Title

Crosslinked Polycyclodextrin Oligomers as Potential Anticancer Drug Carriers

Date of Award

2020

Document Type

Thesis

Degree Name

Master of Science in Chemistry, Straight Program

Department

Chemistry

First Advisor

Nina Rosario L. Rojas, PhD Gilbert U. Yu, PhD

Abstract

Cyclodextrin-based drug carriers have been extensively studied for the past decades due to the oligosaccharide’s ability to form inclusion complexes with hydrophobic guest molecules, improving the guest’s apparent solubility and prolonging its release for better biodistribution in pharmaceutical applications. While cyclodextrin blends and graft materials are utilized for various applications such as in drug delivery systems, polymeric matrices bound physically or covalently to cyclodextrins lowers the effective inclusion capability of the materials. Therefore, exploration of crosslinked cyclodextrin polymers which do not involve any material carrier is warranted to synthesize high cyclodextrin content materials. In this study, crosslinked 2-hydroxypropyl cyclodextrin (HPβCD) oligomers were synthesized using butanetetracarboxylic acid (BTCA), a non- halogenated and non-carcinogenic organic crosslinker, to become carriers of the anticancer drug 5-fluorouracil (5FU). Polyesterification between HPβCD’s hydroxyl groups and the crosslinkers’ carboxyl moieties at elevated temperatures yielded water-soluble polycyclodextrin oligomers. FT-IR spectroscopy showed through the presence and shifts of the carbonyl stretching peak that polyesterification has happened between cyclodextrin units and the crosslinker. FT-NMR analysis using 1 H NMR and 13C NMR experiments corroborated the IR findings of successful esterification. 1 H-NMR peak integration revealed that the 1:3 HPCD:BTCA treatment has 67.93% mass HPβCD content. Thermogravimetric Analysis reinforced FTIR and NMR findings of BTCA being present in the material by showing temperature ranges that may correspond to further esterification and decarboxylation in the material. Inclusion complexes between the oligomers and 5FU were synthesized using lyophilization. Through signal shifts and interspectral correlations, 1 H-NMR and 2D NOESY NMR experiments showed formation of inclusion complexes between the oligomers and 5FU. In vitro drug release profile of the 5FU-loaded oligomers through diafiltration at physiological conditions showed that the polycylodextrin oligomer-5 FU inclusion complexes prolonged the release of 5FU longer than the monomeric HPβCD -5FU inclusion complexes. The cytotoxicity of the polycyclodextrin oligomers and their corresponding inclusion complexes with 5FU were evaluated using MTT cell proliferation assay against HCT116 colorectal cancer cells. The oligomers were found to be have significantly higher HCT116 cell viability than their monomeric counterparts. The oligomers loaded with 5FU were also shown to be less cytotoxic than equivalent amounts of free 5-FU after 24 hours, but exhibited similar toxicity after 36 hours, suggesting that prolonged release was facilitated by the polycyclodextrin oligomers.

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