Intracellular thiol-responsive nanosized drug carriers self-assembled by poly(ethylene glycol)-b-poly( -caprolactone)-b-poly(ethylene glycol) having multiple bioreducible disulfide linkages in hydrophobic blocksElectronic supplementary information (ESI) available. See DOI: 10.1039/c5ra25319e

To achieve effective intracellular drug release from nanostructures, we designed high molecular weight (HMW) reducible poly( -caprolactone) (PCL) structures synthesized by a coupling reaction between the low molecular weight (LMW) PCL diol and a single disulfide-containing dicarboxylic acid. The synthesized HMW-reducible PCL (RSPCL) polymers with approximately 7 disulfide bonds were further linked with methoxy poly(ethylene glycol) (mPEG), resulting in mPEG- b -RSPCL- b -mPEG (mPEG-RSPCL) copolymers. In aqueous environments, the mPEG-RSPCL copolymers were self-assembled to construct nanoparticles (NPs) of less than 100 nm with nearly neutral zeta-potentials, and the NPs had negligible cytotoxicity below 0.2 mg mL −1 . In a thiol-rich environment (10 mM), mPEG-RSPCL NPs increased in size over time, and their polymer components completely degraded to mPEG and LMW PCL derivatives. The mPEG-RSPCL NPs were able to load both water-soluble doxorubicin hydrochloride (DOX·HCl) and water-insoluble doxorubicin (DOX). Based on different cellular uptakes of free drugs and drug-loaded NPs in HeLa and HepG2 cells, DOX·HCl-loaded mPEG-RSPCL NPs showed approximately 1.7-3.6-fold and 20-fold higher anti-tumor effects than free DOX·HCl and DOX-loaded mPEG-RSPCL NPs, respectively. Additionally, DOX-mPEG-RSPCL NPs represented similar or lower drug efficacy than free DOX. Especially, DOX·HCl-loaded mPEG-RSPCL NPs represented superior thiol-triggered drug release and killing effects than their control NPs having fewer or no disulfide bonds. In conclusion, the designed mPEG-RSPCL NPs are potentially useful as nanosized drug carriers for the effective intracellular release of hydrophilic and hydrophobic drugs in the cytosol and/or nucleus. Intracellular thiol can trigger effective drug release from polymeric nanoparticles having multiple disulfide linkages in the hydrophobic domain.