifi... more Poly-L-Lysine (PLL) adsorption onto various materials has been widely applied as a surface modification strategy and layer-by-layer fabrication method. Considering the influence of electrostatic charges, a detailed understanding of the influence of solution pH on PLL adsorption process is important for optimization of PLL coating protocols. Herein, PLL adsorption onto different polar and hydrophilic substrates - silica, an amine-terminated self-assembled monolayer (SAM) on gold, and a carboxyl-terminated SAM on gold - across a range of pH conditions was investigated using the quartz crystal microbalance with dissipation. The adsorption kinetics consisted of an initial rapid phase, followed by a second phase where adsorption rate gradually decelerated. These features were interpreted by applying a mean-field kinetic model implying diffusion-limited adsorption in the first phase and reconfiguration of adsorbed PLL molecules in the second phase. The adsorption kinetics and uptake were ...
Fundamentals, Applications and Recent Developments(In 4 Volumes)Volume 1: Materials for NanomedicineVolume 2: Applications in TherapyVolume 3: Applications in DiagnosticsVolume 4: Biology, Safety and Novel Concepts in Nanomedicine, 2014
ABSTRACT Gold nanoparticles are rapidly emerging platforms for multifunctional diagnostic and the... more ABSTRACT Gold nanoparticles are rapidly emerging platforms for multifunctional diagnostic and therapeutic nanotechnologies. Tumor-specific cellular delivery of a gold nanoparticle however, is a complex, multistep process involving systemic circulation, transvascular flux, intratumoral penetration, and intracellular delivery. Each of these steps present unique constrains which determine the optimal architecture for gold nanoparticle construct including at its most fundamental level, size, shape, and surface chemistry. Gold nanoparticles, given their highly well-defined chemical synthesis and surface chemistry, represent one of the most versatile and reliable platforms for designing and understanding tumor-targeting nanotechnologies. Here, we review a recent body of work examining the effects of gold nanoparticle size, shape, and surface chemistry on circulation kinetics, tumor extravasation, interstitial tumor transport, and cellular uptake with the aim of delineating optimal design parameters for each of these processes. Discussions here focus primarily on poly(ethylene glycol)-functionalized gold nanoparticles with an emphasis on practical design considerations for new researchers in the field.
Active targeting of nanoscale drug carriers can improve tumor-specific delivery; however, cellula... more Active targeting of nanoscale drug carriers can improve tumor-specific delivery; however, cellular heterogeneity both within and among tumor sites is a fundamental barrier to their success. Here, we describe a tumor microenvironment-responsive layer-by-layer (LbL) polymer drug carrier that actively targets tumors based on two independent mechanisms: pH-dependent cellular uptake at hypoxic tumor pH and hyaluronan-directed targeting of cell-surface CD44 receptor, a well-characterized biomarker for breast and ovarian cancer stem cells. Hypoxic pH-induced structural reorganization of hyaluronan-LbL nanoparticles was a direct result of the nature of the LbL electrostatic complex, and led to targeted cellular delivery in vitro and in vivo, with effective tumor penetration and uptake. The nanoscale drug carriers selectively bound CD44 and diminished cancer cell migration in vitro, while co-localizing with the CD44 receptor in vivo. Multimodal targeting of LbL nanoparticles is a powerful st...
We studied the anisotropy of the influence of plasmonic fields, arising from the optical excitati... more We studied the anisotropy of the influence of plasmonic fields, arising from the optical excitation of a gold nanoshell plasmon absorption at 770 nm, on the lifetime of the bandgap state of the CdTe core in vertically aligned CdTe-Au core-shell nanorods. The previously observed decrease in the lifetime was studied as a function of the tilt angle between the long axis of the nanorod and the electric field polarization direction of the plasmon inducing exciting light. It is observed that the strongest enhancement to the exciton relaxation rate occurs when the two axes are parallel to one another. These results are discussed in terms of the coupling between the exciton transition moment of the CdTe rod and the electric field polarization direction of the gold nanoshell plasmon at 770 nm, which was determined from theoretical modeling based on the discrete dipole approximation.
The dependence of the plasmon field enhancement of the nonradiative relaxation rate of the band g... more The dependence of the plasmon field enhancement of the nonradiative relaxation rate of the band gap electrons in vertically aligned CdTe-Au core-shell nanorods on the plasmonic gold nanoshell thickness is examined. Increasing the thickness of the gold nanoshell from 15 to 26 nm is found to change the decay curve from being nonexponential and anisotropic to one that is fully exponential and isotropic (i.e., independent of the nanorod orientation with respect to the exciting light polarization direction). Analysis of the kinetics of the possible electronic relaxation enhancement mechanisms is carried out, and DDA simulated properties of the induced plasmonic field of the thin and thick gold nanoshells are determined. On the basis of the conclusions of these treatments and the experimental results, it is concluded that by increasing the nanoshell thickness the relaxation processes evolve from multiple enhancement mechanisms, dominated by highly anisotropic Auger processes, to mechanism(s) involving first-order excited electron ejection process(es). The former is shown to give rise to nonexponential anisotropic decays in the dipolar plasmon field of the thin nanoshell, while the latter exhibits an exponential isotropic decay in the unpolarized plasmonic field of the thick nanoshell.
ABSTRACT Gold nanoparticles are rapidly emerging platforms for multifunctional diagnostic and the... more ABSTRACT Gold nanoparticles are rapidly emerging platforms for multifunctional diagnostic and therapeutic nanotechnologies. Tumor-specific cellular delivery of a gold nanoparticle however, is a complex, multistep process involving systemic circulation, transvascular flux, intratumoral penetration, and intracellular delivery. Each of these steps present unique constrains which determine the optimal architecture for gold nanoparticle construct including at its most fundamental level, size, shape, and surface chemistry. Gold nanoparticles, given their highly well-defined chemical synthesis and surface chemistry, represent one of the most versatile and reliable platforms for designing and understanding tumor-targeting nanotechnologies. Here, we review a recent body of work examining the effects of gold nanoparticle size, shape, and surface chemistry on circulation kinetics, tumor extravasation, interstitial tumor transport, and cellular uptake with the aim of delineating optimal design parameters for each of these processes. Discussions here focus primarily on poly(ethylene glycol)-functionalized gold nanoparticles with an emphasis on practical design considerations for new researchers in the field.
Infections associated with orthopedic implants cause increased morbidity and significant healthca... more Infections associated with orthopedic implants cause increased morbidity and significant healthcare cost. A prolonged and expensive two-stage procedure requiring two surgical steps and a 6-8 week period of joint immobilization exists as today's gold standard for the revision arthroplasty of an infected prosthesis. Because infection is much more common in implant replacement surgeries, these issues greatly impact long-term patient care for a continually growing part of the population. Here, we demonstrate that a single-stage revision using prostheses coated with self-assembled, hydrolytically degradable multilayers that sequentially deliver the antibiotic (gentamicin) and the osteoinductive growth factor (BMP-2) in a time-staggered manner enables both eradication of established biofilms and complete and rapid bone tissue repair around the implant in rats with induced osteomyelitis. The nanolayered construct allows precise independent control of release kinetics and loading for ea...
Layer-by-layer (LbL) based self-assembly of nanoparticles is an emerging and powerful method to d... more Layer-by-layer (LbL) based self-assembly of nanoparticles is an emerging and powerful method to develop multifunctional and tissue responsive nanomedicines for a broad range of diseases. This unique assembly technique is able to confer a high degree of modularity, versatility, and compositional heterogeneity to nanoparticles via the sequential deposition of alternately charged polyelectrolytes onto a colloidal template. LbL assembly can provide added functionality by directly incorporating a range of functional materials within the multilayers including nucleic acids, synthetic polymers, polypeptides, polysaccharides, and functional proteins. These materials can be used to generate hierarchically complex, heterogeneous thin films on an extensive range of both traditional and novel nanoscale colloidal templates, providing the opportunity to engineer highly precise systems capable of performing the numerous tasks required for systemic drug delivery. In this review, we will discuss the recent advancements towards the development of LbL nanoparticles for drug delivery and diagnostic applications, with a special emphasis on the incorporation of biostability, active targeting, desirable drug release kinetics, and combination therapies into LbL nanomaterials. In addition to these topics, we will touch upon the next steps for the translation of these systems towards the clinic.
Layer-by-layer (LbL) self-assembly is a versatile technique from which multicomponent and stimuli... more Layer-by-layer (LbL) self-assembly is a versatile technique from which multicomponent and stimuli-responsive nanoscale drug carriers can be constructed. Despite the benefits of LbL assembly, the conventional synthetic approach for fabricating LbL nanoparticles requires numerous purification steps that limit scale, yield, efficiency, and potential for clinical translation. In this report, we describe a generalizable method for increasing throughput with LbL assembly by using highly scalable, closed-loop diafiltration to manage intermediate purification steps. This method facilitates highly controlled fabrication of diverse nanoscale LbL formulations smaller than 150 nm composed from solid-polymer, mesoporous silica, and liposomal vesicles. The technique allows for the deposition of a broad range of polyelectrolytes that included native polysaccharides, linear polypeptides, and synthetic polymers. We also explore the cytotoxicity, shelf life and long-term storage of LbL nanoparticles produced using this approach. We find that LbL coated systems can be reliably and rapidly produced: specifically, LbL-modified liposomes could be lyophilized, stored at room temperature, and reconstituted without compromising drug encapsulation or particle stability, thereby facilitating large scale applications. Overall, this report describes an accessible approach that significantly improves the throughput of nanoscale LbL drug-carriers that show low toxicity and are amenable to clinically relevant storage conditions.
Large dsRNA molecules can cause potent cytotoxic and immunostimulatory effects through the activa... more Large dsRNA molecules can cause potent cytotoxic and immunostimulatory effects through the activation of pattern recognition receptors; however, synthetic versions of these molecules are mostly limited to simple sequences like poly-I:C and poly-A:U. Here we show that large RNA molecules generated by rolling circle transcription fold into periodic-shRNA (p-shRNA) structures and cause potent cytotoxicity and gene silencing when delivered to cancer cells. We determined structural requirements for the dumbbell templates used to synthesize p-shRNA, and showed that these molecules likely adopt a co-transcriptionally folded structure. The cytotoxicity of p-shRNA was robustly observed across four different cancer cell lines using two different delivery systems. Despite having a considerably different folded structure than conventional dsRNA, the cytotoxicity of p-shRNA was either equal to or substantially greater than that of poly-I:C depending on the delivery vehicle. Furthermore, p-shRNA caused greater NF-κB activation in SKOV3 cells compared to poly-I:C, indicating that it is a powerful activator of innate immunity. The tuneable sequence and combined gene silencing, immunostimulatory and cytotoxic capacity of p-shRNA make it an attractive platform for cancer immunotherapy.
Angewandte Chemie (International ed. in English), Jan 22, 2015
Packaging multiple small interfering RNA (siRNA) molecules into nanostructures at precisely defin... more Packaging multiple small interfering RNA (siRNA) molecules into nanostructures at precisely defined ratios is a powerful delivery strategy for effective RNA interference (RNAi) therapy. We present a novel RNA nanotechnology based approach to produce multiple components of polymerized siRNA molecules that are simultaneously self-assembled and densely packaged into composite sponge-like porous microstructures (Multi-RNAi-MSs) by rolling circle transcription. The Multi-RNAi-MSs were designed to contain a combination of multiple polymeric siRNA molecules with precisely controlled stoichiometry within a singular microstructure by manipulating the types and ratios of the circular DNA templates. The Multi-RNAi-MSs were converted into nanosized complexes by polyelectrolyte condensation to manipulate their physicochemical properties (size, shape, and surface charge) for favorable delivery, while maintaining the multifunctional properties of the siRNAs for combined therapeutic effects. These ...
ABSTRACT Global incidence and mortality from cancer is projected to more than double between 2008... more ABSTRACT Global incidence and mortality from cancer is projected to more than double between 2008 and 2030, resulting in an additional 8.7 million new cases and 5.6 million deaths annually (United Nations, 2009). Head and neck cancers (HNCs) account for approximately 12 percent of current incidence and mortality worldwide. HNC is more prevalent in less developed regions than in economically developed countries (8 versus 15 percent) and most arise from the squamous cell lining of the upper aerodigestive tract. Despite advances in diagnostic imaging and treatment, there has been little change in survival rates over the past 50 years. There is a dire need to improve early detection of HNC and therapeutic outcomes. Nanoscience refers to the study and application of structures ranging from 1 to 100 nm in size. Materials of these dimensions differ dramatically from their atomic, molecular, or bulk counterparts. At the nanoscale, new physical properties emerge as interfacial properties dominate and electrons become restricted. The equally matched size between nanoparticles and cellular organelles and biomolecules allows potential interactions of these materials within cells. This chapter discusses several promising diagnostic/therapeutic nanotechnologies with special emphasis on rational design, photonic properties/applications, and relevance to head and neck cancer.
Plasmonic photothermal therapy (PPTT) is a minimally-invasive oncological treatment strategy in w... more Plasmonic photothermal therapy (PPTT) is a minimally-invasive oncological treatment strategy in which photon energy is selectively administered and converted into heat sufficient to induce cellular hyperthermia. The present work demonstrates the feasibility of in vivo PPTT treatment of deep-tissue malignancies using easily-prepared plasmonic gold nanorods and a small, portable, inexpensive near-infrared (NIR) laser. Dramatic size decreases in squamous cell carcinoma xenografts were observed for direct (P < 0.0001) and intravenous (P < 0.0008) administration of pegylated gold nanorods in nu/nu mice. Inhibition of average tumor growth for both delivery methods was observed over a 13-day period, with resorption of >57% of the directly-injected tumors and 25% of the intravenously-treated tumors. Published by Elsevier Ltd.
Layer-by-Layer (LbL) assembly is a highly tunable, modular approach to surface-limited functional... more Layer-by-Layer (LbL) assembly is a highly tunable, modular approach to surface-limited functionalization of materials with nanoscale precision over the composition and properties of the film components. This high level of control affords the capability to design systems that are multi-functional in nature, with temporal and spatial control over the release of a diverse range of materials and therapeutics of interest. Surface-mediated interactions are of particular interest in biological settings where this interface between delivery systems and cells/biological environment govern binding and internalization on a cellular level and the pharmacokinetic properties of the system at a higher level in vivo. Application of this approach to nanomedicine has been successful in designing hydrated, protein-resistive long-circulating nanoparticles, as well as systems that shed a hydrated shell used for enhanced persistence in the bloodstream and EPR-based accumulation in the hypoxic tumor micro...
Nanoscale drug delivery is a power full tool for the treatment of solid tumors. Although a range ... more Nanoscale drug delivery is a power full tool for the treatment of solid tumors. Although a range of approaches have been described over the past several years, the vast majority seek to improve cytotoxic chemotherapies that have been in use for decades. Nanoscale delivery strategies integrating rational drug combinations, synthetic lethal RNA interference, stimuli-responsive drugs, or so-called molecularly targeted cancer therapeutics are and remain underexplored. Here, we present work from our laboratory describing the development of a range of such nanoscale platforms for drug delivery to solid tumors. These include: (i) self-assembled peptide co-polymer nanoparticles for synthetic lethal RNA interference of DNA damage response in ovarian and lung cancers, (ii) multivalent anti-androgen and anti-estrogen gold nanoparticles for the treatment of hormone-refractory breast and prostate cancers, (iii) photo-responsive nanoparticles that deliver drugs or achieve photothermal ablation in...
Synergistic and synthetic lethal drug delivery to solid tumors can be difficult to achieve using ... more Synergistic and synthetic lethal drug delivery to solid tumors can be difficult to achieve using traditional pharmaceutical excipients and nanotechnologies. Ideally, these strategies not only require that drug compounds with vastly differing size, charge, and hydrophobicity be co-delivered to tumor cells, but also that delivery (i) targets multiple cell populations within a heterogeneous tumor, (ii) is non-toxic to healthy tissues, and (iii) circumvents known mechanisms of resistance. Here, we describe recent progress in our laboratory utilizing self-assembled polymer drug carriers to address these difficult challenges. (i) We report the development of a nanoscale drug carrier based on Layer-by-Layer (LbL) polymer self-assembly that is capable of simultaneously targeting both cancer stem cells and the hypoxic tumor microenvironment in vitro and in vivo. (ii) We also describe the discovery of a novel DNA damage signal effector whose loss is synthetic lethal in ovarian cancer cells th...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2015
Crosstalk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is c... more Crosstalk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is critical for tumor initiation, maintenance, and adaptive resistance to targeted therapy in a variety of solid tumors. Combined blockade of these pathways - horizontal blockade - is a promising therapeutic strategy; however, compounded dose-limiting toxicity of free small molecule inhibitor combinations is a significant barrier to its clinical application. AZD6244 (selumetinib), an allosteric inhibitor of Mek1/2, and PX-866, a covalent inhibitor of PI3K, were co-encapsulated in a tumor-targeting nanoscale drug formulation - Layer-by-Layer (LbL) nanoparticles. Structure, size, and surface charge of the nanoscale formulations were characterized, in addition to in vitro cell entry, synergistic cell killing, and combined signal blockade. In vivo tumor-targeting and therapy was investigated in breast tumor xenograft-bearing NCR nude mice by live animal fluorescence/bioluminescence imaging, west...
The journal of physical chemistry. B, Jan 10, 2015
Poly-L-Lysine (PLL) adsorption onto various materials has been widely applied as a surface modifi... more Poly-L-Lysine (PLL) adsorption onto various materials has been widely applied as a surface modification strategy and layer-by-layer fabrication method. Considering the influence of electrostatic charges, a detailed understanding of the influence of solution pH on PLL adsorption process is important for optimization of PLL coating protocols. Herein, PLL adsorption onto different polar and hydrophilic substrates - silica, an amine-terminated self-assembled monolayer (SAM) on gold, and a carboxyl-terminated SAM on gold - across a range of pH conditions was investigated using the quartz crystal microbalance with dissipation. The adsorption kinetics consisted of an initial rapid phase, followed by a second phase where adsorption rate gradually decelerated. These features were interpreted by applying a mean-field kinetic model implying diffusion-limited adsorption in the first phase and reconfiguration of adsorbed PLL molecules in the second phase. The adsorption kinetics and uptake were ...
Fundamentals, Applications and Recent Developments(In 4 Volumes)Volume 1: Materials for NanomedicineVolume 2: Applications in TherapyVolume 3: Applications in DiagnosticsVolume 4: Biology, Safety and Novel Concepts in Nanomedicine, 2014
ABSTRACT Gold nanoparticles are rapidly emerging platforms for multifunctional diagnostic and the... more ABSTRACT Gold nanoparticles are rapidly emerging platforms for multifunctional diagnostic and therapeutic nanotechnologies. Tumor-specific cellular delivery of a gold nanoparticle however, is a complex, multistep process involving systemic circulation, transvascular flux, intratumoral penetration, and intracellular delivery. Each of these steps present unique constrains which determine the optimal architecture for gold nanoparticle construct including at its most fundamental level, size, shape, and surface chemistry. Gold nanoparticles, given their highly well-defined chemical synthesis and surface chemistry, represent one of the most versatile and reliable platforms for designing and understanding tumor-targeting nanotechnologies. Here, we review a recent body of work examining the effects of gold nanoparticle size, shape, and surface chemistry on circulation kinetics, tumor extravasation, interstitial tumor transport, and cellular uptake with the aim of delineating optimal design parameters for each of these processes. Discussions here focus primarily on poly(ethylene glycol)-functionalized gold nanoparticles with an emphasis on practical design considerations for new researchers in the field.
Active targeting of nanoscale drug carriers can improve tumor-specific delivery; however, cellula... more Active targeting of nanoscale drug carriers can improve tumor-specific delivery; however, cellular heterogeneity both within and among tumor sites is a fundamental barrier to their success. Here, we describe a tumor microenvironment-responsive layer-by-layer (LbL) polymer drug carrier that actively targets tumors based on two independent mechanisms: pH-dependent cellular uptake at hypoxic tumor pH and hyaluronan-directed targeting of cell-surface CD44 receptor, a well-characterized biomarker for breast and ovarian cancer stem cells. Hypoxic pH-induced structural reorganization of hyaluronan-LbL nanoparticles was a direct result of the nature of the LbL electrostatic complex, and led to targeted cellular delivery in vitro and in vivo, with effective tumor penetration and uptake. The nanoscale drug carriers selectively bound CD44 and diminished cancer cell migration in vitro, while co-localizing with the CD44 receptor in vivo. Multimodal targeting of LbL nanoparticles is a powerful st...
Uploads
Papers by Erik Dreaden