高分子纳米化CD47抗体用于恶性肿瘤的研究

整合素相关蛋白CD47是一种癌细胞免于宿主免疫系统攻击的保护性受体，利用抗CD47抗体抑制或阻断CD47的信号路径，是非常有潜力的肿瘤免疫治疗新途径。但是，CD47同时也是一种人体必需的重要蛋白质，它广泛分布于红细胞、脑细胞等正常组织细胞表面。因此，裸CD47抗体对肿瘤的治疗存在严重的脱靶问题，需使用高剂量，并可能带来严重副作用。本项目拟以酚醛缩合、苯硼酸络合、凝血靶向为基础，制备四种含EGCG基元的高分子纳米载体用于担载CD47抗体，利用纳米载体对所担载药物的保护、缓释、靶向输送作用，显著减少CD47抗体的脱靶现象，大幅度提升疗效。本项目将围绕高分子纳米化抗体药物在肿瘤处的富集、释放、功能发挥展开一系列研究，包括抗体的体内药代动力学和生物分布，巨噬细胞和T细胞活化，以及杀伤肿瘤和抑制肿瘤转移的效果。本项目研究成果可为纳米载药体系输送蛋白类特别是抗体类抗肿瘤药物提供新思路。

Integrin-associated protein CD47 is a protective receptor of tumor cell against host immune system attack. Inhibition through anti-CD47 antibody or blocking CD47 signaling pathway is a potentially tumor immunotherapeutic avenue. However, CD47 is in contrast a human indispensably important protein. It is widely expressed in normal tissue cell surface, such as placenta, erythrocyte, hepatocyte, brain cells. Therefore, there would be serious off-target problem in naked CD47 antibody based cancer therapy, that high therapeutic doses should be employed, and side-effect would be emerged. In this proposal, based on phenol formaldehyde condensation, boronic acid complexation, clotting targeting, four (-)-Epigallocatechin Gallate (EGCG)-motif polymer nano-ized carriers will be prepared for loading CD47 antibody. With the protection, controlled-release, targeting transportation of loaded drugs, the off-targeting phenomenon will be greatly decreased, and the therapeutic efficiency will be highly enhanced. In this proposal, studies on tumor accumulation, release, functional performance of antibody drug will be carried out, including in vivo pharmacokinetics and biologic distribution, macrophage activation, T cell priming, and cancer damage and tumor metastasis inhibition efficiency. This study will render guiding effect and reference value for antibody drug nano-ized preparation and application, and provide new avenue for anticancer study of nanocarrier transporting protein drugs, especially antibody drugs.