Deformable hydrogel microparticles as delivery vehicles to the vascular wall

可变形水凝胶微粒作为血管壁的递送载体

• 批准号: 8935782
• 负责人: Omolola Eniola-Adefeso
• 金额: $ 7.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-26 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8935782
• 关键词: Adverse effects; Affect; Architecture; Arteries; Attention; Behavior; Binding; Biological Assay; Blood; Blood Vessels; Blood capillaries; Blood flow; Bypass; Caliber; Characteristics; Chemistry; Chronic; Cleaved cell; Clinical Trials; Coronary; Coronary Arteriosclerosis; Diagnosis; Dimensions; Disease; Drug Carriers; Endothelial Cells; Endothelium; Engineering; Epitopes; Erythrocytes; Event; Failure; Gelatinase B; Genes; Geometry; Goals; Health; Health Care Costs; Human; Hydrogels; In Vitro; Inflammation; Injection of therapeutic agent; Intervention; Kinetics; MMP9 gene; Measures; Microcirculation; Molecular Weight; Morbidity - disease rate; Oligonucleotides; Operative Surgical Procedures; Oral Administration; Particulate; Patients; Pattern; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Physiological; Process; Shapes; Site; Solutions; Staging; Surface; System; Therapeutic; Tissues; Work; angiogenesis; base; capillary; crosslink; density; design; drug efficacy; hemodynamics; imaging agent; improved; in vivo; interstitial; monolayer; monomer; mortality; nanoparticle; particle; percutaneous coronary intervention; pre-clinical research; prevent; response; targeted delivery; therapeutic target

DESCRIPTION (provided by applicant): Vascular-targeted carriers (VTCs) offer unique opportunities for improving diagnosis and treatment of many serious human ailments, including coronary artery disease (CAD), by non-invasively providing localized delivery of imaging agents or potent therapeutics. CAD is the leading cause of morbidity and mortality in the world. Current remedies for CAD include surgical bypass of the affected artery, percutaneous coronary interventions, and oral administration of statin drugs. Improvements in these treatments are necessary since, for instance, major coronary events can still occur in 50% of patients who have undergone aggressive statin therapy. Chronic inflammation and associated processes (e.g. angiogenesis) are involved at all stages of CAD, and VTCs directed to CAD via biomolecules expressed on the vascular wall in association with these processes may provide a viable, non-surgical approach to preventing or even reversing established CAD. However, nanoparticles (NPs) that are typically proposed for use as carriers in targeting therapeutics to the vascular wal have been recently shown to not effectively transport to the vascular wall in blood flow due to high entrapment in the red blood cell core of blood flow. Conversely, microparticles (MPs), particularly in the 2 - 3 �m diameter size range, effectively localize to the vascular wall in bloo flow. Nevertheless, NPs remain highly attractive over MPs for targeted disease intervention owing to their high potential for achieving intracellular (e.g., gene) and interstitial delivery. Or overall goal is to develop a smart delivery system to dramatically improve NP transport in blood flow, thus fully realizing the potential of vascular-targeted NPs (VTNPs) for disease intervention. Specifically, we propose to develop protease-degradable hydrogel MPs with tunable geometries, surface characteristics, and deformability to serve as carriers for the delivery of agent- loaded VTNPs to the vascular wall in medium to large blood vessels relevant in CAD. The proposed specific aims are: (1) to fabricate and characterize the hemodynamics of NP-loaded, protease-degradable hydrogel MPs in human blood flow, and (2) to evaluate protease-induced degradation of VTNP-loaded hydrogel MPs. We hypothesize that highly deformable and degradable hydrogel MPs loaded with VTNPs can be fabricated and in the size range that would allow for their high capacity to localize to the vascular wall from human blood flow and that protease-degradable cross-linkers within the hydrogel MPs matrix can be effectively cleaved to release loaded VTNPs upon contact with disease-associated proteases that are upregulated by the inflamed endothelium. Overall, our systematic integration of the advantages of the high vascular wall localization efficiency of MPs and the internalization capabilities of th embedded NPs can serve as a more effective strategy for targeting agent for diagnosis and treatment of CAD. Drug carriers engineered with the understanding of hemodynamics, vessel architecture, and disease-specific epitopes will offer improved in vivo efficacy over contemporary carriers whose design are focused on targeting epitope alone.

描述（由申请人提供）：血管靶向载体（VTC）通过非侵入性地提供显像剂或有效治疗剂的局部递送，为改善许多严重人类疾病（包括冠状动脉疾病（CAD））的诊断和治疗提供了独特的机会。 CAD 是世界上发病和死亡的主要原因。目前治疗 CAD 的方法包括对受影响动脉进行搭桥手术、经皮冠状动脉介入治疗和口服他汀类药物。这些治疗方法的改进是必要的，因为例如，在接受积极的他汀类药物治疗的患者中，50% 的患者仍可能发生重大冠状动脉事件。慢性炎症和相关过程（例如血管生成）涉及 CAD 的所有阶段，通过与这些过程相关的血管壁上表达的生物分子针对 CAD 的 VTC 可能提供一种可行的非手术方法来预防甚至逆转已形成的 CAD。然而，通常建议用作针对血管壁的靶向治疗的载体的纳米粒子（NP）最近被证明由于在血流的红细胞核心中的高度截留而不能有效地在血流中转运至血管壁。相反，微粒 (MP)，特别是直径尺寸范围为 2 - 3 微米的微粒，可有效定位于血流中的血管壁。尽管如此，由于纳米粒子在实现细胞内（例如基因）和间质传递方面具有很高的潜力，因此在有针对性的疾病干预方面，纳米粒子仍然比 MP 更具吸引力。总体目标是开发一种智能递送系统，显着改善纳米颗粒在血流中的转运，从而充分发挥血管靶向纳米颗粒（VTNP）用于疾病干预的潜力。 具体来说，我们建议开发具有可调几何形状、表面特征和可变形性的蛋白酶可降解水凝胶 MP，作为将负载药物的 VTNP 递送到 CAD 相关中型至大血管的血管壁的载体。提出的具体目标是：(1) 制造并表征人体血流中负载 NP 的蛋白酶可降解水凝胶 MP 的血流动力学，以及 (2) 评估蛋白酶诱导的负载 VTNP 的水凝胶 MP 的降解。我们假设可以制造负载 VTNP 的高度可变形和可降解的水凝胶 MP，其尺寸范围使其能够从人体血流中定位到血管壁，并且水凝胶 MP 基质内的蛋白酶可降解交联剂可以在与由发炎的内皮上调的疾病相关蛋白酶接触时有效裂解以释放负载的 VTNP。总的来说，我们系统地整合了MP的高血管壁定位效率和嵌入的NP的内化能力的优势，可以作为诊断和治疗CAD的靶向剂的更有效的策略。基于对血流动力学、血管结构和疾病特异性表位的理解而设计的药物载体将比当代仅针对表位的设计的载体提供更好的体内功效。