Nanoparticles for targeting drug delivery to the injured vascular wall

描述(申请人提供)：这项提案的长期目标是开发新型纳米颗粒，即“模仿血小板的纳米颗粒”，作为一种药物载体，可以靶向血管成形术等心血管干预后受损的血管壁并将治疗剂输送到损伤的血管壁。我们的策略是通过表达在受损内皮细胞(ECs)上的P-选择素或沉积在受损内皮下的vWF来模拟血小板(一种血细胞类型)的糖蛋白Ib(GPIB)的结合，这在高切条件下循环血小板与受损血管壁的最初相互作用中是至关重要的。在我们的方案中，与包括抗P-选择素抗体在内的现有靶向策略相比，使用GPIB纳米粒进行靶向给药的主要优点是，GPIB能与损伤内皮细胞上表达的P-选择素和损伤内皮下沉积的vWF结合，从而使更多的纳米粒作为药物载体积累到损伤的壁上，从而实现有效的药物传递。为了实现我们的目标，我们有三个具体的目标：(1)利用标准的复乳法制备载药(地塞米松)的可生物降解的GPIB纳米粒。(2)采用平行流平板系统、表面包被P-选择素或vWF的表面以及活化的内皮细胞，研究这些纳米粒子的体外靶向活性和有效性。(3)用大鼠球囊损伤模型评价我们的新型类血小板纳米粒子的体内疗效。这些特定目标的评估参数包括GPIB的结合位置和稳定性、纳米颗粒性质的变化、流动条件下GPIB纳米颗粒在激活的内皮细胞中的黏附和摄取以及这些纳米颗粒在炎症的内皮细胞和损伤的大鼠动脉中的药理活性。心血管干预通常会损伤血管壁，导致炎症和再狭窄等晚期病理情况的发展。我们新型类血小板纳米颗粒的开发是一种独特的策略，可以快速靶向受损的内皮细胞和内皮下层，并将治疗剂输送到受损的内皮细胞和内皮下，以获得更有效的治疗这些并发症的方法。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to develop novel nanoparticles, "platelet-mimicking nanoparticles," as a drug carrier that can target and deliver a therapeutic agent to the injured vessel wall after cardiovascular interventions such as angioplasty. Our strategy is to mimic the binding of the glycoprotein Ib (GPIb) of platelets (a blood cell type) through either P-selectin expressed in damaged endothelial cells (ECs) or vWF deposited on injured subendothelium, which is critical for the initial interaction of circulating platelets onto the injured vessel wall under high shear conditions. The major advantage of using GPIb-nanoparticles for targeting drug delivery in our proposal, compared to current targeting strategies including anti-P-selectin antibodies, is that GPIb specially binds to both P- selectin expressed on damaged ECs and vWF deposited on injured subendothelium, thereby accumulating more nanoparticles as drug carriers to the injured wall site for effective drug delivery. To accomplish our goal, three specific aims are: (1) Develop drug (dexamethasone)-loaded biodegradable GPIb-nanoparticles using a standard double emulsion method. (2) Investigate the targeting activity and effectiveness of these nanoparticles in vitro using the parallel flow plate system, surfaces coated with P-selectin or vWF, and activated ECs. (3) Evaluate the efficacy of our novel platelet-mimicking nanoparticles in vivo using rat balloon injury models. The assessed parameters for these specific aims include the binding sites and stability of GPIb, changes in nanoparticle properties, the adhesion and uptake of GPIb-nanoparticles in activated endothelial cells under flow conditions as well as pharmacological activities of these nanoparticles in inflamed ECs and injured rat arteries. Cardiovascular interventions often injure the vessel wall, leading to the development of late pathological conditions such as inflammation and restenosis. The development of our novel platelet- mimicking nanoparticles is a unique strategy to rapidly target and deliver therapeutic agents to damaged ECs and subendothelium, despite the shear influence, for more effective therapies to treat these complications.