Biocompatible and bioreducible micelles fabricated from novel α-amino acid-based poly(disulfide urethane)s: design, synthesis and triggered doxorubicin release

Abstract

α-Amino acid-based functional biopolymers are highly appealing for various biomedical applications including controlled drug delivery. In this paper, we report the design and development of novel reductively biodegradable α-amino acid-based poly(disulfide urethane)s, denoted as AAPU(SS)s, as well as PEG-AAPU(SS)-PEG triblock copolymer micelles for triggered intracellular doxorubicin (DOX) release. AAPU(SS)s were synthesized with controlled M_n ranging from 4.6 to 35.7 kg mol⁻¹via polycondensation reaction between two α-amino acid derivatives, disulfide-linked bis(ethyl L-serinate) (SS-BSER) and L-lysine ethyl ester diisocyanate (LDI). AAPU(SS)s are amorphous with a glass transition temperature (T_g) of 31.7–49.2 °C and were degraded into low molecular weight fragments under a reductive condition. PEG-AAPU(SS)-PEG copolymer could be readily obtained by treating AAPU(SS) with mPEG-NCO. PEG-AAPU(SS)-PEG formed micelles with a mean diameter of 155 nm. The in vitro release studies showed that drug release from DOX-loaded PEG-AAPU(SS)-PEG micelles was significantly accelerated in the presence of 10 mM glutathione (GSH). MTT assays revealed that DOX-loaded PEG-AAPU(SS)-PEG micelles caused effective growth inhibition of both RAW 264.7 and drug resistant MCF-7 cells (MCF-7/ADR) while the corresponding blank micelles were non-cytotoxic even at a high concentration of 1.0 mg mL⁻¹. Confocal microscopy showed that PEG-AAPU(SS)-PEG micelles efficiently transported and released DOX into the perinuclear and nuclear regions of MCF-7/ADR cells. These biocompatible and bioreducible α-amino acid-based poly(disulfide urethane) micelles have appeared to be a particularly interesting platform for triggered intracellular anticancer drug delivery.