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.
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. 2018 Apr 1;70:177-185. doi: 10.1016/j.actbio.2018.01.015. Epub 2018 Feb 14.
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 (CC) peptide-functionalized reduction-responsive chimaeric polymersomes (CC-RCPs) for efficient encapsulation and targeted delivery of PEM to H460 human lung cancer cells in vitro and in vivo. PEM-loaded CC-RCPs (PEM-CC-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-functionalized PEG-P(TMC-DTC) in the presence of PEM followed by self-crosslinking. PEM-CC-RCPs displayed an optimal CC 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-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-RCPs exhibited 22-fold longer circulation time and 9.1-fold higher accumulation in H460 tumor than clinical formulation Alimta®. Moreover, CC-RCPs showed obviously better tumor penetration than RCPs. Remarkably, PEM-CC-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.
Multitargeted antifolate agent pemetrexed (PEM, Alimta®) 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) peptide-functionalized reduction-responsive chimaeric polymersomes (CC-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®. 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.
肺癌是全球发病率和增长率最快的恶性肿瘤之一。培美曲塞二钠（PEM，商品名：力比泰）是一种亲水性小分子药物，目前用于治疗肺癌患者。然而，PEM 存在清除快、生物利用度低、肿瘤细胞选择性和穿透性差等问题。在这里，我们报告了肺癌特异性 CSNIDARAC（CC）肽功能化还原响应嵌段聚合物囊泡（CC-RCPs），用于体外和体内高效封装和靶向递送培美曲塞（PEM）至 H460 人肺癌细胞。PEM 负载的 CC-RCPs（PEM-CC-RCPs）是通过聚乙二醇-b-聚（三亚甲基碳酸酯-co-二硫代三亚甲基碳酸酯）-b-聚乙基亚胺（PEG-P（TMC-DTC）-PEI）与 CC 功能化 PEG-P（TMC-DTC）的共自组装，然后进行自交联，在 PEM 的存在下获得的。PEM-CC-RCPs 对 H460 细胞的靶向性最佳 CC 密度为 9.0%，PEM 负载量为 14.2wt%，水动力粒径约为 60nm，谷胱甘肽触发 PEM 释放。MTT 试验表明，PEM-CC-RCPs 对 H460 细胞的效力分别比非靶向 PEM-RCPs 和游离 PEM 对照组高 2.6 倍和 10 倍。有趣的是，PEM-CC-RCPs 在体内的循环时间延长了 22 倍，在 H460 肿瘤中的积累增加了 9.1 倍，优于临床制剂力比泰。此外，CC-RCPs 显示出比 RCPs 更好的肿瘤穿透性。值得注意的是，与 PEM-RCPs 和力比泰对照组相比，12.5mg PEM 当量/kg 的 PEM-CC-RCPs 有效抑制了 H460 异种移植瘤的生长，并显著延长了小鼠的存活时间。这些肺癌特异性和还原响应的嵌段聚合物囊泡为靶向肺癌治疗提供了一种独特的培美曲塞纳米制剂。
