腹腔注射智能纳米载药系统治疗癌症腹腔转移的研究

The treatment of metastasis is a major difficulty in clinical cancer therapy. Nano-drug delivery system (NDS) can achieve targeted drug delivery, release drug in a controlled pattern, and relieve the side-effects of loaded drug. NDS can passively target tumor through the blood vessels in tumor tissue after intravenous injection. It has been demonstrated that NDS are capable to treat vascularized tumor xenograft with certain size. However, NDS is unable to penetrate biological barriers and reach the small-sized, unvascularized early metastasis, thus restrict its range of applications. Enterocoelia and peritoneum is a prone metastatic site. Intraperitoneal injection has already been put onto the shelf of clinical cancer treatment for peritoneal metastasis. In this project, we are going to prepare polymer-silica nanohybrid as NDS, and intraperitoneally administrate the NDS to treat peritoneum metastasis. Upon intraperitoneal administration, NDS can bypass the peritoneum-plasma barrier and get in direct touch with the metastasis. Meanwhile, the modified targeting groups can make it selectively enriched in tumor, thereby improve the therapeutic efficacy and relieve the side-effects of loaded anticancer drugs. β-cyclodextrin will be linked by disulfide bond to the surface of the smart NDS as a “gatekeeper” to guard the release window of the drug carrier, which can be triggered by the high-concentration glutathione in cancerous cells to release drug specifically in cancer cell. We propose to evaluate therapeutic efficiency on animal model with peritoneal metastasis. The biodistribution and safety of the intraperitoneally administrated NDS will also be studied. This project aims to expand the application fields of NDS in cancer therapy and will offer basis for its future clinical applications.

转移瘤的处理是癌症临床治疗中的一大难点。纳米载药系统（NDS）可靶向传输药物，实现负载药物的可控释放，并降低其毒副作用。静脉注射的NDS可经血管被动靶向肿瘤，对血管化的肿瘤有良好疗效。但NDS无法透过生物屏障进入尚未血管化的新生转移瘤，因此应用受到了限制。腹腔是癌症转移的主要部位之一，临床中以腹腔注射作为治疗腹腔转移的手段。本项目拟用腹腔注射聚合物-氧化硅复合NDS的方法治疗腹腔转移瘤，以此绕开腹膜-血浆屏障的阻碍，使NDS直接接触肿瘤。同时，通过修饰靶向基团使NDS选择性富集于转移瘤处，以提高药效降低毒副作用。通过进一步功能化，利用二硫键连接的β-环糊精作为释药窗口的“门卫分子”，使智能NDS可选择性响应癌细胞中的高浓度谷胱甘肽释放药物。用动物模型评价此疗法的疗效，研究腹腔注射后材料的生物分布及安全性。本项目旨在拓宽NDS对癌症治疗的应用范畴，为其进一步应用于临床治疗腹腔转移瘤提供依据。

在癌症转移之后，如何对转移瘤进行处理是癌症临床治疗中的一大难点。纳米载药系统（Nanosized drug delivery system, NDS）可通过靶向传输药物，降低抗癌药物的毒副作用。虽然NDS可经由增强渗透滞留效应，经静脉注射后，透过高通透性的肿瘤血管靶向肿瘤，但无法透过生物屏障进入尚未血管化的新生转移瘤。腹腔是癌症转移的主要部位之一，本项目利用腹腔注射了具有靶向肿瘤及响应性释放开关的氧化硅交联的聚合物胶束作为NDS治疗腹腔转移瘤，以此绕开腹膜-血浆屏障的阻碍，使NDS直接接触肿瘤。相对腹腔直接注射抗癌药物阿霉素的疗法，腹腔注射NDS可显著降低毒副作用，并增强疗效。本项目另外探索了利用MTH1抑制剂TH588增强光动力学疗法对肿瘤的疗效。该项目结题时已取得一系列进展，发表了第一或通讯作者SCI论文4篇，其中2篇发表于IF>10的顶级期刊，其中材料领域顶尖期刊Advanced Functional Materials与Science子刊Science Advances各1篇，完成了项目设定的各项工作目标。