Taraka Sai Pavan Grandhi

Sensitizing cancer cells to TRAIL-induced death by micellar delivery of mitoxantrone

TNFα-related apoptosis-inducing ligand (TRAIL) induces death selectively in cancer cells. However, subpopulations of cancer cells are either resistant to or can develop resistance to TRAIL-induced death. As a result, strategies that overcome this resistance are currently under investigation. We have recently identified several US FDA-approved drugs with TRAIL-sensitization activity against prostate, breast and pancreatic cancer cells. Mitoxantrone, a previously unknown TRAIL sensitizer identified in the screen, was successfully encapsulated in methoxy-, amine- and carboxyl-terminated PEG-DSPE micelles in order to facilitate delivery of the drug to cancer cells. All three micelle types were extensively characterized for their physicochemical properties and evaluated for their ability to sensitize cancer cells to TRAIL-induced death. Our results indicate that micelle-encapsulated mitoxantrone can be advantageously employed in synergistic treatments with TRAIL, leading to a biocompatible delivery system and amplified cell killing activity for combination chemotherapeutic cancer treatments.

GOLD NANOPARTICLES IN CANCER IMAGING AND THERAPEUTICS

The use of nanomedicine in the war on cancer diseases has progressed significantly in the recent past. Liposomal- and albumin-based chemotherapeutic agents as well as tumor contrast agents (e.g. Gd-DTPA, ferumoxides) have received FDA approval for human clinical use, while many other agents are in different phases of pre-clinical investigation and clinical trials. Plasmonic gold nanoparticles hold great promise as potential theranostic devices for detection and ablation of cancer diseases. This review discusses recent progress in the imaging, photothermal therapy, and nucleic acid/drug delivery using gold nanoparticles (spheres, shells, rods, cages) in vitro and in vivo. Issues relating to toxicity, biocompatibility, biodistribution, cellular uptake, and targeting efficiency are also discussed.

Design, Synthesis, and Functionalization of Nanomaterials for Therapeutic Drug Delivery

Nanomaterials have the potential to solve some of the toughest challenges facing modern medicine. Their unique optical, magnetic and chemical properties at the nanoscale make them different from their macroscale counterparts. Successful application of nanomaterials can revolutionize therapeutics, diagnostics and imaging in several biomedical applications. Self-assembled amphiphilic polymeric nanoparticles have been employed to carry poorly soluble chemotherapeutic drugs. Loading of anticancer chemotherapeutic drugs into self assembled polymeric nanoparticles have shown to increase their circulation time, tumor localization and therapeutic potential. This book chapter provides an introductory discussion to organic nanotechnologies for drug delivery. Promising advances in the field of nanomedicine will be discussed and an outlook to the future will be provided.

Chemomechanically engineered 3D organotypic platforms of bladder cancer dormancy and reactivation

Tumors undergo periods of dormancy followed by reactivation leading to metastatic disease. Arrest in the G0/G1 phase of the cell cycle and resistance to chemotherapeutic drugs are key hallmarks of dormant tumor cells. Here, we describe a 3D platform of bladder cancer cell dormancy and reactivation facilitated by a novel aminoglycoside-derived hydrogel, Amikagel. These 3D dormant tumor microenvironments (3D-DTMs) were arrested in the G0/G1 phase and were highly resistant to anti-proliferative drugs. Inhibition of targets in the cellular protein production machinery led to induction of endoplasmic reticulum (ER) stress and complete ablation of 3D-DTMs. Nanoparticle-mediated calcium delivery significantly accelerated ER stress-mediated 3D-DTM death. Transfer of 3D-DTMs onto weaker and adhesive Amikagels resulted in selective reactivation of a sub-population of N-cadherin deficient cells from dormancy. Whole-transcriptome analyses further indicated key biochemical differences between dormant and proliferative cancer cells. Taken together, our results indicate that 3D bladder cancer microenvironments of dormancy and reactivation can facilitate fundamental advances and novel drug discovery in cancer.

Investigation into Pseudo-Capacitance Behavior of Glycoside-Containing Hydrogels

Electrochemical pseudocapacitors are an attractive choice for energy storage applications because they offer higher energy densities than electrostatic or electric double layer capacitors. They also offer higher power densities in shorter durations of time, as compared to batteries. Recent efforts on pseudocapacitors include biocompatible hydrogel electrolytes and transition metal electrodes for implantable energy storage applications. Pseudocapacitive behavior in these devices has been attributed to the redox reactions that occur within the electric double layer, which is formed at the electrode-electrolyte interface. In the present study, we describe a detailed investigation on redox reactions responsible for pseudocapacitive behavior in glycoside-containing hydrogel formulations. Pseudocapacitive behavior was compared among various combinations of biocompatible hydrogel electrolytes, using carbon tape electrodes and transition metal electrodes based on fluorine-doped tin oxide. The hydrogels demonstrated a pseudocapacitive response only in the presence of transition metal electrodes but not in the presence of carbon electrodes. Hydrogels containing amine moieties showed greater energy storage than gels based purely on hydroxyl functional groups. Furthermore, energy storage increased with greater amine content in these hydrogels. We claim that the redox reactions in hydrogels are largely based on Lewis acid-base interactions, facilitated by amine and hydroxyl side groups along the electrolyte chain backbones, as well as hydroxylation of electrode surfaces. Water plays an important role in these reactions, not only in terms of providing ionic radicals but also in assisting ion transport. This understanding of redox reactions will help determine the choice of transition metal electrodes, Lewis acid-base pairs in electrolytes, and medium for ionic transport in future biocompatible pseudocapacitors.

Aminoglycoside-derived amphiphilic nanoparticles for molecular delivery

The development of effective drug carriers can lead to improved outcomes in a variety of disease conditions. Aminoglycosides have been used as antibacterial therapeutics, and are attractive as monomers for the development of polymeric materials in various applications. Here, we describe the development of novel aminoglycoside-derived amphiphilic nanoparticles for drug delivery, with an eye towards ablation of cancer cells. The aminoglycoside paromomycin was first cross-linked with resorcinol diglycidyl ether leading to the formation of a poly (amino ether), PAE. PAE molecules were further derivatized with methoxy-terminated poly(ethylene glycol) or mPEG resulting in the formation of mPEG-PAE polymer, which self-assembled to form nanoparticles. Formation of the mPEG-PAE amphiphile was characterized using (1)H NMR, (13)C NMR, gel permeation chromatography (GPC) and FTIR spectroscopy. Self-assembly of the polymer into nanoparticles was characterized using dynamic light scattering, zeta potential analyses, atomic force microscopy (AFM) and the pyrene fluorescence assay. mPEG-PAE nanoparticles were able to carry significant amounts of doxorubicin (DOX), presumably by means of hydrophobic interactions between the drug and the core. Cell-based studies indicated that mPEG-PAE nanoparticles, loaded with doxorubicin, were able to induce significant loss in viabilities of PC3 human prostate cancer, MDA-MB-231 human breast cancer, and MB49 murine bladder cancer cells; empty nanoparticles resulted in negligible losses of cell viability under the conditions investigated. Taken together, our results indicate that the mPEG-PAE nanoparticle platform is attractive for drug delivery in different applications, including cancer.

Parallel fabrication of macroporous scaffolds

Scaffolds generated from naturally occurring and synthetic polymers have been investigated in several applications because of their biocompatibility and tunable chemo‐mechanical properties. Existing methods for generation of 3D polymeric scaffolds typically cannot be parallelized, suffer from low throughputs, and do not allow for quick and easy removal of the fragile structures that are formed. Current molds used in hydrogel and scaffold fabrication using solvent casting and porogen leaching are often single‐use and do not facilitate 3D scaffold formation in parallel. Here, we describe a simple device and related approaches for the parallel fabrication of macroporous scaffolds. This approach was employed for the generation of macroporous and non‐macroporous materials in parallel, in higher throughput and allowed for easy retrieval of these 3D scaffolds once formed. In addition, macroporous scaffolds with interconnected as well as non‐interconnected pores were generated, and the versatility of this approach was employed for the generation of 3D scaffolds from diverse materials including an aminoglycoside‐derived cationic hydrogel (“Amikagel”), poly(lactic‐co‐glycolic acid) or PLGA, and collagen. Macroporous scaffolds generated using the device were investigated for plasmid DNA binding and cell loading, indicating the use of this approach for developing materials for different applications in biotechnology. Our results demonstrate that the device‐based approach is a simple technology for generating scaffolds in parallel, which can enhance the toolbox of current fabrication techniques.

Chemotherapeutic Drug-Conjugated Microbeads Demonstrate Preferential Binding to Methylated Plasmid DNA

Plasmid DNA (pDNA) is an attractive therapeutic biomolecule in several diseases including cancer, AIDS, cystic fibrosis, Parkinsons disease, and Alzheimers disease. Increasing demand for plasmid DNA as a therapeutic biomolecule for transgene expression or vaccine applications necessitate novel approaches to bioprocessing. The synthesis, characterization and evaluation of aminoglycoside-derived hydrogel microbeads (Amikabeads) for pDNA binding is described previously. Here, the generation and evaluation of novel chemotherapeutic drug-conjugated microbeads for application in pDNA binding and recovery is described. Chemotherapeutic drug-conjugated Amikabeads demonstrate higher binding of methylated pDNA compared to unmethylated pDNA in presence of high salt concentrations. Desorption of plasmids from drug-conjugated microbeads is facilitated by the use of organic modifiers. The observed differences in binding methylated versus unmethylated DNA can make drug-conjugated microbeads useful in diagnostic as well as therapeutic applications. These results demonstrate that anti-cancer drugs represent a diverse set of ligands that may be exploited for molecular engineering of novel DNA binding materials for applications in delivery, diagnostics, and biomanufacturing.