具有抗耐药与多靶点抗癌作用的多功能原位凝胶的基础研究

Because of the toxic side effects, poor targeting and drug resistance in traditional chemotherapy , antitumor treatments face tremendous challenges. This study choose cytotoxic drug paclitaxel, small molecular tyrosine kinase inhibitor lapatinib and P-gp substrate cyclosporin A as model drug, encapsulate all of them in one drug delivery system constituted by thermo-sensitive Pluronic F127. The in situ injectable hydrogel can form drug deposit after local injection (intratumorally and/or intertumorally), release different nature drugs in the same rate, so as to achieve targeting and combined therapy, and finally increase the antitumor effects. By designing appropriate formulations and experimental programmes, the different nature drugs will be encapsulated in the same delivery system to controll the release of drug. The pharmaceutical characteristics , interaction and in vitro, in vivo anticancer effects also will be evaluated. The mechanism of this system will be studied and to validate the hypothesis of combined administration, anti-drug resistance and localization targeting. The new strategies for refractory tumor explorated in this study provides the way to fight the problems of high system toxicity, poor selectivity and multi-drug resistance, it is of great theoretical significance. The design and program in this study is innovative. Some pre-study has been conducted already and the investigators are capable for this study.

传统化疗存在全身给药所带来的毒副作用大、靶向性差以及耐药现象突出等重大问题，使抗肿瘤治疗面临巨大挑战。本研究以温度敏感型高分子材料Pluronic F127为主体载体材料，将高效广谱的抗微管生成药物紫杉醇、小分子靶向药物（酪氨酸激酶抑制剂）拉帕替尼和P-gp强底物环孢素A共同包载于凝胶系统中，通过定位注射给药（如瘤内和瘤周），原位凝胶形成药物贮库，不同药物同步释放，实现抗耐药和多靶点抗肿瘤的靶向治疗和联合治疗，以达到增效减毒的目的。拟通过处方设计和优化，控制不同药物的释放速度，研究其相互作用，评价其体内外过程和作用规律等，验证联合给药、抗耐药和定位靶向结合的科学假说，探索给药系统发挥作用的分子机制。本研究探索肿瘤治疗的新策略，为解决全身给药毒性高、选择性差以及多药耐药问题提供新思路，具有重要的理论意义。本研究的设计思路和研究内容等具有明显的创新性。本研究具有较好的前期工作基础，研究力量较强

本课题制备了紫杉醇纳米颗粒（PTX NPs）和拉帕替尼微米颗粒（LAPA MPs），并将其同时载入温敏凝胶F127中，实现了紫杉醇局部短期和拉帕替尼局部长期的释放效果；选取了三种细胞系探讨药物联用效果及潜在机理，结果表明HER2和P-gp蛋白均可以使拉帕替尼增强紫杉醇的细胞毒作用，从而增强协同效果；HER2阳性和耐药肿瘤模型的药效试验结果表明联合药物制剂优于单一药物制剂，且在联合制剂组中PL-gel相比于P-gel+L-oral组，药效相当但毒性更低。研究体现了一定的创新性，例如，首次将紫杉醇和拉帕替尼用于局部联合治疗；模拟临床联合给药方案，设计了两种药物不同程度的释放速率；制备了杂合荧光探针的不同药物颗粒，方便追踪观察；发现两药联合的作用规律等。通过本研究，我们设计了一种很有前景的新型药物共递送系统，同时在体内外评价方法的构建上做了积极的探索，对促进药剂学科的发展具有一定的意义。本课题发表的论文有5篇，其中SCI论文4篇，申请相关专利2项。