权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10212959
负责人：
Dmitri Simberg
金额：
$ 55.46万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/10212959
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

项目摘要

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