The Alternative Complement Pathway and Hemocompatibility of Nanosurfaces

项目摘要 静脉注射的纳米粒药物被吞噬细胞清除并引发免疫反应， 包括细胞因子释放和假性过敏(Doxil®高达10%，Onpattro®高达30%)。的确有 大量临床前证据表明血清补体系统参与了这些疾病 回应。对患者补体激活机制的理解和设计 预防策略可以提高纳米药物的安全性和有效性。我们发现 细胞膜衍生的补体抑制物可有效阻断补体激活 并防止健康献血者血液中的白细胞摄取纳米颗粒。此外， 针对纳米颗粒表面的补体沉积而设计的抑制剂显示 皮摩尔活度，对于我们测试的所有纳米配方。现有的数据提出了一种新的假设 其中不到1%的纳米颗粒作为补体级联的引发剂。我们的长期合作 目标是进行纳米药物与补体抑制剂联合的临床试验。这样的一个 试验将为纳米医学领域提供关于补体在 人体的血液相容性、清除和输液反应。这项提案的主要目标是 1)进一步了解纳米颗粒启动补体的机制；2)设计一种 快速配对试验检测纳米粒药物对补体的激活作用；3)研究 纳米粒子结合抑制物在体外和狗中确定的患者队列的血液中的有效性。 这项研究将改变现有的隐身设计范式：它将使控制和精细- 纳米级药物传递和成像系统的生物相容性研究 抑制剂。

Project Abstract Intravenously injected nanoparticulate drugs are cleared by phagocytes and elicit immune reactions, including cytokine release and pseudoallergy (up to 10% in Doxil® and 30% in Onpattro®). There is substantial preclinical evidence on the involvement of the serum complement system in these responses. Understanding the mechanisms of complement activation in patients and designing preventive strategies can improve the safety and efficiency of nanoparticle-based drugs. We found that cell membrane-derived inhibitors of complement can effectively shut off complement activation and prevent the uptake of nanoparticles by leukocytes in the blood of healthy donors. Furthermore, the inhibitors that are designed to target complement deposits on the nanoparticle surface showed picomolar activity, for all nanoformulations we tested. The available data suggest a novel hypothesis wherein less than 1% of nanoparticles act as initiators of the complement cascade. Our long-term goal is to conduct a clinical trial of combination of nanomedicines with complement inhibitors. Such a trial will provide the nanomedicine field with the ultimate answers on the role of complement in hemocompatibility, clearance, and infusion reactions in humans. The main objectives of this proposal are 1) to further understand mechanisms of complement initiation by nanoparticles; 2) to design a rapid companion test to measure complement activation by nanoparticle-based drugs; 3) to study the efficacy of nanoparticle-binding inhibitors in blood of defined cohorts of patients in vitro and in dogs. This research will shift the existing paradigm of stealth design: it will enable the control and fine- tuning of the biocompatibility of nano-sized drug delivery and imaging systems using specific inhibitors.