Date of Completion

4-26-2019

Embargo Period

4-21-2021

Keywords

Nanoparticles, Cancer, Bioresponsive, Doxorubicin

Major Advisor

Xiuling Lu

Associate Advisor

Diane Burgess

Associate Advisor

Rajeswari Kasi

Associate Advisor

José Manautou

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Polymeric nanoparticles from amphiphilic copolymers are deemed as flexible platforms for effective delivery of chemotherapeutic drugs to tumor tissues. The use of cholesterol as the hydrophilic segment can confer stability upon dilution and high drug loading capacity to these type of nanoparticles due to the tendency of cholesteryl groups to aggregate and form liquid crystal phases. On the other hand, the incorporation of polyethylene glycol as the hydrophilic block provides colloidal stability and reduced opsonization. Building on previous research in the laboratory, the overall goal of the present dissertation was to further advance the development and understanding of novel and rationally designed cholesterol-based polymeric nanoparticles as delivery systems to improve the therapeutic index of highly toxic anticancer drugs.

Two types of cholesterol-based nanoparticles encapsulating the anticancer drug doxorubicin were developed and comprehensively evaluated in this study. The first type, formed by an amphiphilic brush-like block copolymer, displayed significant tumor growth inhibitory activity in a mouse model and an improved safety profile compared to the free form of the drug. However, slow drug release seemed to prevent this formulation from displaying better efficacy results.

As a solution to the drug release pitfall, a second type of nanoparticle was developed, incorporating a cleavable (redox-sensitive) disulfide bond in the polymer structure to facilitate bioresponsive drug release inside cancer cells overexpressing the reducing scavenger molecule glutathione. Evidence of the significant influence of the method of preparation on the characteristics and performance of these doxorubicin-loaded redox-sensitive polymeric nanoparticles was observed, underlying the relevance of implementing systematic approaches like quality by design (QbD) to the development of nanomedicines. On the other hand, proof of the cleavable nature of these second-generation nanoparticles and superior in vitro performance compared to the non-cleavable platform was obtained, as well as evidence of their in vivo efficacy and improved safety profile when evaluated against free doxorubicin (DOX-HCl) and the commercial pegylated liposomal form (Doxil®)

These findings support future translational efforts regarding the developed redox-sensitive cholesterol-based polymeric nanoparticles as carriers to improve the therapeutic index of toxic chemotherapeutic drugs, particularly in the context of personalized medicine.

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