School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China.
Key Laboratory of Functional Molecules for Biomedical Research, Zhengzhou 450001, China.
Int J Mol Sci. 2024 May 20;25(10):5553. doi: 10.3390/ijms25105553.
Multidrug resistance (MDR) is frequently induced after long-term exposure to reduce the therapeutic effect of chemotherapeutic drugs, which is always associated with the overexpression of efflux proteins, such as P-glycoprotein (P-gp). Nano-delivery technology can be used as an efficient strategy to overcome tumor MDR. In this study, mesoporous silica nanoparticles (MSNs) were synthesized and linked with a disulfide bond and then coated with lipid bilayers. The functionalized shell/core delivery systems (HT-LMSNs-SS@DOX) were developed by loading drugs inside the pores of MSNs and conjugating with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and hyaluronic acid (HA) on the outer lipid surface. HT-LMSNs-SS and other carriers were characterized and assessed in terms of various characteristics. HT-LMSNs-SS@DOX exhibited a dual pH/reduction responsive drug release. The results also showed that modified LMSNs had good dispersity, biocompatibility, and drug-loading capacity. In vitro experiment results demonstrated that HT-LMSNs-SS were internalized by cells and mainly by clathrin-mediated endocytosis, with higher uptake efficiency than other carriers. Furthermore, HT-LMSNs-SS@DOX could effectively inhibit the expression of P-gp, increase the apoptosis ratios of MCF-7/ADR cells, and arrest cell cycle at the G0/G1 phase, with enhanced ability to induce excessive reactive oxygen species (ROS) production in cells. In tumor-bearing model mice, HT-LMSNs-SS@DOX similarly exhibited the highest inhibition activity against tumor growth, with good biosafety, among all of the treatment groups. Therefore, the nano-delivery systems developed herein achieve enhanced efficacy towards resistant tumors through targeted delivery and redox-responsive drug release, with broad application prospects.
多药耐药性（MDR）是由于长期接触化疗药物而导致的治疗效果降低，通常与外排蛋白（如 P-糖蛋白（P-gp））的过度表达有关。纳米递药技术可以作为克服肿瘤 MDR 的有效策略。在本研究中，合成了介孔硅纳米粒子（MSNs）并通过二硫键连接，然后用脂质双层包覆。通过将药物载入 MSNs 的孔内，并在脂质外层与 D-α-生育酚聚乙二醇 1000 琥珀酸（TPGS）和透明质酸（HA）缀合，开发了功能化的壳核递药系统（HT-LMSNs-SS@DOX）。HT-LMSNs-SS 和其他载体的各种特性进行了表征和评估。HT-LMSNs-SS@DOX 表现出双重 pH/还原响应的药物释放。结果还表明，改性 LMSNs 具有良好的分散性、生物相容性和载药能力。体外实验结果表明，HT-LMSNs-SS 被细胞内化，主要通过网格蛋白介导的内吞作用，摄取效率高于其他载体。此外，HT-LMSNs-SS@DOX 可以有效抑制 P-gp 的表达，增加 MCF-7/ADR 细胞的凋亡率，并将细胞周期阻滞在 G0/G1 期，同时增强诱导细胞内产生过多活性氧（ROS）的能力。在荷瘤模型小鼠中，HT-LMSNs-SS@DOX 同样表现出对肿瘤生长的最高抑制活性，所有治疗组中具有良好的生物安全性。因此，本文开发的纳米递药系统通过靶向递药和氧化还原响应性药物释放，实现了对耐药肿瘤的增效作用，具有广阔的应用前景。
