Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemical and Biomolecular Engineering

First Advisor

Daniel A. Hammer

Abstract

The field of drug delivery is rapidly expanding to bridge the gap between novel drugs that are created and their effective entry into diseased tissue. In one growing area of research, synthetic polymers are being utilized to meet these needs. The precise control over their chemistry allows polymers to be tuned to the drug delivery application and make them attractive candidates for research. The focus of this dissertation is to engineer responsive polymersomes for drug delivery and understand their ability to reduce drug toxicity, increase absorption in diseased cells and tissue, and control the release of drug in vitro and in vivo. Gemcitabine, a nucleoside analog, was encapsulated in the aqueous core of nano-polymersomes composed of the biodegradable and biocompatible polymer PEO-PCL, and the in vitro toxicity of this novel drug delivery construct was tested against Panc-1 cells. The polymersome formulation performed at par with the free drug with one-log cell killing at 1 ìM of gemcitabine. The polymersome was also able to control the release of gemcitabine, and this release was modulated by the degradation kinetics of the ester linkages in the membrane. Photodynamic therapy was performed against OVCAR-5 (ovarian cancer) cells. A hydrophobic photosensitizer, benzoporphrin derivative monoacid A (BPD-MA) was encapsulated the in the membrane of polymersomes composed of PEO14-PBD22 (OB14.5) polymer, and its phototoxicity was compared to an existing photosensitizer formulation called verteporfin that is currently used in the clinic for age-related macular degeneration (AMD). The polymersome formulation outperformed verteporfin both at the in vitro and in vivo level. Additionally, we investigated the photorupture of giant polymersomes encapsulating a near IR fluorophore (porphyrin dimer, PZn2) in the hydrophobic membrane and dextran in the aqueous lumen. Polymersomes synthesized from softer polymers released more of a reporter dye than stiffer polymersomes when illuminated with 690 nm of light. Finally, we investigated the fractionation of giant polymersomes in a deterministic lateral displacement device and developed a hydrodynamic model to predict this fractionation based on the attractive and repulsive forces experienced by the polymersome.

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