Deformable hydrogel microparticles as delivery vehicles to the vascular wall

描述（由申请人提供）：血管靶向载体（VTCs）通过非侵入性地提供显像剂或强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是世界上发病率和死亡率的主要原因。目前治疗冠心病的方法包括手术搭桥、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，50%接受他汀类药物积极治疗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（如血管生成）参与CAD的所有阶段，而VTCs通过与这些过程相关的血管壁上表达的生物分子定向到CAD，可能提供一种可行的、非手术的方法来预防甚至逆转已建立的CAD。然而，纳米颗粒（NPs）通常被提议作为靶向治疗血管壁的载体，最近已被证明不能有效地在血流中运输到血管壁，因为它在血流的红细胞核心中被高度捕获。相反，微颗粒（MPs），特别是在2 - 3微米直径范围内，在血流中有效地定位于血管壁。尽管如此，相对于MPs， NPs在靶向疾病干预方面仍然具有很高的吸引力，因为它们具有实现细胞内（如基因）和间质传递的巨大潜力。总体目标是开发一种智能递送系统，显著改善NP在血流中的运输，从而充分发挥血管靶向NPs （VTNPs）在疾病干预中的潜力。

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.