靶向抑制肿瘤局部血小板功能的纳米载体构建及其抗乳腺癌转移的研究

Breast cancer is one of the most common women malignancies, and has become "the first killer" for women. Despite recent advances in therapeutic strategies, recurrence and metastasis are the main causes of breast cancer related mortality. Therefore, it is pivotal to develop a safe and efficient treatment method against breast cancer metastasis. Increasing evidences have demonstrated that platelets play a crucial role in tumor cell metastasis by directly interacting with tumor cells or secreting active factors. Targeting platelet function is capable of effectively inhibiting tumor metastasis. Based on the fact that the nanoparticle drug delivery system has been widely used for enhanced tumor therapy efficiency, the aim of this study is to develop multifunctional active nanoparticles as drug carriers for specific delivery of tumor-associated platelet inhibitor or antibody to prolong survival time and improve life quality of breast cancer patients with metastasis. The novel functionalized amphiphilic block copolymer would be used to self-assemble into micellar nanoparticles (MNP) in aqueous solution. The MNPs will be coated by MMP-2-sensitive peptide bilayer to specifically deliver anti-platelet antibody or small molecular drugs into the tumor tissues after systemic administration. We will assess the effects of physicochemical properties of nanocarriers on the drug loading and delivery and test anti-tumor metastatic effects in tumor-bearing mice. This study would provide evidence for designing nanoscale drug delivery systems for metastatic breast cancer treatment and would provide a new strategy for curing cure breast cancer.

乳腺癌是威胁女性健康的主要恶性肿瘤，而肿瘤转移是导致中晚期乳腺癌患者生存期短和生活质量差的主要原因。发展安全、高效的新型抗乳腺癌转移治疗手段，具有积极的临床前意义。研究表明，血小板在肿瘤细胞转移过程中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或分泌多种生物活性因子促进肿瘤转移。本项目拟针对肿瘤微环境中过表达基质金属蛋白酶-2（MMP-2）的生物学特征，设计并构建MMP-2响应型多功能载药纳米颗粒，实现抗血小板药物或抗体对肿瘤组织的靶向输运和可控释放。通过选择性抑制或清除肿瘤局部血小板，控制肿瘤的转移和快速生长，并阐明其作用机制。本项目将为抗血小板治疗抑制转移应用于临床提供新思路，同时为提高中晚期乳腺癌患者生存期和生活质量提供新的治疗技术。

为了提高现有乳腺癌的治疗效果，切实提高乳腺癌患者的生存期与生活质量，项目组以促进乳腺癌远端转移的始动因素—血小板为治疗靶点，设计、构筑多种肿瘤微环境响应的抗肿瘤智能纳米药物，靶向清除/抑制肿瘤局部血小板成分，阻断血小板与肿瘤细胞之间的相互作用，从而有效抑制乳腺癌的进展与远端转移。研究结果表明，将抗血小板治疗与化疗或免疫治疗联合起来，将会极大提高现有乳腺癌治疗方法的疗效，显著提高乳腺癌荷瘤小鼠的生存期。在本项目的资助下，项目组发展智能抗肿瘤纳米药物5种，发表高水平SCI论文9篇，其中包括Nature Biomedical Engineering、Nature Communications、Advanced Sciences、Nano Letters等国际权威期刊4篇；申请中国发明专利3项，转化专利1项，并成功孵化一家高科技生物医药公司“北京君全智药生物科技有限公司”，积极推动智能纳米药物的临床前转化工作。本项目另辟蹊径，从靶向干预肿瘤局部血小板的全新角度出发，发展了多种具有临床应用潜力的多功能智能纳米药物，为中晚期乳腺癌的有效治疗提供了全新思路和技术手段，具有较好的临床意义和社会价值。