State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University , Nanjing 210009, China.
ACS Appl Mater Interfaces. 2016 Aug 31;8(34):22431-41. doi: 10.1021/acsami.6b04885. Epub 2016 Aug 16.
A multistimuli responsive drug delivery system (DDS) based on sulfhydryl and amino-cofunctionalized mesoporous silica nanoparticles (SH/NH2-MSNs) has been developed, in which the multifunctional hyaluronic acid (HA) derivatives were grafted onto the SH/NH2-MSNs by disulfide bonds for targeting delivery, controlling drug release and reversing multidrug resistance (MDR). The doxorubicin (Dox) loaded multifunctional HA derivatives modified mesoporous silica nanoparticles (Dox/HHS-MSNs) were enzyme and redox sensitive, which could respond to the intracellular stimuli of hyaluronidase (HAase) and glutathione (GSH) successively and prevent drug leakage before reaching the tumor tissues. The cellular uptake experiments showed that Dox/HHS-MSNs were vulnerable to be endocytosed into the Dox-resistant human breast adenocarcinoma (MCF-7/ADR) cells, efficiently realized the endolysosomal escape and remained in the cytoplasm. Because of orchestrating multiple actions above including active targeting, endolysosomal escape and efficient multilevel drug release, Dox/HHS-MSNs could induce the strongest apoptosis and cytotoxicity of MCF-7/ADR cells. Furthermore, a series of in vivo studies on MCF-7/ADR tumor-bearing xenograft mouse models demonstrated that Dox/HHS-MSNs possessed the enhanced tumor-targeting capacity and the best therapeutic efficacy to reverse cancer MDR.
一种基于巯基和氨基共功能化介孔硅纳米粒子（SH/NH2-MSNs）的多刺激响应药物递送系统（DDS）已经被开发出来，其中多功能透明质酸（HA）衍生物通过二硫键接枝到 SH/NH2-MSNs 上，用于靶向递送、控制药物释放和逆转多药耐药（MDR）。负载多西紫杉醇（Dox）的多功能透明质酸衍生物修饰的介孔硅纳米粒子（Dox/HHS-MSNs）是酶和氧化还原敏感的，它可以分别响应细胞内透明质酸酶（HAase）和谷胱甘肽（GSH）的刺激，在到达肿瘤组织之前防止药物泄漏。细胞摄取实验表明，Dox/HHS-MSNs 很容易被内吞进入多西紫杉醇耐药的人乳腺癌腺癌细胞（MCF-7/ADR），有效地实现了内体逃逸并保留在细胞质中。由于协调了包括主动靶向、内体逃逸和高效多级药物释放在内的多种作用，Dox/HHS-MSNs 可以诱导 MCF-7/ADR 细胞最强的细胞凋亡和细胞毒性。此外，一系列在 MCF-7/ADR 荷瘤异种移植小鼠模型上的体内研究表明，Dox/HHS-MSNs 具有增强的肿瘤靶向能力和逆转癌症 MDR 的最佳治疗效果。
