Galactose-installed photo-crosslinked pH-sensitive degradable micelles for active targeting chemotherapy of hepatocellular carcinoma in mice.
In this study, we designed and developed galactose-installed photo-crosslinked pH-sensitive degradable micelles (Gal-CLMs) for active targeting chemotherapy of hepatocellular carcinoma in mice. Gal-CLMs were readily obtained from co-self-assembly of poly(ethylene glycol)-b-poly(mono-2,4,6-trimethoxy benzylidene-pentaerythritol carbonate-co-acryloyl carbonate) (PEG-b-P(TMBPEC-co-AC)) and Gal-PEG-b-poly(ε-caprolactone) (Gal-PEG-b-PCL) copolymers followed by photo-crosslinking. Notably, paclitaxel (PTX)-loaded Gal-CLMs (Gal-PTX-CLMs) showed a narrow distribution (PDI=0.08-0.12) with average sizes ranging from 92.1 to 136.3nm depending on the Gal contents. The release of PTX from Gal-CLMs while inhibited at physiological pH was enhanced under endosomal pH conditions. MTT assays in asialoglycoprotein receptor (ASGP-R) over-expressing HepG2 cells demonstrated that half-maximal inhibitory concentration (IC50) values of Gal-PTX-CLMs decreased from 11.7 to 2.9 to 1.1μg/mL with increasing Gal contents from 10% to 20% to 30%, supporting receptor-mediated endocytosis mechanism. The in vivo biodistribution studies in human hepatoma SMMC-7721 tumor-bearing nude mice displayed that Gal20-PTX-CLMs resulted in significantly enhanced drug accumulation in the tumors over non-targeting PTX-CLM counterpart. In accordance, Gal20-PTX-CLMs caused much greater tumor growth inhibition than non-targeting PTX-CLMs as well as non-crosslinking Gal20-PTX-NCLM controls (average tumor volume: ca. 35mm(3)versus 144mm(3) and 130mm(3), respectively). Histological analysis showed that Gal20-PTX-CLMs induced more extensive apoptosis of tumor cells while less damage to normal liver and kidney compared to Taxol. Ligand-installed photo-crosslinked pH-responsive degradable micelles have a great potential for targeted cancer chemotherapy.
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China.
Yan
Y
Zou
Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Medical College, Soochow University, Suzhou 215123, China.
Yuan
Y
Song
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China.
Weijing
W
Yang
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China. Electronic address: fhmeng@suda.edu.cn.
Fenghua
F
Meng
Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Medical College, Soochow University, Suzhou 215123, China.
Haiyan
H
Liu
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China. Electronic address: zyzhong@suda.edu.cn.
Zhiyuan
Z
Zhong
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001672:Biocompatible Materials / Q000138:chemical synthesis / Q000737:chemistry*; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D004339:Drug Compounding; D065546:Drug Liberation; D005690:Galactose / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008819:Mice, Nude; D008823:Micelles; D058990:Molecular Targeted Therapy; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D055668:Photochemical Processes; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D001672:Biocompatible Materials; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D008823:Micelles; D017239:Paclitaxel; D005690:Galactose
Crosslinked micelles; Degradable micelles; Galactose; Hepatocellular carcinoma; pH-sensitive