EGFR-targeted multifunctional polymersomal doxorubicin induces selective and potent suppression of orthotopic human liver cancer in vivo.
Fang Y1,Yang W1,Cheng L2*（程亮）,Meng F1*（孟凤华）,Zhang J1,Zhong Z1*（钟志远）
1 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, PR China.
2 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, PR China; Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China.
Acta Biomater.2017，64:323--333
Liver cancer is a globally leading malignancy that has a poor five-year survival rate of less than 20%. The systemic chemotherapeutics are generally ineffective for liver cancers partly due to fast clearance and low tumor uptake. Here, we report that GE11 peptide functionalized polymersomal doxorubicin (GE11-PS-DOX) effectively targets and inhibits epidermal growth factor receptor (EGFR)-positive SMMC7721 orthotopic human liver tumor xenografts in mice. GE11-PS-DOX with a GE11 surface density of 10% displayed a high drug loading of 15.4 wt%, a small size of 78 nm, and glutathione-triggered release of DOX. MTT assays, flow cytometry and confocal microscopy studies revealed that GE11-PS-DOX mediated obviously more efficient DOX delivery into SMMC7721 cells than the non-targeting PS-DOX and clinically used liposomal doxorubicin (Lipo-DOX) controls. The in vivo studies showed that GE11-PS-DOX had a long circulation time and an extraordinary accumulation in the tumors (13.3 %ID/g). Interestingly, GE11-PS-DOX caused much better treatment of SMMC7721 orthotopic liver tumor-bearing mice as compared to PS-DOX and Lipo-DOX. The mice treated with GE11-PS-DOX (12 mg DOX equiv./kg) exhibited a significantly improved survival rate (median survival time: 130 days versus 70 and 38 days for PS-DOX at 12 mg DOX equiv./kg and Lipo-DOX at 6 mg DOX equiv./kg, respectively) and achieved 50% complete regression. Notably, GE11-PS-DOX induced obviously lower systemic toxicity than Lipo-DOX. EGFR-targeted multifunctional polymersomal doxorubicin with improved efficacy and safety has a high potential for treating human liver cancers.
链接：https://www.ncbi.nlm.nih.gov/pubmed/29030307