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Date of Award

9-2010

Document Type

Campus Access

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Polymer Science and Engineering

First Advisor

Todd S. Emrick

Second Advisor

Murugappan Muthukumar

Third Advisor

Lawrence M. Schwartz

Subject Categories

Polymer Chemistry

Abstract

Modern polymer research is uncovering new materials for biomedical applications. This thesis centers on novel polymer syntheses towards anti-cancer therapeutics termed polymer "pro-drugs". In particular, aliphatic polyesters are potentially useful for drug delivery due to their biocompatibility and biodegradability. However, conventional aliphatic polyesters lack functionality. Incorporating functionality into aliphatic polyesters carries the potential to tailor their properties, and provides a method to attach drugs covalently. There are significant challenges associated with aliphatic polyester functionalization due to side-reactions including degradation of the polymer backbone. To overcome this challenge, alkyne functionalized lactones were synthesized, and click cycloaddition chemistry was employed to covalently attach novel azides to these alkyne containing aliphatic polyesters.

A novel trimethylsilane protected alkyne d-valerolactone was synthesized and used in the preparation of block copolymers allowing for orthogonal functionalization strategies. Tin (II) mediated ring-opening polymerization of the lactones led to aliphatic polyesters with a narrow molecular weight distribution that had pendent alkynes available for post-polymerization chemistry.

Click cycloaddition chemistry afforded water-soluble aliphatic polyesters by attaching PEGylated and zwitterionic azides to the polymer backbone. Novel phosphorylcholine and phosphobetaine-azides were prepared and grafted to the polyester chain.

Camptothecin (CPT), an anti-cancer drug, was covalently attached to the aliphatic polyesters through a variety of covalent linkers. High pressure liquid chromatography (HPLC) was used to examine the release of CPT from the pro-drugs. With some of the linkers, CPT was seen to release from the aliphatic polyester with half-lives of 2-4 hours in human plasma. Physicochemical characterization techniques, including light scattering and atomic force microscopy (AFM), were used to investigate the properties of the polymeric pro-drug micelles. These micelles were approximately 60-120 nm in hydrodynamic radius. In vitro assays with MCF7 (breast cancer) and COLO205 (colorectal cancer) cells were used to evaluate the cytotoxicity of the polymers pro-drugs. IC50 values as low as 4 μM in COLO205 cells indicated the release of CPT in its cytotoxic form, and the potential of these aliphatic polyesters to function as a drug delivery platform.

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