Electronic Theses and Dissertations

Date of Award

1-1-2018

Document Type

Dissertation

Degree Name

M.S. in Pharmaceutical Science

Department

Pharmaceutics and Drug Delivery

First Advisor

Seongbong Jo

Second Advisor

Michael A. Repka

Third Advisor

Chalet Tan

Relational Format

dissertation/thesis

Abstract

Systemic administration of chemotherapeutics is associated with various side effects deriving from accumulation in off-target sites and acute toxicity of the drugs. In the past decade, engineering targeted drug delivery platforms arose as a novel paradigm to overcome such obstacles and ultimately achieve advanced forms of chemotherapy. This thesis reports successful syntheses of l-RSP, a redox-sensitive self-immolative polymer, and DNS-SN38, thiol-sensitive SN-38 prodrug, as potential candidates for targeted drug delivery platforms. By covalently conjugating a redox-trigger (p-nitrobenzyl alcohol) and self-immolative linker (p-hydroxybenzyl alcohol) to the cyclization spacer (n-2-(hydroxyethyl)ethylene diamine), a novel self-immolative monomer was obtained. Polymerization of the respective monomer yielded a linear redox-sensitive polymer (l-RSP) that is capable of systemic degradation via sequential 1,6-elimination and 1,5-cyclization reactions upon redox-stimulus. Ultimately, the polymer’s potential for biomedical application was simulated through in vitro redox-triggered release of paclitaxel from polymeric nanoparticles. SN-38 (7-ethyl-10-hydroxy-camptothecin), a potent metabolite of irinotecan (CPT-11), has been extensively investigated in the past for direct usage in order to fully exploit its cytotoxic potency. Here, 2,4-dinitrobenzene sulfonyl (DNS) moiety was conjugated to SN-38 to furnish a thiol-sensitive prodrug, denoted as DNS-SN38, that can be activated in the intracellular regions with GSH abundance. Furthermore, due to strong electron-withdrawing potential of DNS, the inherent fluorescence of SN-38 could be virtually quenched with intact conjugation. By investigating the prodrug’s activation property upon thiol-sensitive trigger cleavage via fluorescence activation and cytotoxicity against A2780 and mCherry+OCSC1-F2 cell lines, its vast potential as a viable theranostic agent was demonstrated.

Concentration/Emphasis

Emphasis: Pharmaceutics

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