新型可注射靶向载药纳米粒/温度敏感水凝胶复合体系的构建及其在转移性乳腺癌治疗中的应用基础研究

Breast cancer is one of the most common malignant diseases in women. Tumor metastasis is the main cause of treatment failure of breast cancer. In this project, we will fabricate a series of novel injectable local drug delivery systems (DTX/Lyp-1-NP@PLEL hydrogel), which consist of cancer targeting drug-loaded nanoparticles and thermo-sensitive hydrogel, trying to suppress breast cancer metastasis in different stages during metastasis. First of all, the cancer targeting drug-loaded system can inhibit the growth and invasion of the primary tumor with minimized systemic toxicity after its local injection. Secondly, the ligand conjugated nanoparticles released from the site of primary tumor are hypothesized to target the lymphatic metastatic tumors due to their special affinity to the cancer cell and lymphatic system. And then, the inhibition of the primary tumor and the suppression of the metastatic tumors lead to an improving treatment of the metastatic breast cancer. Our goal in this study is to establish a platform technology of fabricating a novel injectable biodegradable thermo-sensitive PDLLA-PEG-PDLLA hydrogel, a technology of improving the water-solubility of insoluble drug and achieving targeting drug delivery through nanotechnology. The project will provide a new idea and theoretical basis for the effective treatment of metastatic breast cancer.

乳腺癌是女性恶性疾病中最常见的重大疾病之一，肿瘤转移是导致乳腺癌治疗失败的主要原因。本项目以乳腺癌转移机制为出发点，针对转移发生的多个关键步骤，拟构建用于原发瘤部位局部化疗的DTX/Lyp-1-NP@PLEL hydrogel可注射温敏水凝胶复合体系，尝试在多个环节抑制肿瘤转移。首先，采用原发瘤部位局部给药，提高药物在病灶的靶向富集，抑制原发瘤扩张转移；其次，利用具有淋巴管及乳腺癌细胞双靶向作用的载药纳米粒进行转移癌细胞的靶向追踪，增加淋巴系统的化疗药物分布，降低癌细胞远端转移的程度。以达到在抑制原发瘤生长的同时，能够抑制转移瘤发生，提高转移性乳腺癌的治疗效果。通过本项目实施我们将建立制备新型的局部治疗用可注射、可生物降解、温度敏感型水凝胶（PDLLA-PEG-PDLLA）的平台技术,建立通过纳米技术提高难溶药物水溶性、实现靶向递送的平台技术，为乳腺癌的有效治疗提供新思路和理论依据。

恶性肿瘤具有异质性、耐药性和频繁复发等特点，其中乳腺癌是危害女性健康的第一杀手，目前传统的治疗方法临床获益有限。本项目针对乳腺癌的转移和复发问题，结合医用高分子生物材料的发展和纳米给药系统技术，设计了多种新型药物递送体系，开展了一系列研究工作，主要包括载药纳米粒/温敏水凝胶化疗复合体系、氧化还原响应多功能纳米粒/温敏水凝胶光热治疗治疗体系、化疗/光热治疗联合治疗体系、光热治疗/免疫治疗联合治疗体系等。在Adv Funct Mater, Nano today, Adv Sci, Biomaterials, Nano Research, Theranostics等国际重要学术刊物上发表39篇论文，申请发明专利2 项。本项目为抑制乳腺癌生长、转移和复发，提高乳腺癌治疗效果，提供了新思路和理论依据。