紫杉醇－姜黄素介孔SiO2/脂质复合“隐形”递药系统协同靶向抑制乳腺癌及其促癌细胞凋亡机制探讨

Taxol and curcumin deriving from clinical are two active ingredients against breast cancer. Combination use of them can induce apoptosis of breast cells, inhibit tumor angiogenesis and reduce cytotoxicity of paclitaxel. Meanwhile, combination therapy effect of taxol and.curcumin is better than single use of each one. This study will co-entrap taxol and curcumin which treat against breast cancer through different mechanisms into SiO2 / lipid complex "stealth" drug delivery system (PLMSNs) to realize multi-component and multi-target synergy of traditional Chinese medicine. PLMSNs will be used to increase drug loading and to improve the bioavailability of both paclitaxel and curcumin. Long circle effect and EPR effect (enhanced permeability and retention tumor position) of PLMSNs will promote the co-delivery of taxol and curcumin to the tumor lesion. Meanwhile, molecular mechanisms of how taxol and curcumin entrapped in PLMSNs act on canine breast cancer cells cooperatively will get further discussed based on molecular cell biology. Objective of this study is to combine TCM theory with new type of drug delivery system. At the same time, Taxol and curcumin’s synergistic therapeutic effects including blood-activating, stasis-dissolving, detoxification and anticancer on the same lesion are expected to be achieved. Furthermore, drug carrier’s characteristics of high drug loading and long circle targeting therapy will be acquired. This study is also expected to provide research foundation to the construction and evaluation of low-cost, high-performance mesoporous SiO2 / lipid "stealth" complex drug delivery systems of traditional Chinese medicine.

紫杉醇、姜黄素为临床可行的抗乳腺癌活性成分。二者合用能够促乳腺癌细胞凋亡、抗肿瘤血管生成、降低紫杉醇的细胞毒性，且效果优于二者单用。本课题首次选择共同作用于乳腺癌但作用机制不同的紫杉醇和姜黄素，将二者包载于介孔SiO2 /脂质复合“隐形”递药系统（PLMSNs）中，发挥中药多组分整合、多靶点协同作用；采用PLMSNs提高载药量，克服紫杉醇和姜黄素共有的低生物利用度问题；利用PLMSNs的“隐形”长循环作用和在肿瘤部位的渗透滞留增强效应，使紫杉醇和姜黄素同时靶向作用于肿瘤部位，提高疗效，并从细胞分子生物学角度深入探讨PLMSNs中二者协同作用于犬乳腺癌细胞的分子调控机制。通过本课题的研究，将中医药理论与新型给药系统相结合，使中药活性成分在同一病灶发挥活血化瘀、抗癌解毒的协同治疗作用，以期获得药物载体的高容量携带、长循环靶向治疗等特性。

紫杉醇、姜黄素为临床可行的抗乳腺癌活性成分。二者合用能够促乳腺癌细胞凋亡、抗肿瘤血管生成、降低紫杉醇的细胞毒性，且效果优于二者单用。本课题选择共同作用于乳腺癌但作用机制不同的紫杉醇 (Tax) 和姜黄素（Cur），采用模板法成功制得MCM-41型介孔二氧化硅纳米颗粒 (MSNs)，将紫杉醇和姜黄素载入MSNs后，进一步在其外层包覆聚乙二醇化脂质体层构建介孔SiO2 /脂质复合“隐形”递药系统（PLMSNs），经工艺优化后Tax-Cur-PLMSNs中紫杉醇、姜黄素的包封率分别为77.48 %和30.70 %，脂质体层平均厚度10～15nm，递药体系分散均匀，稳定性较好。. 采用CCK8法考察了Tax-Cur-PLMSNs对犬临床乳腺肿瘤细胞系7364的增殖抑制作用，发现两药对犬乳腺肿瘤细胞的增殖抑制存在协同效应，且Tax-Cur-PLMSNs组增殖抑制率明显高于其他各组，呈现缓释效果。Tax-Cur-PLMSNs递药系统对小鼠乳腺肿瘤细胞系（4T1）皮下移植瘤模型的抑瘤药效结果表明，Tax-Cur-PLMSNs静脉给药组与瘤旁瘤内给药组的瘤重显著低于其余各组（P＜0.05），其抑瘤率分别为58.4 %和58.3 %。说明两种给药途径下，TAX-CUR-PLMSNs递药系统对小鼠乳腺肿瘤的生长均有明显抑制作用，且药效优于裸药组。. 体外释药模型拟合结果表明，TAX-CUR-PLMSNs中紫杉醇和姜黄素释药行为均符合Hixon-Crowell模型，说明二者的释放机制都属于溶蚀控制。体内药时曲线结果表明，递药系统能够显著提高紫杉醇和姜黄素的AUC，尤其紫杉醇经递药系统包载、PEG-2000修饰后，AUC和MRT分别增至裸药组的约20倍和2倍，可有效降低其临床给药剂量，从而降低毒副作用。体外细胞摄取与定位研究发现，PLMSNs可以有效携带药物进入7364犬乳腺肿瘤细胞，且具备缓释特性，其亚细胞定位主要位于溶酶体和线粒体。体内荧光示踪结果显示，静脉注射和瘤旁瘤内注射两种给药途径下，PLMSNs均可有效蓄积于肿瘤部位，说明PLMSNs具有一定乳腺肿瘤靶向性。. 通过本课题的研究，将中医药理论与新型给药系统相结合，使中药活性成分在同一病灶发挥活血化瘀、抗癌解毒的协同治疗作用，体现了PLMSNs药物载体的高容量携带、长循环靶向治疗等特性。