Biomedical Polymers Laboratory, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China.
Biomedical Polymers Laboratory, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China.
J Control Release. 2018 Feb 28;272:107-113. doi: 10.1016/j.jconrel.2018.01.011. Epub 2018 Feb 2.
Doxil® is the first FDA-approved anti-cancer nano-drug. Notably, no targeted liposomal formulation has advanced to clinical stage despite tremendous work undertaken, partly due to a low stability of liposomes. Here, we report on novel lipopepsomes self-assembled from poly(ethylene glycol)-b-poly(α-aminopalmitic acid) as a stable and versatile alternative to liposomes for highly efficient encapsulation and tumor-targeted delivery of doxorubicin hydrochloride (Dox·HCl). Interestingly, lipopepsomes could be easily decorated with 20mol% cRGD peptide and loaded with 17.4wt% Dox·HCl, giving cRGD-LPP-Dox with a small size of ~80nm. cRGD-LPP-Dox exhibited a high stability against 10% FBS and restrained drug release under physiological conditions. Flow cytometry, confocal microscopy and MTT assays using αβ-overexpressing A549 tumor cells showed obviously more efficient uptake and higher anticancer activity for cRGD-LPP-Dox than for non-targeted LPP-Dox and clinically used liposomal Dox (Lipo-Dox) controls. Notably, cRGD-LPP-Dox exhibited markedly enhanced toleration and tumor accumulation than Lipo-Dox. The therapeutic studies demonstrated that cRGD-LPP-Dox achieved effective suppression of orthotopic A549 human lung tumor in nude mice, resulting in significantly improved survival rate as compared to LPP-Dox and Lipo-Dox groups. Lipopepsomes with small size, efficient loading of Dox·HCl, high stability and versatile ligand decoration have appeared as a highly attractive nanoplatform for targeted tumor chemotherapy.
多柔比星脂质体（Doxil®）是首个获得美国食品和药物管理局（FDA）批准的抗癌纳米药物。值得注意的是，尽管已经开展了大量工作，但没有一种靶向脂质体制剂能够进入临床阶段，部分原因是脂质体的稳定性较低。在这里，我们报告了一种新型的脂质体自组装体，由聚乙二醇-b-聚（α-氨基棕榈酸）组成，作为脂质体的稳定且多功能替代品，用于高效包封盐酸多柔比星（Dox·HCl）并实现肿瘤靶向递送。有趣的是，脂质体可以很容易地用 20mol%的 cRGD 肽进行修饰，并负载 17.4wt%的 Dox·HCl，得到尺寸约为 80nm 的 cRGD-LPP-Dox。cRGD-LPP-Dox 在 10%胎牛血清（FBS）中具有很高的稳定性，并在生理条件下抑制药物释放。使用αβ过表达的 A549 肿瘤细胞进行流式细胞术、共聚焦显微镜和 MTT 测定表明，与非靶向 LPP-Dox 和临床使用的脂质体多柔比星（Lipo-Dox）对照相比，cRGD-LPP-Dox 具有更高的摄取效率和更强的抗癌活性。值得注意的是，cRGD-LPP-Dox 的耐受性和肿瘤积累明显优于 Lipo-Dox。治疗研究表明，cRGD-LPP-Dox 有效抑制了裸鼠原位 A549 人肺癌肿瘤，与 LPP-Dox 和 Lipo-Dox 组相比，显著提高了存活率。具有小尺寸、高效负载 Dox·HCl、高稳定性和多功能配体修饰的脂质体自组装体已成为一种极具吸引力的靶向肿瘤化疗纳米平台。
