College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Libraries of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Acta Pharmacol Sin. 2021 May;42(5):832-842. doi: 10.1038/s41401-021-00648-x. Epub 2021 Apr 6.
Nanomedicine has attracted increasing attention and emerged as a safer and more effective modality in cancer treatment than conventional chemotherapy. In particular, the distinction of tumor microenvironment and normal tissues is often used in stimulus-responsive drug delivery systems for controlled release of therapeutic agents at target sites. In this study, we developed mesoporous silica nanoparticles (MSNs) coated with polyacrylic acid (PAA), and pH-sensitive lipid (PSL) for synergistic delivery and dual-pH-responsive sequential release of arsenic trioxide (ATO) and paclitaxel (PTX) (PL-PMSN-PTX/ATO). Tumor-targeting peptide F56 was used to modify MSNs, which conferred a target-specific delivery to cancer and endothelial cells under neoangiogenesis. PAA- and PSL-coated nanoparticles were characterized by TGA, TEM, FT-IR, and DLS. The drug-loaded nanoparticles displayed a dual-pH-responsive (pH = 6.5, pH = 5.0) and sequential drug release profile. PTX within PSL was preferentially released at pH = 6.5, whereas ATO was mainly released at pH = 5.0. Drug-free carriers showed low cytotoxicity toward MCF-7 cells, but ATO and PTX co-delivered nanoparticles displayed a significant synergistic effect against MCF-7 cells, showing greater cell-cycle arrest in treated cells and more activation of apoptosis-related proteins than free drugs. Furthermore, the extracellular release of PTX caused an expansion of the interstitial space, allowing deeper penetration of the nanoparticles into the tumor mass through a tumor priming effect. As a result, FPL-PMSN-PTX/ATO exhibited improved in vivo circulation time, tumor-targeted delivery, and overall therapeutic efficacy.
纳米医学引起了越来越多的关注，并在癌症治疗方面比传统化疗更安全、更有效。特别是，肿瘤微环境和正常组织的区别通常用于刺激响应性药物输送系统，以在靶部位控制治疗剂的释放。在这项研究中，我们开发了用聚丙烯酸（PAA）和 pH 敏感脂质（PSL）涂覆的介孔硅纳米粒子（MSNs），用于协同递药和双重 pH 响应顺序释放三氧化二砷（ATO）和紫杉醇（PTX）（PL-PMSN-PTX/ATO）。肿瘤靶向肽 F56 用于修饰 MSNs，使其在新血管生成下对癌症和内皮细胞具有靶向特异性递送。用 TGA、TEM、FT-IR 和 DLS 对 PAA 和 PSL 涂覆的纳米粒子进行了表征。载药纳米粒子显示出双重 pH 响应（pH = 6.5，pH = 5.0）和顺序药物释放特性。PSL 内的 PTX 优先在 pH = 6.5 下释放，而 ATO 主要在 pH = 5.0 下释放。无载药载体对 MCF-7 细胞的细胞毒性低，但 ATO 和 PTX 共递药纳米粒子对 MCF-7 细胞表现出显著的协同作用，处理细胞中的细胞周期停滞更多，凋亡相关蛋白的激活更多。此外，PTX 的细胞外释放导致细胞外间隙扩张，通过肿瘤引发效应使纳米粒子更深地渗透到肿瘤组织中。结果，FPL-PMSN-PTX/ATO 表现出改善的体内循环时间、肿瘤靶向递送和整体治疗效果。
