补体C3介导的超顺磁氧化铁偶联CD33单抗载药纳米颗粒靶向治疗急性髓系白血病的实验性研究

Acute myeloid leukemia (AML) is the most common type of leukemia and is still the highest fatality disease among people under age 35 due to the lacking of effective treatments. We found that the superparamagnetic iron oxide (SPIO) nanoworm (NW) can activate the complement component and bind complement component 3 (C3) and IgG proteins, C3 induces SPIO uptake by leukocytes, while other types of cells cannot internalize SPIO NW. These results suggest that we can utilize characteristics of SPIO NW's automatic packaging of drugs, antibody and specific overexpressed C3 receptor (CD11b) and other tumor molecules on leukemia tumor cell surface to achieve targeted therapy for AML. The project aims to 1) construct the compound of SPIO/anti-CD33 monoclonal antibody/chemotherapy drug (SPIO NW/anti-CD33/CTD) and demonstrate that SPIO/anti-CD33/CTD can trigger endocytosis of AML cells both in vitro and in vivo, and 2) investigate the mechanisms of complement activation by SPIO/anti-CD33/CTD using different approaches such as selectively blocking complement activation pathway, and controlling the C3 or anti-CD33 antibody binding amount, and understand the relationship between the expression levels of CD11b or CD33 and uptake of SPIO/anti-CD33/CTD. Based on these experiments, our goals are 1) to demonstrate the dual targeting function of SPIO/anti-CD33/CTD to AML tumor via C3 and anti-CD33 antibody; 2) uncover the methods and mechanisms of endocytosis of SPIO/anti-CD33/CTD by AML cells. The project will provide the theoretical basis to develop new method for AML immunotherapy.

急性髓系白血病（AML)是最常见的白血病类型，由于缺乏有效疗法仍是35岁以下人群致死率最高的疾病。我们发现葡聚糖修饰的蠕虫状超顺磁氧化铁纳米颗粒(SPIO NW)能激活补体、动态结合C3及IgG等蛋白并诱导白细胞特异性吞噬，提示有望利用SPIO NW自动组装药物、抗体及白血病细胞特异性表达某些肿瘤抗原、C3受体(CD11b)等因素实现白血病的靶向治疗。本研究拟构建SPIO NW偶联CD33单抗载药纳米颗粒，观察其能否在体内外诱导AML细胞特异性吞噬；选择性阻断补体激活途径明确SPIO NW纳米颗粒激活补体方式；通过调节纳米颗粒粘附C3及抗CD33抗体量、调控细胞表达CD11b、CD33水平控制纳米颗粒进入AML细胞的量及靶向性，从而阐明SPIO NW通过补体及抗CD33抗体双重靶向AML肿瘤细胞，揭示铁纳米颗粒进入AML细胞的机制及调控手段，为开发白血病新免疫疗法提供理论基础及实验依据。

急性髓系白血病(AML)是最常见的白血病类型，由于缺乏有效疗法仍是35岁以下人群致死 率最高的疾病。我们发现葡聚糖修饰的蠕虫状超顺磁氧化铁纳米颗粒(SPIO NW)能激活补体、动态结合C3及IgG等蛋白并诱导白细胞特异性吞噬，利用SPIO NW自动组装药物、抗体 及白血病细胞特异性表达某些肿瘤抗原、C3受体(CD11b)等因素实现白血病的靶向治疗。本研究构建SPIO NW偶联CD33单抗载药纳米颗粒，观察其能否在体内外诱导AML细胞特异性吞噬; 选择性阻断补体激活途径明确SPIO NW纳米颗粒激活补体方式;通过调节纳米颗粒粘附C3及抗C D33抗体量、调控细胞表达CD11b、CD33水平控制纳米颗粒进入AML细胞的量及靶向性，从而阐明SPIO NW通过补体及抗CD33抗体双重靶向AML肿瘤细胞，揭示铁纳米颗粒进入AML细胞的机制及调控手段，为开发白血病新免疫疗法提供理论基础及实验依据。