血小板靶向/荧光多功能纳米药物构建及其抗乳腺癌转移作用研究

It has been well-known that breast cancer is one of the most common women malignancies, and has become "the first killer" for women. Despite recent advances in therapeutic strategy, recurrence and metastasis are the main causes resulting in the mortality of breast cancer patient. Therefore, the development of safe and efficient treatment method against breast cancer metastasis is urgently needed. Increasing studies have demonstrated that platelets play a crucial role in tumor cell metastasis by directly interacting with tumor cells to promote their transendothelial action and to shield tumor cells from immune attack in the circulation. Targeting platelet function should be an effective method to inhibit breast cancer metastasis. Based on the fact that the nanoparticle drug delivery system has been widely used for enhanced tumor therapy efficiency and the ability of integrating various functional groups, the purpose of this study is to identify the specific markers expressed on tumor-associated platelet surfaces. Based on the screening of platelet-specific markers, we will develop multifunctional fluorescent nanoparticles as drug carriers for targeted delivery of anti-platelet antibody or active antibody fragment to inhibit and trace circulating platelets and thus inhibit tumor metastasis. The novel quantum dot-modified amphiphilic copolymer or liposome nanoparticles would able to specifically deliver anti-platelet antibody or small molecular drugs into the tumor tissues after systemic administration and trace circulating tumor cells or metastasis sites. We will assess the effects of physicochemical properties of nanocarriers on the drug loading and delivery and determine anti-tumor metastatic effects in tumor-bearing mice. The in vivo distribution and behaviors of nanoparticles will also be investigated by real time imaging and biochemical analysis. This study provides evidence for designing nanoscale drug delivery system for metastatic breast cancer treatment and imaging and has brought hope to completely cure breast cancer.

乳腺癌是女性高发的恶性肿瘤之一，远处转移是患者致死的最重要因素，因此寻找抗乳腺癌转移的新思路，具有积极的临床前意义。近年来，大量的研究表明，血小板在肿瘤转移过程中的多个环节发挥至关重要的作用，它可以通过直接粘附到肿瘤细胞表面促进细胞跨越血管内皮进入血液循环，并作为保护层使循环中的肿瘤细胞进行免疫逃逸，同时亦可以促进肿瘤细胞在远端器官驻留，形成转移灶。因此，靶向抑制血小板功能有望为抗乳腺癌转移提供全新思路。本研究主要采取全转录组和蛋白质组测序技术以及二者关联度分析技术，筛选和鉴定血小板表面结合肿瘤细胞的关键受体/信号分子，揭示二者相互作用机制；并基于此，构建靶向抑制相关分子的纳米药物载体，同时整合量子点技术，最终获得一种诊疗一体化的多功能纳米药物；阐明纳米药物的理化特性影响药物装载和输运的机制；通过影像准确定位循环肿瘤细胞和转移灶，进行精准治疗，为抗乳腺癌转移提供全新诊疗一体化技术。

本项目的总体研究目标是筛选并鉴定介导血小板与肿瘤细胞之间相互作用的血小板表面关键受体或信号蛋白，并以此为靶点构建诊疗一体化的多功能纳米药物，实现靶向抑制乳腺癌转移以及示踪循环肿瘤细胞和/或转移灶，提供有效抗乳腺癌转移的新方法和技术。在本项目的资助下，课题组共发表相关SCI学术论文5篇，其中nature子刊2篇，项目申请人均为第一作者或通讯作者（含共同）；推动专利转化1项。本项目的研究成果为临床乳腺癌的有效治疗提供全新的策略，有望提高乳腺癌治愈率、提高患者带瘤生存质量，同时有望推广到其他多种肿瘤类型，有效的抑制肿瘤的增殖与转移。在本项目的资助下，项目负责人先后入选中组部万人计划“青年拔尖”、北京市杰青、中科院创新交叉团队负责人等人才计划支持项目；荣获IFAM优秀青年科学家奖，荣获北京市自然科学一等奖（第二完成人）、中国药学会科学技术二等奖（第四完成人）等。培养博士后2名，培养博士研究生4名（其中1名获得2021年度国家奖学金），培养硕士研究生5名（其中2名获得硕士学位），培养中科院大学大四本科毕设生3名。