肿瘤组织及细胞内梯度pH响应的载药金纳米笼构建及在光热–化疗联合治疗中的应用

To enhance the curative effect and decrease the toxicity of chemotheraputic drugs are the main topics in chemotherapy of cancer. The combination of photothermal therapy and chemotherapy could remarkably improve the anti-cancer efficiency by the simultaneous delivery of chemotheraputic drug and photothermal agent to tumor site (gold nanocages, etc.). However, it is difficult to regulate the in vivo drug delivery and release behaviors of photothermal agent-based drug carriers. Gradient pH-sensitive drug delivery systems could regulate the different demands of their physicochemical properties and drug release profiles in circulatory system, tumor tissues, and tumor cells, so that are promising in tumor-targeting delivery and pH-triggered intracellular drug release. A combination of the photothermal agent-based drug delivery system and pH-responsible drug delivery system could provide us a multifunctional and intelligent system for tumor treatment. This programme designed a series of tumor/intracellular gradient pH-sensitive gold nanocages for anti-cancer drug delivery. The relationship between the chemical structure of the nano carrier and its stability in circulatory system, its tumor tissue targeting property, controlled drug release profile and anti-cancer efficiency in vitro and in vivo will be studied. This design could decrease the side effect and enhance the therapeutic efficiency of chemotherapeutic drugs, and will provide the scientist with new ideas for the clinical applications of gold nanocages as drug carriers.

如何提高治疗效果、降低毒副作用是肿瘤化疗中面临的两大难题。通过光热转换材料担载化疗药物，进行光热–化疗联合治疗，可提高肿瘤治疗效果，但难以实现向肿瘤组织的靶向传输和胞内可控药物释放。本项目拟通过不同的pH响应化学键分别将化疗药物和聚乙二醇键合至光热转换材料金纳米笼上，构建梯度pH响应的纳米药物载体。利用血液微环境、肿瘤组织和细胞内梯度下降的pH值，逐级脱去聚乙二醇和药物，协调药物在体内不同传输阶段中对载体理化性质和药物释放性能的不同需求，得到肿瘤细胞靶向、可控药物释放、可光热治疗、可成像的多功能纳米载药体系。探讨梯度pH响应性能对其体内循环稳定性、肿瘤细胞靶向性、药物释放可控性及光热–化疗联合治疗效果等的影响规律，探讨化疗和光热疗法联合增强肿瘤治疗效果的生物学效应和机制，实现肿瘤治疗方式的多元化、智能化。本项目的顺利实施将为设计制备新的纳米载药体系，提高肿瘤治疗效果提供理论和实验依据。

为了有效提高药物治疗效果，降低毒副作用，需要使药物载体在循环过程中保持稳定，然而在进入肿瘤组织后，能够迅速被肿瘤细胞捕获并吞噬，随后在肿瘤细胞内快速释放药物，从而杀伤肿瘤。因此，如何统筹协调解决药物在体内不同传输阶段对药物载体的理化性能和药物释放性能的不同需求的矛盾是肿瘤治疗中亟需解决的关键问题。人体正常生理环境和血液呈中性（pH~7.35），然而，由于肿瘤细胞的无氧糖酵解（Warburg效应）的影响，导致肿瘤组织呈现微酸性环境（pH~6.5-7.2），而肿瘤细胞内的内涵体和溶酶体则具有更低的pH（分别为5.0-6.5和4.5-5.0）。这一血液—肿瘤组织—肿瘤细胞微环境中pH值梯度降低的生理现象为我们提供了一个实现药物的肿瘤靶向传输和可控释放的契机。.本项目中，我们用具有不同pH响应点的pH响应化学键分别将化疗药物和聚乙二醇键合至光热转换材料金纳米笼上，构建了梯度pH响应载药金纳米笼。结果显示，所制备的梯度pH响应载药金纳米笼可在血液微环境中保持稳定，而在肿瘤组织和细胞内梯度下降的pH环境中，逐级脱去表面的PEG配体和键合的药物阿霉素。体内外光热-化疗联合治疗结果表明，所制备的梯度pH响应载药金纳米笼可在肿瘤组织中大量富集、在肿瘤细胞中快速释放药物，在优选的治疗条件和方案下，梯度pH响应载药金纳米笼可以介导优异的肿瘤治疗效果。所制备的梯度pH响应载药金纳米笼表现除了良好的体内外生物相容性，无显著急慢性毒性。.项目圆满地完成了项目地研究内容，实现了预期研究目标。共发表相关论文10篇，申请专利19项。项目的顺利实施为设计制备新的纳米载药体系，提高肿瘤治疗效果提供理论和实验依据。