Date on Master's Thesis/Doctoral Dissertation

12-2014

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Committee Chair

Frieboes, Hermann Bueno

Committee Co-Chair (if applicable)

Ceresa, Brian

Committee Member

Steinbach, Jill

Committee Member

O’Toole, Martin

Committee Member

Cunningham, Albert

Subject

Drug delivery devices; Nanoparticles--Medical aspects; Cancer--Treatment

Abstract

Nano-scale particles sized 10—400 nm administered systemically preferentially extravasate from tumor vasculature due to the enhanced permeability and retention effect. Therapeutic success remains elusive, however, because of inhomogeneous particle distribution within tumor tissue. Insufficient tumor vascularization limits particle transport and also results in avascular hypoxic regions with non-proliferating cells, which can regenerate tissue after nanoparticle-delivered cytotoxicity or thermal ablation. In this study, gold nanoparticles were functionalized with phosphatidylcholine (two-layer) or phosphatidylcholine and HDL (three-layer) in the formation of “layered” nanoparticles. The diffusivity of both two- and three layered colloidal gold nanoparticles and silica gold nanoshells were examined in 3D cell cultures. Both two- and three layered nanoparticles showed enhanced diffusivity in comparison to previously developed PEGylated nanoparticles. As the two layer nanoparticles displayed enhanced diffusivity in comparison to three layer nanoparticles, the two layered nanoparticles were further examined in vivo using mice implanted with orthotopic pancreatic adenocarcinomas. The two layer colloidal gold nanoparticles showed enhanced diffusivity in comparison to silica gold nanoshells in vivo, suggesting that smaller nanoparticles were able to localize and diffuse from vasculature better than larger nanoparticles. Overall accumulation of solid gold nanoparticle accumulated in the tumor and filtering organs (liver and spleen) was 2X higher than silica gold nanoshells. Thus, two layer colloidal gold nanoparticles were loaded with cisplatin or paclitaxel to determine optimal drug release kinetics. Drug release from paclitaxel-loaded nanoparticles displayed a slower release while cisplatin-loaded nanoparticles experienced an initial burst of drug release followed by a slower release of remaining drug. Lastly, drug-loaded colloidal gold nanoparticles were tested in 3D cell cultures to determine their cytotoxicity. Both two and three layer nanoparticles loaded with cisplatin orpaclitaxel showed similar efficacy to drug alone, suggesting their viable use in vivo for cancer treatment. This study has demonstrated the potential use of layered nanoparticles for increasing the delivery of chemotherapeutics deeper into tumor tissue.

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