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：
10653068
负责人：
Dmitri Simberg
金额：
$ 63.39万
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/10653068
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 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 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 irinotecan iron oxide iron oxide nanoparticle molecular imaging nano nanoGold nanodrug nanoengineering 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.

项目摘要静脉注射的纳米药物是类，并引起iMitimune现实，包含细胞因子释放和伪铝（在Doxil®中最多10％，Onpattro®中的30％）。关于血清补体系统在这些中涉及的大量临床前证据反应。预防性策略可以提高我们发现的纳米颗粒的安全性补体的细胞膜衍生物可以有效地关闭补体激活并防止健康供体血液中白细胞吸收纳米颗粒。旨在靶向纳米颗粒表面靶向综合的抑制剂显示对我们测试的所有nanformations picomolar活性。其中，纳米颗粒的少于1％作为汇编级联的发起人目的是进行纳米医学与补体抑制剂组合的临床试验。试验将为纳米医学领域提供有关汇编作用的最终答案该提案的主要目标是人类的血液相容性，清除和输注反应。 1）进一步了解纳米颗粒的编译启动机制；快速伴侣测量基于纳米颗粒的药物的补体激活；纳米颗粒结合吸入器在体外和狗中定义的患者人群的血液中的功效。这项研究将是隐形设计的现有范式：它可以控制和罚款使用特定的特定抑制剂。

项目成果

期刊论文数量（42）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hitting the sweet spot: exploiting HIV-1 glycan shield for induction of broadly neutralizing antibodies.

DOI：
10.1097/coh.0000000000000639
发表时间：
2020-09
期刊：
Current opinion in HIV and AIDS
影响因子：
4.1
作者：
Wagh K;Hahn BH;Korber B
通讯作者：
Korber B

Complement Inhibitors Block Complement C3 Opsonization and Improve Targeting Selectivity of Nanoparticles in Blood.

DOI：
10.1021/acs.bioconjchem.0c00342
发表时间：
2020-07-15
期刊：
Bioconjugate chemistry
影响因子：
4.7
作者：
Gaikwad H;Li Y;Gifford G;Groman E;Banda NK;Saba L;Scheinman R;Wang G;Simberg D
通讯作者：
Simberg D

PEGylated Liposomes Accumulate in the Areas Relevant to Skin Toxicities via Passive Extravasation across "Leaky" Endothelium.

DOI：
10.1021/acsnano.2c00423
发表时间：
2022-04-26
期刊：
ACS NANO
影响因子：
17.1
作者：
Li, Yue;Lofchy, Laren;Wang, Guankui;Gaikwad, Hanmant;Fujita, Mayumi;Simberg, Dmitri
通讯作者：
Simberg, Dmitri

Translational gaps in animal models of human infusion reactions to nanomedicines.

人类对纳米药物输注反应的动物模型中的转化差距。

DOI：
10.2217/nnm-2018-0064
发表时间：
2018
期刊：
Nanomedicine (London, England)
影响因子：
0
作者：
Moghimi,SMoein;Simberg,Dmitri
通讯作者：
Simberg,Dmitri

Watching the gorilla and questioning delivery dogma.

DOI：
10.1016/j.jconrel.2017.07.021
发表时间：
2017-09-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Anchordoquy TJ;Simberg D
通讯作者：
Simberg D