Development of Micellar Novel Drug Carrier Utilizing Temperature-Sensitive Block Copolymers Containing Cyclodextrin Moieties

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Abstract

A drug-delivery system for albendazole (ABZ) based on β-cyclodextrin has been synthesized. Well-defined statistical copolymers, composed of N-isopropylacrylamide (NIPAAM) and trimethylsilylpropargyl acrylate (TMSPA), have been prepared by reversible addition–fragmentation chain transfer (RAFT) polymerization. The reactivity ratios were determined to be rTMSPA = 1.12 and rNIPAAm = 0.49, in the absence of RAFT agent, and rTMSPA = 1.35 and rNIPAAm = 0.35, in the presence of RAFT agent using the average of different techniques. Block copolymers were prepared using a POEGMEA40 macro-RAFT agent chain extended with NIPAAm and TMSPA in various feed ratios. After deprotection, the polymers were reacted with 6I-azido-6I-deoxy-β-cyclodextrin via Huisgen azide–alkyne 1,3-dipolar cycloaddition, resulting in thermo-responsive block copolymers with pendant β-cyclodextrin groups, which were then acetylated to modify the polarity and inclusion-complex formation of β-cyclodextrin with the drug albendazole (ABZ). Only block copolymers with small amounts of cyclodextrin were observed to have an LCST while the copolymers containing higher β-cyclodextrin fractions increased the LCST of PNIPAAm beyond measurable temperature ranges. Encapsulation of ABZ increased the LCST. The loading efficiency increased in the polymer β-cyclodextrin conjugate compared to native β-cyclodextrin with the highest loading observed in the block copolymer after all remaining cyclodextrin hydroxyl groups had been acetylated. While β-cyclodextrin is toxic, attachment of a polymer lowered the toxicity to nontoxic levels. The ABZ-loaded polymers were all observed to be highly toxic to OVCAR-3 ovarian cancer cell lines with the acetylated polymer showing the highest toxicity.

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