Vascular delivery of nanocarriers by erythrocyres

红细胞对纳米载体的血管输送

• 批准号: 9922385
• 负责人: Vladimir R Muzykantov
• 金额: $ 70.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922385
• 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

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细胞界面是 对许多人类疾病的治疗干预。为了实现精确的干预，许多实验室 包括美国的偶联药物和具有亲和配体的药物载体，这些药物和药物载体的目标是将货物 内皮细胞。另一方面，通过非亲和力机制在组织中积累的载体可能 进一步提高药物输送能力。我们已经发现可逆的关联 具有红细胞(RBC)表面的纳米载体(NCS)提供了一种靶向结合的新策略 和无针对性的方法。吸附在分离的红细胞上的NCS(RBC/NC)迅速转移到 注射部位下游的血管，避免肝脏摄取。试点数据表明，我们可以 协同红细胞的力量-搭便车和亲和力靶向。RBC上的加载提供了几乎 肺内EC靶向NCS的摄取增加了三个数量级。此外，以RBC为靶点 NCS在体内安全地负载到红细胞上，这使得我们可以避免输血。要将这些结合在一起 为了实现从RBCs到ECs的转移，我们设计了双靶点NCS(DTNC) 通过结合到各向异性“Janus”粒子的相反面上，与红细胞和EC结合的配体。 微调每个方面的亲和力，最大限度地时空控制靶向红细胞和转移 敬ECS。我们确定了选择性地将NCS靶向脑与肺的配体。这项提案的目标是 就是定义这一新颖的范式转换策略的机制并使之能够翻译。我们会 采用相互增强的模型：体外(微流体)、体外(灌流的人肺)和体内 (幼稚VS病态动物)。我们将研究NC加载到RBC上，并转移到和 红细胞搭便车在受体细胞中的定位和药物传递的影响 目标。目标1：将NC加载到RBC上。我们将：A)确定RBC加载的最佳NC设计；B) 工程红细胞靶向NC体内负载；以及，C)确定NC负载的生物相容性 红细胞。目标2：NC卸货和转移。我们将表征和优化血管移植 非靶向NCS与EC-靶向和双靶NCS：A)迁移的动力学和幅度；B) NCS的细胞寻址和运输；以及，C)调节转移的病理生理因素。 目标3：转译红细胞搭便车。我们将：a)评估以下项目的有益影响和意外影响 通过RBC/NC递送抗炎剂；B)细化NC靶向人RBC；以及，C) 概述了在人类肺灌流中进行的动物研究的主要发现。这项研究将取得进展：a) 靶向纳米载体与“超载体”红细胞相结合的药物输送系统的设计； 了解重要的血管界面；c)开发精确的靶向 治疗ALI/ARDS以及可能的中风和其他常见急性危象的药物疗法。