Synergistic Approaches in Molecular and Nanoscale Therapeutics and Delivery Systems for Cancer Diseases
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Rege, Kaushal
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Abstract
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) polymermediated
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. I will also briefly introduce our research on
gold nanorod-polypeptide based plasmonic "nanomatrices" which are capable of
simultaneously administering hyperthermia and chemotherapeutic drugs for ablation of
cancer cells. Finally, I will introduce our work on the discovery and nanoparticle-mediated
delivery of clinically relevant chemotherapeutic sensitizers of TRAIL-induced apoptosis in
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 (bio)materials chemistry 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 several disciplines in medicine and biotechnology.
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Date
2011-10-12
Extent
62:30 minutes
Resource Type
Moving Image
Resource Subtype
Lecture