Huang Yushu, Xu Yanyun, Wu Yanqian, Chen Tiandong, Lu Wei, Yu Jiahui
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
Colloids Surf B Biointerfaces. 2019 Nov 1;183:110413. doi: 10.1016/j.colsurfb.2019.110413. Epub 2019 Aug 4.
A novel bioinspired nanoplatform capable of fast endocytosis, lysosomal pH-triggered drug release, and reduced drug efflux based on PBA-PEG-b-P(Glu-co-GluDA) copolymer was developed in this study. The synthesized copolymer could facilitate doxorubicin encapsulation with relatively high drug-loading content and efficiency. Inspired by mussel byssal threads, a core crosslinking strategy based on the coordination between catechol and ferric ions was introduced to improve the stability of nanomicelles and realize lysosomal pH-controlled drug release. This nanoplatform could maintain integrity even after being dissolved in a good solvent, demonstrating its the potential to withstand infinite dilution of plasma after intravenous injection. Moreover, this nanoplatform demonstrated lysosomal pH-triggered drug release, and the cumulative release amount of doxorubicin under a simulated lysosomal condition was 13 times higher than that under a simulated plasma condition. Moreover, as a result of the high binding capacity between phenylboronic acid (PBA) and sialic acid on the surface of human hepatoma cell line (HepG2), the fast and enhanced endocytosis in addition to lysosomal pH-triggered release property and significantly low efflux, this nanoplatform exhibits improved delivery efficiency of doxorubicin into the nucleus and notably outstanding antiproliferative effects compared with doxorubicin. Furthermore, the PBA modification remarkably increased the mean fluorescence intensity of this nanoplatform endocytosed by HepG2 cells to twice that of doxorubicin after one hour of incubation. The nanoplatform exhibited an inhibition rate of 70% against tumor growth. Thus, this novel nanoplatform based on PBA-PEG-b-P(Glu-co-GluDA) copolymer displayed multifunctionality and exhibited great potential as an intelligent nanoplatform for antitumor drug delivery.
本研究开发了一种基于PBA-PEG-b-P(Glu-co-GluDA)共聚物的新型仿生纳米平台，该平台能够实现快速内吞、溶酶体pH触发的药物释放，并减少药物外排。合成的共聚物能够以相对较高的载药含量和效率促进阿霉素的包封。受贻贝足丝启发，引入了一种基于儿茶酚与铁离子配位的核心交联策略，以提高纳米胶束的稳定性并实现溶酶体pH控制的药物释放。即使溶解在良溶剂中，该纳米平台仍能保持完整性，表明其在静脉注射后能够耐受血浆无限稀释的潜力。此外，该纳米平台表现出溶酶体pH触发的药物释放，在模拟溶酶体条件下阿霉素的累积释放量比模拟血浆条件下高13倍。此外，由于苯基硼酸（PBA）与人肝癌细胞系（HepG2）表面的唾液酸具有高结合能力，除了溶酶体pH触发释放特性和显著低的外排外，还具有快速且增强的内吞作用，与阿霉素相比，该纳米平台表现出改善的阿霉素向细胞核的递送效率和显著出色的抗增殖效果。此外，PBA修饰显著提高了HepG2细胞内吞该纳米平台的平均荧光强度，孵育1小时后达到阿霉素的两倍。该纳米平台对肿瘤生长的抑制率为70%。因此，这种基于PBA-PEG-b-P(Glu-co-GluDA)共聚物的新型纳米平台具有多功能性，作为一种用于抗肿瘤药物递送的智能纳米平台展现出巨大潜力。
