肿瘤微环境响应性载药纳米凝胶靶向抑制肿瘤淋巴道转移的应用研究

Malignant tumor metastasis mainly occurs via lymphatic ways, and chemical therapy are widely used in the treatment of lymphatic tumor metastasis but suffers from limited efficiency for non-specific distribution. With its controllable size, environment-responsiveness and drug-loading ability, nanogels are very promising carriers to load anti-cancer drugs, but currently it is mainly used for the treatment of primary tumors, the possibility of nanogels serve as tumor lymphatic metastasis inhibitor is seldom investigated. We have found that dextran-based nanogels with a certain size can selectively accumulate in lymphatic vessel in previous studies, so developing a tumor-microenvironment responsive anti-cancer drug loaded nanogels to targetedly inhibit lymphatic tumor metastasis is very worthtrying. Certain issues need to be clarified: 1. How to control nanogels’ size to target lymphatic vessels; 2. whether the nanogels can release its loaded drug in a tumor-mircoenvironment responsive way; 3. whether the nanogels can effectively prevent and treat tumor lymphatic metastasis. Based on these questions, this project is aimed to fabricate an ideal tumor lymphatic metastasis inhibitor through adjusting the fabrication parameters to guarantee a proper size range to target lymphatic vessels, investigating the tumor-microenvironment responsive release of anti-cancer drugs via in vitro drug release profile and cell-based experiments, and confirming the anti-cancer effect of the nanogels both on cell and tumor lymphatic metastasis animal models. For animal models, we would like to evaluate the ability of the nanogels to prevent tumor metastasis before metastasis actually happens and to inhibit tumor metastasis after it happens, so as to offer some new knowledge for nanogels as lymphatic metastasis inhibitors.

淋巴转移是恶性肿瘤转移的主要途径，化疗是其重要治疗措施，但因无法实现靶向给药和可控释药导致治疗效果差。纳米凝胶因具有粒径可控性、环境响应性和药物负载能力，有望成为理想的肿瘤淋巴道转移抑制剂。然而，其应用主要局限于肿瘤原发灶的治疗，尚无报道在抑制肿瘤淋巴道转移方面的应用。本课题组前期已证实一定粒径范围的葡聚糖基纳米凝胶能够靶向定位淋巴道，受此启发，拟研发一种肿瘤微环境响应性载药纳米凝胶用来抑制肿瘤淋巴道转移，但尚需明确几个核心问题：1.如何调控粒径实现靶向淋巴道；2.能否实现肿瘤微环境响应性释药；3.能否有效预防和治疗肿瘤淋巴道转移。针对上述问题，本项目拟通过调控合成参数控制粒径分布以实现淋巴道靶向定位，利用细胞学实验研究其肿瘤微环境响应性释药性能及体外抑瘤能力。同时结合肿瘤淋巴道转移的动物模型，从预防和治疗两方面评估其抑制肿瘤淋巴道转移的可行性，以期为抑制恶性肿瘤的淋巴道转移提供新思路。

靶向抑制肿瘤淋巴道转移是临床亟待攻克的重大难题，如何实现淋巴转移通路药物的靶向定位和可控释药是解决的关键。为解决这一难题，按照项目最初设计的研究思路，本课题组在前期研究的基础上，通过调控葡聚糖基纳米凝胶的投料比、载药量、单体和交联剂等合成参数，控制其粒径范围位于淋巴道高度选择性范围之内，实现了载药葡聚糖基纳米凝胶的淋巴道靶向性；通过改变PH值和GSH体外模拟肿瘤弱酸性/还原性的微环境，证实了载药葡聚糖基纳米凝胶具有环境响应性解交联的特性，同时实现了环境响应性释药性能。在此基础上，通过建立乳腺癌淋巴道转移动物模型作为评估手段，设置多个不同针对性的实验组和对照组，从细胞学和组织学两个层面证实了载药葡聚糖基纳米凝胶抑制肿瘤淋巴道转移的可行性。本项目相关研究成果已发表SCI收录论文4篇，已接受SCI论文2篇，已修回SCI论文3篇，申请相关专利1项，帮助培养研究生2名，全面完成了各项研究任务与考核指标。这些研究成果对于葡聚糖基纳米凝胶在肿瘤淋巴道转移的临床应用转化奠定了坚实的基础。