PMID- 29410335 OWN - NLM STAT- MEDLINE DCOM- 20190509 LR - 20220331 IS - 1878-7568 (Electronic) IS - 1742-7061 (Linking) VI - 70 DP - 2018 Apr 1 TI - Lung cancer specific and reduction-responsive chimaeric polymersomes for highly efficient loading of pemetrexed and targeted suppression of lung tumor in vivo. PG - 177-185 LID - S1742-7061(18)30026-6 [pii] LID - 10.1016/j.actbio.2018.01.015 [doi] AB - Lung cancer is one of the worldwide leading and fast-growing malignancies. Pemetrexed disodium (PEM, Alimta(R)), 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 (CC(9)) peptide-functionalized reduction-responsive chimaeric polymersomes (CC(9)-RCPs) for efficient encapsulation and targeted delivery of PEM to H460 human lung cancer cells in vitro and in vivo. PEM-loaded CC(9)-RCPs (PEM-CC(9)-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 CC(9)-functionalized PEG-P(TMC-DTC) in the presence of PEM followed by self-crosslinking. PEM-CC(9)-RCPs displayed an optimal CC(9) density 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 assays showed that PEM-CC(9)-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-CC(9)-RCPs exhibited 22-fold longer circulation time and 9.1-fold higher accumulation in H460 tumor than clinical formulation Alimta(R). Moreover, CC(9)-RCPs showed obviously better tumor penetration than RCPs. Remarkably, PEM-CC(9)-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(R) controls. These lung cancer specific and reduction-responsive chimaeric polymersomes provide a unique pemetrexed nanoformulation for targeted lung cancer therapy. STATEMENT OF SIGNIFICANCE: Multitargeted antifolate agent pemetrexed (PEM, Alimta(R)) is currently used for treating lung cancer patients and has low side-effects. However, PEM suffers from issues like fast elimination, low bioavailability, poor tumor cell selectivity and penetration. Scarce work on targeted delivery of PEM has been reported, partly because most conventional nanocarriers show a low and instable loading for hydrophilic, negatively charged drugs like PEM. Herewith, we report on lung cancer specific CSNIDARAC (CC(9)) peptide-functionalized reduction-responsive chimaeric polymersomes (CC(9)-RCPs) which showed efficient PEM encapsulation (14.2 wt%, 60 nm) and targeted delivery of PEM to H460 human lung cancer cells, leading to effective suppression of H460 tumor xenografts and significantly prolonged survival rates of mice than Alimta(R). To the best of our knowledge, this represents a first report on targeted nanosystems that are capable of efficient loading and targeted delivery of PEM to lung tumors. CI - Copyright (c) 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. FAU - Yang, Weijing AU - Yang W AD - 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. FAU - Yang, Liang AU - Yang L AD - 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. FAU - Xia, Yifeng AU - Xia Y AD - 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. FAU - Cheng, Liang AU - Cheng L AD - 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. Electronic address: chengliang1983@suda.edu.cn. FAU - Zhang, Jian AU - Zhang J AD - 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. FAU - Meng, Fenghua AU - Meng F AD - 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. Electronic address: fhmeng@suda.edu.cn. FAU - Yuan, Jiandong AU - Yuan J AD - BrightGene Bio-Medical Technology Co., Ltd., Suzhou 215123, PR China. FAU - Zhong, Zhiyuan AU - Zhong Z AD - 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. Electronic address: zyzhong@suda.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180214 PL - England TA - Acta Biomater JT - Acta biomaterialia JID - 101233144 RN - 04Q9AIZ7NO (Pemetrexed) SB - IM MH - Animals MH - Cell Line, Tumor MH - *Drug Delivery Systems MH - Female MH - Humans MH - Lung Neoplasms/*drug therapy/metabolism/pathology MH - Mice MH - Mice, Inbred BALB C MH - Neoplasms, Experimental/*drug therapy/metabolism/pathology MH - *Pemetrexed/chemistry/pharmacokinetics/pharmacology MH - Xenograft Model Antitumor Assays OTO - NOTNLM OT - Lung cancer OT - Pemetrexed OT - Polymersomes OT - Reduction-sensitive OT - Targeted delivery EDAT- 2018/02/08 06:00 MHDA- 2019/05/10 06:00 CRDT- 2018/02/08 06:00 PHST- 2017/11/11 00:00 [received] PHST- 2018/01/11 00:00 [revised] PHST- 2018/01/12 00:00 [accepted] PHST- 2018/02/08 06:00 [pubmed] PHST- 2019/05/10 06:00 [medline] PHST- 2018/02/08 06:00 [entrez] AID - S1742-7061(18)30026-6 [pii] AID - 10.1016/j.actbio.2018.01.015 [doi] PST - ppublish SO - Acta Biomater. 2018 Apr 1;70:177-185. doi: 10.1016/j.actbio.2018.01.015. Epub 2018 Feb 14.