Wang Shuo, Zhang Chao, Liu Huandi, Fan Xueyu, Fu Shuangqing, Li Wei, Zhang Honglei
State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding 071002, China.
Department of Life Science, Hengshui University, Hengshui 053000, China.
Nanomaterials (Basel). 2024 Oct 16;14(20):1657. doi: 10.3390/nano14201657.
The combination of paclitaxel (PTX) with other chemotherapy drugs (e.g., gemcitabine, GEM) or genetic drugs (e.g., siRNA) has been shown to enhance therapeutic efficacy against tumors, reduce individual drug dosages, and prevent drug resistance associated with single-drug treatments. However, the varying solubility of chemotherapy drugs and genetic drugs presents a challenge in co-delivering these agents. In this study, nanoparticles loaded with PTX were prepared using the biodegradable polymer material poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx). These nanoparticles were surface-modified with target proteins (Affibody molecules) and RALA cationic peptides to create core-shell structured microspheres with targeted and cationic functionalization. A three-drug co-delivery system (PTX@PHBHHx-ARP/siRNA) were developed by electrostatically adsorbing siRNA chains containing GEM onto the microsphere surface. The encapsulation efficiency of PTX in the nanodrug was found to be 81.02%, with a drug loading of 5.09%. The chemogene adsorption capacity of siRNA was determined to be 97.3%. Morphological and size characterization of the nanodrug revealed that PTX@PHBHHx-ARP/siRNA is a rough-surfaced microsphere with a particle size of approximately 150 nm. This nanodrug exhibited targeting capabilities toward BT474 cells with HER2 overexpression while showing limited targeting ability toward MCF-7 cells with low HER2 expression. Results from the MTT assay demonstrated that PTX@PHBHHx-ARP/siRNA exhibits high cytotoxicity and excellent combination therapy efficacy compared to physically mixed PTX/GEM/siRNA. Additionally, Western blot analysis confirmed that siRNA-mediated reduction of Bcl-2 expression significantly enhanced cell apoptosis mediated by PTX or GEM in tumor cells, thereby increasing cell sensitivity to PTX and GEM. This study presents a novel targeted nanosystem for the co-delivery of chemotherapy drugs and genetic drugs.
紫杉醇（PTX）与其他化疗药物（如吉西他滨，GEM）或基因药物（如siRNA）联合使用已被证明可增强对肿瘤的治疗效果，降低单个药物剂量，并防止与单药治疗相关的耐药性。然而，化疗药物和基因药物不同的溶解性给这些药物的共同递送带来了挑战。在本研究中，使用可生物降解的聚合物材料聚（3-羟基丁酸酯-co-3-羟基己酸酯）（PHBHHx）制备了负载PTX的纳米颗粒。这些纳米颗粒用靶蛋白（亲和体分子）和RALA阳离子肽进行表面修饰，以创建具有靶向和阳离子功能化的核壳结构微球。通过将含有GEM的siRNA链静电吸附到微球表面，开发了一种三药共递送系统（PTX@PHBHHx-ARP/siRNA）。发现纳米药物中PTX的包封率为81.02%，载药量为5.09%。siRNA的化学基因吸附能力测定为97.3%。纳米药物的形态和尺寸表征显示，PTX@PHBHHx-ARP/siRNA是一种表面粗糙的微球，粒径约为150nm。这种纳米药物对HER2过表达的BT474细胞具有靶向能力，而对HER2低表达的MCF-7细胞的靶向能力有限。MTT分析结果表明，与物理混合的PTX/GEM/siRNA相比，PTX@PHBHHx-ARP/siRNA具有高细胞毒性和优异的联合治疗效果。此外，蛋白质免疫印迹分析证实，siRNA介导的Bcl-2表达降低显著增强了PTX或GEM介导的肿瘤细胞凋亡，从而增加了细胞对PTX和GEM的敏感性。本研究提出了一种用于化疗药物和基因药物共同递送的新型靶向纳米系统。
