肿瘤穿透肽修饰的酶响应型双药长循环纳米递药系统靶向治疗胃癌的效果评价和机制研究

Gastric cancer is one of the most common malignant tumors in the world. Paclitaxel is currently the first-line chemotherapy for gastric cancer. However, the clinical application is subject to certain restrictions because of its toxic and side effects and secondary resistance. Applicants have found that ursolic acid can synergistically enhance the anti-tumor effect of paclitaxel during participating in the early phase of research of Natural Science Foundation of China (NSFC), which adopts polyamidoamine dendrimer (PAMAM) to construct new drug-loaded nanoparticles. Imagine that ursolic acid and paclitaxel connect with the surface amino groups of PAMAM through Gly-Phe-Leu-Gly. This peptide chain can be hydrolyzed specially by high-expressed cathepsin B in tumor cells to achieve the release of responsiveness of drug enzymes, high concentration of drug within the tumor, and alleviate systemic toxic and side effects, while modify the connection of PCBMA and PAMAM (amphoteric polymers of tumor-penetrating peptide - iRGD) that makes this drug-loaded nanoparticles has functions of in vivo long-circulating, targeting tumor penetration and release of responsiveness of specific enzymes. In vitro/in vivo experiments confirm that this new nanoscale drug delivery system has the functions of release of responsiveness of enzymes, tumor targeting and anti-tumor effects. And the synergistic inhibitory tumor mechanism between two drugs is discussed based on “oxidation therapy”, which provides the scientific basis for its clinical application.

胃癌是全球范围内最常见的恶性肿瘤之一，紫杉醇是目前胃癌化疗的一线治疗药物，但其毒副作用和继发的耐药性使临床应用受到一定限制。申请人在前期参与的国家自然科学基金研究中发现熊果酸可以协同增强紫杉醇抗肿瘤效果，结合纳米载药技术采用树枝状聚合物聚酰胺-胺（PAMAM）构建新型纳米载药微球，设想将熊果酸和紫杉醇通过肽链Gly-Phe-Leu-Gly与PAMAM表面氨基连接，该肽链能被肿瘤细胞内高表达的组织蛋白酶B特异性水解，以达到药物酶响应性释放，实现肿瘤内药物的高浓度，减轻全身毒副作用，同时将修饰了肿瘤穿透肽iRGD的两性聚合物聚甜菜碱甲基丙烯酰胺（PCBMA）与PAMAM连接，使该纳米载药微球同时具有体内长循环及肿瘤靶向渗透、特异性酶响应释放功能。通过体内外实验明确该纳米递药系统的酶响应性释放、肿瘤靶向性及抗肿瘤效果，并探讨两药之间基于“氧化疗法”的协同抑瘤机制，为其在临床应用提供科学依据。

紫杉醇是目前胃癌化疗的一线治疗药物，但其毒副作用和继发的耐药性使临床应用受到一定限制。本课题建立在熊果酸协同增强紫杉醇抗肿瘤的基础上，结合纳米载药技术采用树枝状聚合物聚酰胺-胺（PAMAM）构建新型纳米载药微球，通过优化熊果酸与紫杉醇双药纳米微球的制备条件，将熊果酸和紫杉醇通过肽链Gly-Phe-Leu-Gly与PAMAM表面氨基连接，达到了药物酶响应性释放，实现了肿瘤内药物的高浓度，对纳米药物载体和纳米载药微球相关特征的测定，并且证明了通过将肿瘤穿透肽iRGD修饰在纳米微球上以后，该纳米载药微球同时具有体内长循环及肿瘤靶向渗透功能。通过体外实验证明了两药之间基于“氧化疗法”的协同抑瘤机制，体内相关实验工作正在进行。本项目的实施为探索一种全新有效的胃癌靶向性药物治疗方案提供新思路。项目资助发表核心论文2篇，发表SCI论文3篇，最高影响因子13.9，项目投入经费18万，目前支出16.2万元，各项支出基本与预算相符，剩余经费计划用于本项目研究的后续支出。