The Alternative Complement Pathway and Hemocompatibility of Nanosurfaces

项目摘要 腹腔内注射的纳米颗粒药物被吞噬细胞清除并引起免疫反应， 包括细胞因子释放和假性过敏（Doxil®中高达10%，Onpattro®中高达30%）。有 大量的临床前证据表明，血清补体系统参与了这些疾病， 应答了解患者补体激活的机制， 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剂可以有效地关闭补体激活 并防止健康献血者血液中的白细胞吸收纳米颗粒。此外，委员会认为， 设计用于靶向纳米颗粒表面上的补体沉积物的抑制剂显示， 皮摩尔活性，对于我们测试的所有纳米制剂。现有的数据提出了一个新的假设 其中少于1%的纳米颗粒充当补体级联的引发剂。我们的长期 目的是进行纳米药物与补体抑制剂联合的临床试验。这样的 这项试验将为纳米医学领域提供关于补体在 血液相容性、清除率和人体输注反应。本提案的主要目标 1）进一步理解纳米颗粒引发补体的机制; 2）设计一种 快速伴侣试验，以测量基于纳米颗粒的药物的补体激活; 3）研究 纳米颗粒结合抑制剂在体外确定的患者队列和犬血液中的功效。 这项研究将改变现有的隐身设计范式：它将使控制和精细- 使用特定的纳米药物递送和成像系统的生物相容性的调整 抑制剂的

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.