Graduation Date

Summer 8-17-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Ram I. Mahato

Abstract

The aims of this thesis is to first develop novel combination chemotherapies of two anticancer agents and their appropriate drug delivery platforms to treat chemoresistant prostate cancer, and second develop a polymeric conjugate of a biodegradable polymer and novel tubulin destabilizer to treat lung metastatic melanoma.

In Chapter 1, a general introduction of polymeric nanocarriers including polymeric micelles and polymer drug conjugates for cancer therapy was given. In Chapter 2, we described a combination therapy of paclitaxel (PTX) polymer conjugate and cyclopamine (CYP) polymer conjugate, which had the potential to treat chemoresistant prostate cancer. We first synthesized mPEG-b-PCC-g-PTX-g-DC (P-PTX) and mPEG-b-PCC-g-CYP-g-DC (P-CYP) polymer-drug conjugates, which they self-assembled into micelles. The combination of P-PTX and P-CYP alleviated PTX resistance and suppressed tumor colony formation. Further, combination therapy inhibited Hedgehog (Hh) signaling and upregulated tumor suppressor miRNAs. We established orthotopic prostate tumor in nude mice and there was significant tumor growth inhibition in the group treated with the combination therapy of P-PTX and P-CYP compared with monotherapy. In Chapter 3, we designed a novel microtubule destabilizer QW-296 and combined it with a newly synthesized Hh signaling inhibitor MDB5 to treat taxane-resistant prostate cancer. The combination of QW-296 and MDB5 exhibited stronger anticancer activity towards chemoresistant prostate cancer cells than single drug treatment, and the results revealed that they synergistically worked together via distinct but complementary mechanisms. To improve the translation and promote therapeutic efficacy of the two novel anticancer agents, we synthesized an amphiphilic copolymer mPEG-p(TMC-MBC) that could self-assemble into polymeric micelles and encapsulate two hydrophobic drugs with high drug loading. We established a model of orthotopic prostate tumor in nude mice to evaluate in vivo efficacy of QW-296, MDB5 and their combination. The results confirmed that combination of QW-296 and MDB5 in micelles showed maximum inhibition of tumor growth compared with monotherapy or combination therapy in co-solvent. In Chapter 4, we introduced a new microtubule destabilizer SMART-OH and its polymer-drug conjugate, methoxy-poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl-propylene carbonate-graft-SMART-graft-dodecanol) (abbreviated as P-SMART). Similar to its parent drug, P-SMART showed significant anticancer activity against melanoma cells in cytotoxicity, colony formation, and cell invasion studies. In addition, P-SMART treatment led to cell cycle arrest at G2/M phase and cell accumulation in sub-G1 phase. We established a model of metastatic melanoma to the lung in C57/BL6 albino mice to determine in vivo efficacy of P-SMART and SMART-OH at the dose of 20 mg/kg. P-SMART treatment resulted in significant inhibition of tumor growth and prolonged mouse median survival. In the end, Chapter 5 summarized the featured results of this thesis and gave some suggestions for future studies.

Available for download on Friday, July 26, 2019

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