Lung cancer specific and reduction-responsive chimaeric polymersomes for highly efficient loading of pemetrexed and targeted suppression of lung tumor in vivo
Weijing Yang a, Liang Yang a, Yifeng Xia a, Liang Cheng a,b,*（程亮）, Jian Zhang a, Fenghua Meng a, *（孟凤华）, Jiandong Yuan c, Zhiyuan Zhong a,*（钟志远）
a 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
b Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China
c BrightGene Bio-Medical Technology Co., Ltd., Suzhou 215123, PR China
Acta Biomaterialia 70 (2018) 177--185
Lung cancer is one of the worldwide leading and fast-growing malignancies.Pemetrexed disodium(PEM, Alimta®), a small hydrophilic drug, is currently used for treating lung cancer patients. However, PEM suffers from issues like fast elimination, low bioavailability, poor tumor cell selectivity and penetration. Here, we report on lung cancer specific CSNIDARAC (CC9) peptide-functionalized reduction-responsive chimaeric polymersomes (CC9-RCPs) for efficient encapsulation and targeted delivery of PEM to H460 human lungcancer cellsin vitroandin vivo. PEM-loaded CC9-RCPs (PEM-CC9-RCPs) was obtained from co-self-assembly of poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) and CC9-functionalized PEG-P(TMC-DTC) in the presence of PEM followed by self-crosslinking. PEM-CC9-RCPs displayed an optimal CC9density of 9.0% in targeting H460 cells, a high PEM loading content of 14.2 wt%, a small hydrodynamic size of ca. 60 nm and glutathione-triggered PEM release.MTT assaysshowed that PEM-CC9-RCPs was 2.6- and 10- fold more potent to H460 cells than the non-targeting PEM-RCPs and free PEM controls, respectively. Interestingly, PEM-CC9-RCPs exhibited 22-fold longer circulation time and 9.1-fold higher accumulation in H460 tumor than clinical formulation Alimta®. Moreover, CC9-RCPs showed obviously better tumor penetration than RCPs. Remarkably, PEM-CC9-RCPs at 12.5 mg PEM equiv./kg effectively suppressed growth of H460 xenografts and significantly prolonged mouse survival time as compared to PEM-RCPs and Alimta® controls. These lung cancer specific and reduction-responsive chimaeric polymersomes provide a unique pemetrexed nanoformulation for targeted lung cancer therapy.
链接：https://www.sciencedirect.com/science/article/pii/S1742706118300266?via%3Dihub