CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China , Hefei 230026 Anhui, China.
College of Chemistry and Environmental Engineering, Shenzhen University , Shenzhen, Guangdong 518060, People's Republic of China.
ACS Appl Mater Interfaces. 2017 May 31;9(21):17727-17735. doi: 10.1021/acsami.7b02808. Epub 2017 May 17.
Smart nanocarriers attract considerable interest in the filed of precision nanomedicine. Dynamic control of the interaction between nanocarriers and cells offers the feasibility that in situ activates cellular internalization at the targeting sites. Herein, we demonstrate a novel class of enzyme-responsive asymmetric polymeric vesicles self-assembled from matrix metalloproteinase (MMP)-cleavable peptide-linked triblock copolymer, poly(ethylene glycol)-GPLGVRG-b-poly(ε-caprolactone)-b-poly(3-guanidinopropyl methacrylamide) (PEG-GPLGVRG-PCL-PGPMA), in which the cell-penetrating PGPMA segments asymmetrically distribute in the outer and inner shells with fractions of 9% and 91%, respectively. Upon treatment with MMP-2 to cleave the stealthy PEG shell, the vesicles undergo morphological transformation into fused multicavity vesicles and small nanoparticles, accompanied by redistribution of PGPMA segments with 76% exposed to the outside. The vesicles after dePEGylation show significantly increased cellular internalization efficiency (∼10 times) as compared to the original ones due to the triggered availability of cell-penetrating shells. The vesicles loading hydrophobic anticancer drug paclitaxel (PTX) in the membrane exhibit significantly enhanced cytotoxicity against MMP-overexpressing HT1080 cells and multicellular spheroids. The proposed vesicular system can serve as a smart nanoplatform for in situ activating intracellular drug delivery in MMP-enriched tumors.
智能纳米载体在精准纳米医学领域引起了相当大的兴趣。纳米载体与细胞之间相互作用的动态控制为在靶向部位原位激活细胞内化提供了可行性。在此，我们展示了一类新型的酶响应不对称聚合物囊泡，它由基质金属蛋白酶（MMP）可切割肽连接的三嵌段共聚物聚乙二醇-GPLGVRG-嵌段-聚（ε-己内酯）-嵌段-聚（3-胍基丙基甲基丙烯酰胺）（PEG-GPLGVRG-PCL-PGPMA）自组装而成，其中穿透细胞的 PGPMA 片段分别以 9%和 91%的分数不对称地分布在外层和内层。用 MMP-2 处理以切割隐形的 PEG 壳后，囊泡经历形态转变为融合的多腔囊泡和小纳米颗粒，同时 PGPMA 片段重新分布，有 76%暴露在外面。与原始囊泡相比，去 PEG 化后的囊泡由于穿透细胞的外壳的触发可用性，表现出显著增加的细胞内化效率（约 10 倍）。在膜中装载疏水性抗癌药物紫杉醇（PTX）的囊泡对 MMP 过表达的 HT1080 细胞和多细胞球体表现出显著增强的细胞毒性。所提出的囊泡系统可用作在富含 MMP 的肿瘤中原位激活细胞内药物递送的智能纳米平台。
