The Alternative Complement Pathway and Hemocompatibility of Nanosurfaces

纳米表面的替代补体途径和血液相容性

• 批准号: 10053157
• 负责人: Dmitri Simberg
• 金额: $ 49.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10053157
• 关键词: Acute; Alternative Complement Pathway; Autoimmune Diseases; Binding; Biological Assay; Blood; Canis familiaris; Cell membrane; Chimeric Proteins; Clinical; Clinical Trials; Companions; Complement; Complement 3d Receptors; Complement Activation; Complement Inactivators; Dangerousness; Data; Deposition; Development; Disease remission; Dose; Doxorubicin Hydrochloride Liposome; Drug Delivery Systems; Electron Microscopy; Engineering; Family suidae; Funding; Goals; Human; Image; Immobilization; Immune; Immune response; In Vitro; Incubated; Infection; Infusion procedures; Intervention; Intravenous; Leukocytes; Liposomes; Literature; Measurement; Measures; Monitor; Mus; Pathway interactions; Patients; Phagocytes; Pharmaceutical Preparations; Phase; Plasma; Prevention strategy; Proteins; Proteomics; Reaction; Research; Role; Safety; Serum; Sterically Stabilized Liposome; Surface; Sushi Domain; System; Testing; base; biomaterial compatibility; clinical development; cohort; complement system; crosslink; cytokine; design; efficacy study; experimental study; ferumoxytol; hemocompatibility; high throughput screening; imaging system; immunoreaction; improved; in vivo; inhibitor/antagonist; irinotecan; iron oxide; iron oxide nanoparticle; molecular imaging; nanoGold; nanodrug; nanoformulation; nanomaterials; nanomedicine; nanoparticle; nanoparticulate; nanosized; nanotechnology platform; novel; novel strategies; pre-clinical; prevent; response; side effect; superparamagnetism; technological innovation; uptake

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.

项目摘要 静脉注射的纳米颗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® 中高达 10%，Onpattro® 高达 30%）。有 大量临床前证据表明血清补体系统参与这些疾病 回应。了解患者补体激活的机制并设计 预防策略可以提高纳米颗粒药物的安全性和效率。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摄取纳米颗粒。此外， 旨在靶向纳米颗粒表面补体沉积的抑制剂表明 对于我们测试的所有纳米制剂，皮摩尔活性。现有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 目标是进行纳米药物与补体抑制剂组合的临床试验。这样一个 试验将为纳米医学领域提供补体作用的最终答案 人类的血液相容性、清除率和输注反应。本提案的主要目标 1) 进一步了解纳米粒子引发补体的机制； 2）设计一个 快速伴随测试，测量纳米颗粒药物对补体的激活； 3）研究 纳米颗粒结合抑制剂在体外和狗的特定患者群体的血液中的功效。 这项研究将改变现有的隐身设计范式：它将实现控制和精细化 使用特定的纳米药物输送和成像系统的生物相容性调整 抑制剂。