Synergistic Approaches in Molecular and Nanoscale Therapeutics and Delivery Systems for Cancer Diseases

ChEMS Seminar

 

Speaker: Kaushal Rege, Ph.D.

Assistant Professor of Chemical Engineering

Graduate Faculty, Harrington Biomedical Engineering Program and Biological Design Program

Arizona State University

 

Cancer diseases place an enormous burden on the human condition. While surgery and radiation therapy are common primary interventions for localized disease, new developments in chemotherapy, gene therapy, immunotherapy, are under investigation in cases of recurrent, aggressive and metastatic disease. The complexity and heterogeneity associated with advanced cancer diseases manifest as multiple resistance mechanisms to treatment. This, in turn, necessitates approaches that act synergistically in order to overcome these resistances, leading to effective cancer cell death.

Research in my laboratory involves the discovery and delivery of synergistic treatments for enhancing the efficacy of molecular and nanoscale therapeutics in three related areas: (1) polymer-mediated gene delivery, (2) nanoparticle-induced hyperthermia, and (3) chemotherapeutic drug combinations, all focused on enhancing apoptosis (programmed suicide) of cancer cells.

Gene therapy involves the administration of genetic material in order to overcome the consequences due to genetic mutations that characterize several diseases, including cancer. Polymers are safer alternatives to viral delivery vectors, but polymer-mediated delivery typically suffers from low efficacies of protein expression. The bulk of this presentation will describe the synergistic use of materials discovery together with anti-cancer chemotherapeutic drugs for enhancing the efficacy of polymer-mediated gene delivery. We first employed combinatorial syntheses and parallel screening in order to rapidly synthesize and identify polymers that demonstrated higher transgene (e.g. GFP or luciferase) expression and lower cytotoxicities compared to current polymeric standards. At the sub-cellular level, escape from intracellular vesicles (endolysozomal compartments), transport in the cytoplasm, and nuclear entry are barriers that significantly limit the efficacy of polymeric delivery systems. Chemotherapeutic mediators that modulate intracellular trafficking, nuclear import, and cell cycle dynamics were therefore employed for overcoming these barriers leading to enhanced polymer-mediated transgene expression. This strategy, in which anti-cancer chemotherapeutic modulators were employed to increase the expression of the pro-apoptotic p53 protein, was employed to enhance cancer cell death.

As an orthogonal example of synergistic approaches, polymers developed in our laboratory were employed for enhancing adenovirus-mediated gene expression, and therefore death, in bladder cancer cells that resist viral infection. Finally, I will introduce our work on the discovery and nanoparticle-mediated delivery of clinically relevant chemotherapeutic drug combinations for ablation of prostate and pancreatic cancer cells. The use of microfluidic devices in facilitating this drug discovery process will also be briefly mentioned.

Our research demonstrates that a synergistic approach which combines molecular engineering and cancer cell biology can be employed for the discovery, optimization, and delivery of combination treatments leading to enhanced efficacies of molecular and nanoscale systems. Ongoing and future work involves detailed mechanistic elucidation of these findings and their evaluation using appropriate models in vivo.  Materials and mechanisms from our research also have the potential to impact other disciplines in medicine and biotechnology.

 

Biosketch:

Dr. Rege is an Assistant Professor of Chemical Engineering and a member of the graduate faculty in the Biomedical Engineering and Biological Design programs at Arizona State University (ASU) in Tempe, AZ.  Hegraduated with a B.Tech. in Chemical Engineering in 1998 from National Institute of Technology (NIT), Warangal, India. He received his Ph.D. in Chemical Engineering in 2004 from Rensselaer Polytechnic Institute (RPI) in Troy, NY.

Dr. Rege’s research at ASU is primarily in molecular and nanoscale bioengineering with applications in therapeutic discovery and delivery for cancer diseases. He has thirty-nine manuscripts either published or accepted for publication, in addition to three submitted, and several in preparation. He was co-editor of a book titled Methods in Bioengineering: Nanoscale Bioengineering and Nanomedicine, published by Artech House in 2009 and has co-edited thematic issues for journals. He is an Associate Editor of a new journal Nano LIFE and is on the editorial board of the Journal of Nanomedicine and Nanotechnology. Dr. Rege received a Young Investigator Award from the Defense Threat Reduction Agency (DTRA) and also an Outstanding Faculty Achievement Award in Chemical Engineering from ASU in 2010. Dr. Rege serves as PI on one NIH R01, three NIH R21, two NSF, one DTRA, and one Arizona Biomedical Research Commission (ABRC) awards. His students have won poster awards at the AIChE national conference, and he serves as co-chair of the graduate program in chemical engineering at ASU.