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.

项目概要 血液和组织之间的多功能内皮界面是重要靶点 对许多人类疾病的治疗干预。为了实现精确干预，许多实验室 包括我们将药物和药物载体与亲和配体结合，将货物靶向 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。我们发现可逆缔合 纳米载体（NC）与红细胞（RBC）表面提供了一种结合靶向的新策略 和非针对性的方法。吸附在分离红细胞 (RBC/NC) 上的 NC 快速转移到 注射部位下游的脉管系统并避免肝脏摄取。试点数据表明我们可以 协同红细胞搭便车和亲和靶向的力量。红细胞上的负载几乎提供了 肺部对 EC 靶向 NC 的吸收增加了三个数量级。此外，RBC靶向 NC 在体内安全地装载到红细胞上，这使我们能够避免输血。要结合这些 为了实现从 RBC 到 EC 的转移，我们设计了双靶点 NC (DTNC) 通过与各向异性“Janus”颗粒配体的相对面缀合，这些配体与红细胞和内皮细胞结合。 微调每个方面的亲和力可最大限度地控制红细胞靶向和转移的时空控制 到 EC。我们确定了选择性地将 NC 靶向大脑而不是肺部的配体。本提案的目标 的目的是定义机制并实现这种新颖的范式转变策略的转化。我们将 采用相辅相成的模型：体外（微流体）、离体（灌注人肺）和体内 （天真动物与病态动物）。我们将研究 NC 加载到 RBC 上以及转移到 和 受体细胞中的定位，以及红细胞搭便车在三个独立的药物递送中的作用 目标。目标 1：将 NC 加载到 RBC 上。我们将： A) 定义 RBC 加载的最佳 NC 设计；二） 工程师体内 RBC 靶向 NC 加载； C) 确定 NC 负载的生物相容性 红细胞。目标2：数控卸载和转移。我们将表征并优化血管转移 非靶向 NC 与 EC 靶向和双靶向 NC：A) 动力学和转移幅度；二） NC 的蜂窝寻址和贩运； C) 调节转移的病理生理因素。 目标 3：转化红细胞搭便车。我们将： A) 评估有益与意外的影响 通过 RBC/NC 输送抗炎剂； B) 完善针对人类红细胞的 NC 靶向；以及，C) 概括灌注人肺动物研究的主要发现。这项研究将推进：A) 将靶向纳米载体与“超级载体”红细胞相结合的药物输送系统的设计；二） 了解重要的血管界面； C) 制定精准目标 用于治疗 ALI/ARDS 以及可能的中风和其他常见急性危机的药物疗法。