Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Epirubicin (EPI) once acted as a main agent for HCC chemotherapy. However, the dosage-dependent side effects seriously limit its application in clinic. The purpose of this study is to develop an effective nanocarrier to improve the efficacy and overcome the limitations of EPI. In this regard, the EPI-complexed micelle (i.e., mPEG-b-PGA/EPI) was prepared via the electrostatic interaction between the

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... mino group in EPI and the carboxyl group in PGA segment of methoxy poly(ethylene glycol)-block-poly(L-glutamic acid) (mPEG-b-PGA), and the subsequent hydrophobic interaction among PGA/EPI complexes. The micelle appeared spherical with a diameter at around 90 nm and possessed a pH-sensitive release property of payload. The cytotoxicity and hemolysis assays in vitro, and the maximum tolerated dose tests in vivo confirmed that mPEG-b-PGA was a kind of safe material with excellent biocompatibility, while the drug-loaded micelle could obviously improve the tolerance of EPI. In addition, mPEG-b-PGA/EPI possessed significantly enhanced antitumor efficacy and security toward the H22-xenografted HCC murine model at macroscopic and microscopic levels compared with free EPI. All these results strongly indicate that mPEG-b-PGA/EPI may be a promising nanoplatform for EPI delivery in the chemotherapy of HCC. of chemotherapy agents [4] . Recently, the molecularly targeted therapies attract much attention in the advanced HCC, which may benefit the efficacy of chemotherapy. However, sorafenib, a first-line treatment agent for the advanced HCC, only upregulates the median survival time by no more than three months compared to placebo, and the phase III clinical trials of other molecularly targeted therapeutic agents even fail to reach the expected efficacy [5, 6] . Therefore, some more effective therapeutic strategies are urgently needed for the treatment of HCC. Nanomedicine, as an emerging pharmacy, provides a potential solution to exceed the limitations of traditional chemotherapy agents [4] . Especially, the polymeric nanoparticles, which are more stable, and possess higher drug loading content (DLC) and drug loading efficiency (DLE) than the other nanocarriers like liposome and protein nanoparticle, may be an ideal choice for controlled agent delivery [7] . With nanoscale dimension and the protection from biocompatible macromolecule, the nanoscale polymeric nanomedicines show the optimized pharmacokinetics than free ones [7] . In addition, the polymeric nanomedicines exhibit more accumulation of agents in tumor site via the enhanced permeability and retention (EPR) effect and/or active targeting strategies [7, 8] . What is more, the stimuli-sensitive nanoparticles designed based on intratumoral or intracellular microenvironment can realize the smart release of therapeutic agents, which achieve quick release in targeted areas while slow or even no release in peripheral circulation [9] . Thus, the efficacies are improved, and the systemic toxicities of chemotherapy are reduced greatly. The amphiphilic block copolymers could self-assemble into micelles in aqueous media forming a shell-core structure and acting as an important kind of polymeric nanocarriers [10]. The hydrophilic shell is able to form an effective protection from plasma proteins, which decrease the clearance of nanoparticle by the reticuloendothelial system (RES), and realize the prolonged circulation half-life [11] . Meanwhile, an effective drug encapsulation can be achieved by the hydrophobic core as a reservoir. With these properties, the nanoscale polymeric micelles could significantly improve the water solubility of hydrophobic drugs, such as curcumin and paclitaxel [12, 13] . Among the amphiphilic matrices of micelles, the polypeptide-based copolymers have been a research hotspot for their excellent biodegradability, precise secondary structures, and facile modifiability [14, 15] . There are many studies have verified the security and effectiveness of such copolymer-based drug-loaded micelles in the chemotherapy of various tumors, including HCC, and so on [16] [17] [18] . Once acting as a main agent for HCC chemotherapy, epirubicin (EPI) exerts cytotoxic effect through disturbing the deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) syntheses, and suppressing topoisomerase II (Topo II). However, the relevant side effects, especially cardiotoxicity, seriously limit its application in clinic [19] . In recent years, there were several successful examples in HCC treatment by employing the EPI-loaded micelles to improve efficacies and reduce systemic toxicities [18, 20] . However, it is worth noted that the loading procedures of hydrophobic drugs involve the use of organic solvents, which may potentially do harm to human bodies [16] . To address this problem, the utilization of electrostatic interaction between cationic drugs, such as EPI and doxorubicin (DOX), and anionic polymers in aqueous media may be a promising approach, and a few attempts have been succeeded [16, 21] . More meaningfully, the drug-loaded micelles based on this technique show pH-sensitive dissociation and can realize the targeting cargo delivery to tumor tissue or cells, where the microenvironment is acidic [16, 22] . In this study, the diblock methoxy poly(ethylene glycol)-block-poly(L-glutamic acid) (mPEG-b-PGA) copolymer was synthesized through the ring-opening polymerization (ROP) of γ-benzyl-L-glutamate N-carboxyanhydride (BLG NCA) initiated by the amino-terminated mPEG (mPEG-NH 2 ) and the subsequent deprotection of benzyl group in the BLG unit. Then, for treatment of HCC, the EPI-loaded micelle (i.e., mPEG-b-PGA/EPI) was prepared via electrostatic interaction between cationic EPI and anionic mPEG-b-PGA, and subsequent intramolecular and intermolecular hydrophobic interactions among PGA/EPI complex segments (Scheme 1). Then, the pH-sensitive EPI release, effective cellular uptake, time-and concentration-dependent cytotoxicity, and good hemocompatibility in vitro, and elevated maximum tolerated dose (MTD), improved