Abstract
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 amino 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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the third leading cause of cancer-related mortality with more than 700,000 deaths occurring every year [1]
The mPEG-b-PGA diblock copolymer was prepared by deprotecting the benzyl group in mPEG-b-PBLG, which was synthesized through the ring-opening polymerization (ROP) of benzyl-L-glutamate N-carboxyanhydride (BLG NCA) with mPEG-NH2 as a macroinitiator
The pH-sensitive mPEG-b-PGA/EPI could be developed through a dialysis method by the combination of electrostatic and hydrophobic interactions to efficiently treat HCC
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the third leading cause of cancer-related mortality with more than 700,000 deaths occurring every year [1]. The five-year survival rate has been improved greatly with the development of diagnostic techniques and surgical intervention, the percentage of patients who can get effective therapy remains low [2]. For most of the HCC patients presenting the advanced stages at diagnosis, chemotherapy is an important treatment protocol to extend the survival [3]. The molecularly targeted therapies attract much attention in the advanced HCC, which may benefit the efficacy of chemotherapy. 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]. Some more effective therapeutic strategies are urgently needed for the treatment of HCC
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