Vascular delivery of nanocarriers by erythrocyres

红细胞对纳米载体的血管输送

基本信息

批准号：
10153877
负责人：
Vladimir R Muzykantov
金额：
$ 70.22万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153877
关键词：
Acute Address Adult Respiratory Distress Syndrome Affinity Animals Anti-Inflammatory Agents Antibodies Avidity Binding Biological Availability Blood Blood Vessels Brain Cardiovascular Diseases Carotid Arteries Cell surface Cells Cerebrovascular system Clinical Research Coupling Data Development Disease Drug Carriers Drug Delivery Systems Drug Design Drug Targeting Drug usage Endothelial Cells Endothelium Engineering Erythrocytes Goals Hematological Disease Hepatic Human Inflammation Infusion procedures Injections Intervention Intravenous Kinetics Ligand Binding Ligands Lung Microfluidics Neurologic Organ Pathologic Pathologic Processes Pharmaceutical Preparations Pharmacotherapy Pilot Projects Sepsis Site Stroke System Therapeutic Intervention Thrombosis Tissues Transfusion Translations base biomaterial compatibility design drug efficacy in vitro Model in vivo nanocarrier novel novel strategies novel therapeutics particle spatiotemporal targeted treatment therapeutic target trafficking uptake vascular bed

项目摘要

Project Summary The multifunctional endothelial interface between blood and tissues is an important target for therapeutic interventions in many human maladies. To achieve precise interventions, many labs including us conjugate drugs and drug carriers with affinity ligands that target cargoes to the endothelium. On the other hand, carriers that accumulate in tissues via non-affinity mechanisms may provide an additional boost in drug delivery capacity. We have found that reversible association of nanocarriers (NCs) with the red blood cell (RBC) surface provides a new strategy combining targeted and non-targeted approaches. NCs adsorbed onto isolated RBCs (RBC/NC) rapidly transfer to the vasculature downstream of the injection site and avoid hepatic uptake. Pilot data show that we can synergize the power of RBC-hitchhiking and affinity targeting. Loading on RBCs provides almost three orders of magnitude boost of uptake of EC-targeted NCs in the lungs. Further, RBC-targeted NCs safely load onto RBCs in vivo, which allows us to avoid transfusion. To combine these advantages and enable transfer from RBCs to ECs, we have designed dual-targeted NCs (DTNCs) by conjugating to opposite facets of anisotropic “Janus” particles ligands that bind to RBCs and EC. Fine-tuning of each facet's avidity maximizes spatiotemporal control of targeting to RBCs and transfer to ECs. We identified ligands selectively targeting NCs to the brain vs lungs. The goal of this proposal is to define the mechanism and enable translation of this novel, paradigm-shifting strategy. We will employ mutually reinforcing models: in vitro (microfluidic), ex vivo (perfused human lungs) and in vivo (naïve vs pathological animals). We will study NC loading onto RBC and the transfer to and localization in recipient cells, and the effect of drug delivery by RBC-hitchhiking in three independent Aims. Aim 1: Loading NC onto RBCs. We will: A) Define optimal NC design for RBC loading; B) Engineer RBC-targeted NC loading in vivo; and, C) Determine the biocompatibility of NC-loaded RBCs. Aim 2: NC unloading and transfer. We will characterize and optimize vascular transfer of untargeted NCs vs EC-targeted and dual-targeted NCs: A) Kinetics and amplitude of transfer; B) Cellular addressing and trafficking of NCs; and, C) Pathophysiological factors modulating transfer. Aim 3: Translational RBC hitchhiking. We will: A) Appraise beneficial vs unintended effects of delivery of anti-inflammatory agents by RBC/NC; B) Refine NC targeting to human RBC; and, C) Recapitulate key findings of animal studies in perfused human lungs. This study will advance: A) Design of drug delivery systems combining targeted nanocarriers with “supercarrier” RBCs; B) Understanding of important vascular interfaces; C) Development of precisely targeted pharmacotherapy for treatment of ALI/ARDS and likely stroke and other common acute crises.

项目摘要血液和组织之间的多功能内皮界面是许多人类疾病的治疗干预措施。为了实现精确的干预措施，许多实验室包括美国共轭药物和具有亲和力配体的药物载体，将货物靶向货物内皮。另一方面，通过非亲和力机制积聚在组织中的载体可能提供额外的促进药物输送能力。我们发现带有红细胞（RBC）表面的纳米载体（NCS）提供了一种结合目标的新策略和非目标方法。 NCS被吸附到孤立的RBC（RBC/NC）上，迅速转移到注射部位下游的脉管系统，避免肝摄取。飞行员数据显示我们可以协同RBC搭行和亲和力定位的力量。在RBC上加载几乎可以在肺中摄入EC靶向的NC的三个数量级增强。此外，针对RBC的目标 NCS安全地加载到体内RBC上，这使我们能够避免输血。结合这些优点并使从RBC转移到ECS，我们设计了双目标NCS（DTNC）通过将与RBC和EC结合的各向异性“ Janus”颗粒的相对相结合。对每个方面的亲戚进行微调，最大化对RBC的目标的时空控制和转移向ECS。我们确定了将NC靶向大脑与肺的配体。该提议的目标是为了定义这种新颖的，范式转移策略的机制并启用翻译。我们将员工相互加固的模型：体外（微流体），离体（灌注人肺）和体内（幼稚与病理动物）。我们将研究NC加载到RBC上，并转移至在受体细胞中的定位，以及在三个独立目标。 AIM 1：将NC加载到RBC上。我们将：a）定义用于RBC加载的最佳NC设计； b）工程师在体内靶向RBC的NC加载；以及，c）确定NC负载的生物相容性 RBCS。目标2：NC卸载和转移。我们将表征并优化未靶向的NCS与EC靶向和双目标NCS：A）传递的动力学和放大器； b） NCS的细胞处理和贩运；并且，c）调节转移的病理生理因素。目标3：翻译RBC搭便车。我们将：a）评估有益与意外影响 RBC/NC递送抗炎剂； b）将NC靶向人RBC；而且，c）概括了灌注人类肺部动物研究的关键发现。这项研究将进步：a）将靶向纳米载体与“超级载体” RBC相结合的药物输送系统的设计； b）了解重要的血管界面； c）开发精确的目标治疗ALI/ARD的药物治疗以及可能中风和其他常见急性犯罪。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Red blood cells: The metamorphosis of a neglected carrier into the natural mothership for artificial nanocarriers.

DOI：
10.1016/j.addr.2021.113992
发表时间：
2021-11
期刊：
Advanced drug delivery reviews
影响因子：
16.1
作者：
Glassman PM;Hood ED;Ferguson LT;Zhao Z;Siegel DL;Mitragotri S;Brenner JS;Muzykantov VR
通讯作者：
Muzykantov VR

Nanoparticle Properties Modulate Their Attachment and Effect on Carrier Red Blood Cells.

DOI：
10.1038/s41598-018-19897-8
发表时间：
2018-01-25
期刊：
Scientific reports
影响因子：
4.6
作者：
Pan DC;Myerson JW;Brenner JS;Patel PN;Anselmo AC;Mitragotri S;Muzykantov V
通讯作者：
Muzykantov V

Cell therapies in the clinic.

DOI：
10.1002/btm2.10214
发表时间：
2021-05
期刊：
Bioengineering & translational medicine
影响因子：
7.4
作者：
Wang LL;Janes ME;Kumbhojkar N;Kapate N;Clegg JR;Prakash S;Heavey MK;Zhao Z;Anselmo AC;Mitragotri S
通讯作者：
Mitragotri S

Nanoparticles in the clinic: An update post COVID-19 vaccines.