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The pH-responsive micelles have enormouspotential as nanosizeddrug carriers for cancer therapy due to their physicochemical changesin response to the tumor intracellular acidic microenvironment. Herein,a series of comb-like amphiphilic copolymers bearing acetal-functionalizedbackbone were developed based on poly[(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl)ethane methacrylate-co-poly(ethylene glycol) methylether methacrylate] [P(TTMA-co-mPEGMA)] as effectivenanocarriers for intracellular curcumin (CUR) release. P(TTMA-co-mPEGMA) copolymers with different hydrophobic–hydrophilicratios were prepared by one-step reversible addition fragmentationchain transfer (RAFT) copolymerization of TTMA and mPEGMA. Their molecularstructures and chemical compositions were confirmed by 1H NMR, Fourier transform infrared spectroscopy (FT-IR) and gel permeationchromatography (GPC). P(TTMA-co-mPEGMA) copolymerscould self-assemble into nanosized micelles in aqueous solution anddisplayed low critical micelle concentration (CMC). All P(TTMA-co-mPEGMA) micelles displayed excellent drug loading capacity,due to the strong π–π conjugate action and hydrophobicinteraction between the PTTMA and CUR. Moreover, the hydrophobic PTTMAchain could be selectively hydrolyzed into a hydrophilic backbonein the mildly acidic environment, leading to significant swellingand final disassembly of the micelles. These morphological changesof P(TTMA-co-mPEGMA) micelles with time at pH 5.0were determined by DLS and TEM. The in vitro CUR release from themicelles exhibited a pH-dependent behavior. The release rate of CURwas significantly accelerated at mildly acidic pH of 4.0 and 5.0 comparedto that at pH 7.4. Toxicity test revealed that the P(TTMA-co-mPEGMA) copolymers exhibited low cytotoxicity, whereasthe CUR-loaded micelles maintained high cytotoxicity for HepG-2 andEC-109 cells. The results indicated that the novel P(TTMA-co-mPEGMA) micelles with low CMC, small and tunable sizes,high drug loading, pH-responsive drug release behavior, and good biocompatibilitymay have potential as hydrophobic drug delivery nanocarriers for cancertherapy with intelligent delivery. [ABSTRACT FROM AUTHOR]