Multimodal Therapeutic Strategy for Pancreatic Cancer: EGFR-Targeted Gelatin-Based Nanoparticles for Combination Wild-Type p53 Gene and Cytotoxic Drug Delivery

Pancreatic adenocarcinoma is the fourth lethal cancer in the United States. Many therapeutic strategies such as the chemotherapy and gene therapy have been applied as therapeutic reagents. However, there are still many limitations for ideal therapeutic outcome, which reflect drug resistance, inefficient delivery and short residence in tumor. Urgent need exists for development of novel therapeutic strategies, which could improve the dismal survival statics for pancreatic cancer patients.;The main objective of this doctoral dissertation was to develop a novel combination therapeutic strategy with wild-type p53 plasmid DNA and gemcitabine for pancreatic cancer. For gene therapy, the major hurdle is to develop a safe and efficient delivery system. To address this problem, we have developed epidermal growth factor receptor (EGFR) targeting peptide-modified thiolated gelatin nanoparticles for active targeting on cancer cells, which have high expression of EGFR receptors. This delivery system was proven to protect the intact structure of genetic material, efficiently deliver genetic material, specifically target on tumor and successfully transfect target cells.;To further enhance therapeutic efficacy, the first-line chemotherapeutic compound gemcitabine was chosen and conjugated to thiolated gelatin polymer through specific disulfide bond between two molecules. Drug-polymer conjugates were used for synthesis of nanoparticles. Combination treatments with both wt-p53 and gemcitabine nanoparticles showed significantly higher cytotoxicity compared to single treatments. In vivo studies have also proven that combinational therapeutic strategy with EGFR-targeted thiolated gelatin nanoparticles has the best efficacy for induction of apoptosis and tumor growth inhibition. This study has shown that EGFR-targeted gelatin nanoparticles can serve as a safe and efficient delivery system for combination gene and drug therapy for pancreatic cancer.