目的: 设计并制备一种新型聚赖氨酸两亲性聚合物纳米递药系统用于奥沙利铂的递送,从而实现提高药效和靶部位药物释放率的效果。方法: 化学合成制备mPssPC聚合物,并通过红外光谱、核磁共振氢谱分析确认聚合物合成成功。通过物理包埋和自组装的方式制备mPssPC NPs和mPssPC-OXA NPs,并通过动态光散射分析、透射电镜观察、稳定性测试和体外药物释放试验对纳米粒子的物理化学性质进行表征。通过体外细胞试验测试mPssPC-OXA NPs细胞毒性、细胞摄取、免疫逃逸效果。结果: 成功制备mPssPC NPs和mPssPC-OXA NPs。mPssPC NPs粒径小（190.77±2.91 nm）,带正电荷（43.20±0.72 mV）,稳定性优异。mPssPC-OXA NPs在透射电镜下呈形状规则的球形,并且mPssPC-OXA NPs的药物释放具有缓释和GSH敏感性药物释放的特点。在体外细胞研究中,mPssPC-OXA NPs能被HCT-116细胞有效摄取并显著抑制肿瘤细胞活性,同时还能有效减少RAW264.7细胞对纳米粒子的吞噬清除。结论: 以聚赖氨酸为基本骨架构建的mPssPC-OXA NPs能促进肿瘤细胞的药物摄取,从而显著提高细胞毒性。同时,mPssPC-OXA NPs能实现免疫逃逸,并能在高谷胱甘肽浓度环境下实现更多更快的药物释放,实现提高靶部位药物浓度的效果。
Abstract
Objective Design and preparation of a novel poly (lysine) amphiphilic polymer nanodelivery system for oxaliplatin (OXA) delivery to achieve improved efficacy and target site drug release rate. Methods The mPssPC polymers were prepared by chemical synthesis, and the successful synthesis of the polymers was confirmed by infrared spectroscopy and nuclear magnetic resonance hydrogen spectroscopy. The mPssPC NPs and mPssPC-OXA NPs were prepared by physical embedding and self-assembly, and the physicochemical properties of the nanoparticles were characterized by dynamic light scattering analysis, transmission electron microscopy observation, stability test and in vitro drug release assay. The cytotoxicity, cellular uptake, and immune escape effects of mPssPC-OXA NPs were tested by in vitro cellular assays. Results mPssPC NPs and mPssPC-OXA NPs were successfully prepared. mPssPC NPs had a small particle size (190.77±2.91 nm), positive charge (43.20±0.72 mV), and excellent stability. mPssPC-OXA NPs showed a spherical shape with regular shape under transmission electron microscopy, and the drug release of mPssPC-OXA NPs was characterised by slow release and GSH-sensitive drug release. In in vitro cellular studies, mPssPC-OXA NPs were effectively taken up by HCT-116 cells and significantly inhibited tumor cell activity, and also effectively reduced phagocytic clearance of nanoparticles by RAW264.7 cells. Conclusion The mPssPC-OXA NPs constructed with polylysine as the basic backbone promoted drug uptake in tumor cells, which significantly increased cytotoxicity. Meanwhile, mPssPC-OXA NPs could achieve immune escape and more and faster drug release in a high glutathione concentration environment, achieving the effect of increasing the drug concentration at the target site.
关键词
聚赖氨酸 /
奥沙利铂 /
HCT-116细胞 /
纳米粒子
Key words
poly (lysine) /
oxaliplatin /
HCT-116 cells /
nanoparticle
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基金
湖南省自然科学基金项目“一种新型还原酶敏感性纳米粒子及其共递送甲氨蝶呤/P13K抑制剂治疗骨肉瘤效力研究”（2022JJ30410）;长沙市自然科学基金“基于还原酶敏感性新型共递送甲氨蝶呤/P13K抑制剂纳米粒子治疗骨肉瘤效力的研究”（kq2202250）;湖南省大学生研究性学习和创新性实验计划项目“负载利格列汀的壳聚糖纳米粒子用于治疗肾纤维化研究”（S202410542134S）
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