Access Type

Open Access Embargo

Date of Award

January 2020

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmaceutical Sciences

First Advisor

Arun Iyer

Abstract

Pancreatic ductal adenocarcinoma is the fourth leading cause of death in the US. Its survival rate is the lowest among other solid tumors due to several factors such as tumor microenvironments, low infiltrating cytotoxic cells, and the propensity of the tumor to metastasize and develop resistance against chemo and radiation therapy. Clinically, using a single agent in treating PDAC showed disappointing results. Therefore, combination therapies with different mechanisms of action are considered. Currently, gemcitabine is the centered of most combination therapies due to it is a cost-effective, well-tolerated, more effective than 5-fluorouracil (5-Flu) in terms of survival rate and showed modest activity in the patients refracted to 5-Flu. Using gemcitabine as a single agent or in combination with other agents such as cisplatin or Everolimus showed modest activity against PDAC. The reason for poor PDAC response to gemcitabine combination therapies might attributed to PDAC poor vasculature and cross-reaction between stroma and cancer cells with collagen deposition. The main goal of this study is to enhance the therapeutic benefit of gemcitabine via conjugating with SPDP-Peg4 grafted on the nanoparticles to (i) improve the systemic circulation time of gem and decrease the overall immunogenicity, (ii) reduce the nanoparticles aggregation and adsorption within the biological systems and (iii) decrease the toxicity of nanoparticles such as erythrocytes aggregation and hemolysis via minimizing nanoparticles – blood cells interactions. Also, gemcitabine anchored to targeted nanoparticles will overcome the hydrophobic drug's poor cellular penetration. The gemcitabine dual-targeted nanoparticles combined with Everolimus showed an excellently synergistic effect on PDAC cell lines and enhanced the tumor regression compared to commercials Gemcitabine + Everolimus.

Available for download on Tuesday, January 25, 2022

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