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Reduction-sensitive reversibly core-cross-linked micellesweredeveloped based on poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide)–lipoic acid (PEG-b-PHPMA-LA) conjugates and investigated for triggered doxorubicin(DOX) release. Water-soluble PEG-b-PHPMA block copolymerswere obtained with Mn,PEGof 5.0 kg/moland Mn,HPMAvarying from 1.7 and 4.1 to7.0 kg/mol by reversible addition–fragmentation chain transfer(RAFT) polymerization. The esterification of the hydroxyl groups inthe PEG-b-PHPMA copolymers with lipoic acid (LA)gave amphiphilic PEG-b-PHPMA-LA conjugates with degreesof substitution (DS) of 71–86%, which formed monodispersedmicelles with average sizes ranging from 85.3 to 142.5 nm, dependingon PHPMA molecular weights, in phosphate buffer (PB, 10 mM, pH 7.4).These micelles were readily cross-linked with a catalytic amount ofdithiothreitol (DTT). Notably, PEG-b-PHPMA(7.0k)-LAmicelles displayed superior DOX loading content (21.3 wt %) and loadingefficiency (90%). The in vitro release studies showed that only about23.0% of DOX was released in 12 h from cross-linked micelles at 37°C at a low micelle concentration of 40 μg/mL, whereasabout 87.0% of DOX was released in the presence of 10 mM DTT underotherwise the same conditions. MTT assays showed that DOX-loaded core-cross-linkedPEG-b-PHPMA-LA micelles exhibited high antitumoractivity in HeLa and HepG2 cells with low IC50(half inhibitoryconcentration) of 6.7 and 12.8 μg DOX equiv/mL, respectively,following 48 h incubation, while blank micelles were practically nontoxicup to a tested concentration of 1.0 mg/mL. Confocal laser scanningmicroscope (CLSM) studies showed that DOX-loaded core-cross-linkedmicelles released DOX into the cell nuclei of HeLa cells in 12 h.These reduction-sensitive disassemblable core-cross-linked micelleswith excellent biocompatibility, superior drug loading, high extracellularstability, and triggered intracellular drug release are promisingfor tumor-targeted anticancer drug delivery. [ABSTRACT FROM AUTHOR]