肿瘤微环境响应性双前药靶向共传输纳米体系用于乳腺癌的治疗研究

To achieve the best effect of the combination therapy，the chemotherapeutics within the combination drug delivery system must at on cells at a certain mass ratio. But due to the complexity of the systemic circulation and the different physicochemical properties of drugs, it is difficult to deliver chemotherapeutic drugs into cells with the optimal mass ratio, and thus difficult to achieve the best effect of the combination therapy. In this project, we intend to design and prepare an active targeting and controlled release of intelligent dual prodrug co-delivery system. In which, doxorubicin and camptothecin were linked to the hyperbranched polymer cores via pH-responsive hydrazone bonds and redox-responsive disulfide bonds, respectively, while a targeting ligand was modified on the surface, The hyperbranched polymer core and prodrug strategy kept the nanoparticles stable in systemic circulation, and then all drugs were well entrapped in nanoparticle. The introduction of tumor microenvironment responsive bonds resulted to a stimuli-responsive controlled release of DOX and CPT upon exposure to an acidic environment of late endosomes and lysosomes or a GSH-rich environment of cytoplasm, respectively. The modification of targeting ligand greatly enriched the nanoparticles in tumor tissues. The nanoparticle could precisely tune the drug content in carriers, efficiently deliver drugs into tumor cells with the optimal mass ratio as design and synchronize the physiological fate of all drugs in systemic circulation, and then play the best efficacy of combination treatment. We proposed a comprehensive study of the preparation and characterization, the drug properties, the in vitro and in vivo targeting efficiency and the efficacy of combination therapy. The project will not only provide a new idea for the design of co-delivery systems for other chemotherapeutic drugs, but also provide new strategies for combination therapy.

联合使用的化疗药物需按照一定的比例作用于细胞才能发挥最佳的治疗效果，但由于体内环境的复杂性和药物理化性质的差异，药物难以按最佳比例传递至并作用于肿瘤细胞，因而难以发挥最佳的治疗效果。本项目拟以超支化聚合物为内核，接枝具有还原敏感的喜树碱前药和pH敏感的阿霉素前药，在其表面修饰肿瘤靶向配体，构建出一种主动靶向肿瘤且智能控释药物的双前药共传输纳米体系。超支化聚合物内核和化疗药物前药化设计，使纳米粒在体循环中保持稳定且几乎不释药物；敏感性化学键的引入，使药物在肿瘤细胞微环境作用下智能、快速释放；靶向配体的修饰，使纳米粒在肿瘤部位富集。该体系可精确调控载药量、高效共传输药物、同步药物命运、并以最佳比例传递至肿瘤细胞，从而发挥最佳的联合治疗效果。本项目将系统研究该体系的制备、药物智能控释特性、体内外靶向性及联合治疗效果等。本项目将为共传输体系的设计提供新的思路，为化疗药物联合治疗肿瘤提供新的策略。

癌症是当前严重威胁人类健康的重大恶性疾病之一，全球癌症负担逐年加重。化疗是目前肿瘤治疗最常用且有效的方式之一，但常用的化疗药物制剂往往是以游离药物形式存在，易引起强的毒副作用。纳米技术的发展为化疗药物的递送提供了新的选择；化疗药物纳米化不仅可以显著提高药物溶解度等理化性质，而且还可以通过被动靶向肿瘤组织、降低毒副作用、提高生物利用度和治疗指数等。但是常规的物理装载形式仍旧存在药物易泄漏等问题，而通过将药物与纳米载体共价连接的前药化策略则能够解决药物过早泄漏的问题。结合肿瘤异常微环境的特性，构建微环境响应性的纳米前药体系，则可以实现药物的可控释放。我们成功制备了一种载药量精准可控的、兼具pH和redox双重敏感特性的喜树碱前药纳米凝胶体系（P(CPT-MAA)），用于乳腺癌的治疗；该体系将喜树碱通过还原响应性的二硫键接枝于具有pH敏感特性的PMAA凝胶骨架中，不仅具有较高的生物安全性，而且可以在肿瘤微环境中响应性释放喜树碱，从而增强抗肿瘤效果。但是肿瘤的异质性，可能会影响药物的释放；同时单一的化疗，可能会引起肿瘤的耐药等问题。进一步，我们构建了一种活性氧（ROS）敏感性的喜树碱前药给药系统；该体系将CPT和光敏剂PPa分别通过ROS敏感的TK键和酰胺键共价接枝于同一聚乙二醇单甲醚（MPEG）上，形成了双前药纳米共递送体系；近红外激光局部照射，PPa快速生成ROS，引发TK键快速断裂，从而实现局部、可控、按需释放CPT；ROS具有光动力治疗作用，实现了化疗和光动力治疗的联合，增强对肿瘤生长的抑制作用。