Nanoparticles for targeting drug delivery to the injured vascular wall

描述（由申请人提供）：该提案的长期目标是开发新型纳米颗粒，“血小板模拟纳米颗粒”，作为药物载体，可以在心血管干预（如血管成形术）后靶向并将治疗剂输送到受伤的血管壁。我们的策略是通过在受损内皮细胞（ECs）中表达的p选择素或沉积在受损内皮下层的vWF来模拟血小板（一种血细胞类型）的糖蛋白Ib （GPIb）的结合，这对于高剪切条件下循环血小板与受损血管壁的初始相互作用至关重要。与目前包括抗P-选择素抗体在内的靶向策略相比，在我们的研究中，使用GPIb纳米颗粒靶向药物递送的主要优势在于，GPIb特异性地结合受损内皮细胞上表达的P-选择素和沉积在受损内皮下层的vWF，从而积累更多的纳米颗粒作为药物载体到受损壁部位，从而有效地递送药物。为了实现我们的目标，有三个具体目标：(1)使用标准的双乳法开发药物（地塞米松）负载的可生物降解的gpib纳米颗粒。(2)利用平行流板系统、p -选择素或vWF包被表面和活化的ECs，在体外研究这些纳米颗粒的靶向活性和有效性。(3)利用大鼠球囊损伤模型评估我们的新型血小板模拟纳米颗粒在体内的效果。这些特定目的的评估参数包括GPIb的结合位点和稳定性，纳米颗粒性质的变化，流动条件下活化内皮细胞中GPIb纳米颗粒的粘附和摄取，以及这些纳米颗粒在发炎的内皮细胞和受伤的大鼠动脉中的药理活性。心血管干预往往会损伤血管壁，导致炎症和再狭窄等晚期病理状况的发展。我们的新型血小板模拟纳米颗粒的开发是一种独特的策略，可以快速靶向并将治疗剂输送到受损的内皮细胞和内皮下层，尽管有剪切影响，但可以更有效地治疗这些并发症。项目的叙述

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. Project Narrative Cardiovascular interventions such as angioplasty and stenting, used to open an area of blockage inside the diseased, narrowed blood vessel, often injure the vessel wall, leading to the development of late pathological conditions such as inflammation and restenosis (re-narrowing of an artery). This research project is to develop novel nanoparticles that mimic the adhesive properties of platelets, a blood cell type, bound to the injured vessel wall for targeting drug delivery. Our platelet- mimicking nanoparticles will rapidly target and deliver drugs only to the damaged vessel wall for an effective treatment, leading to the reduction of the artery's re-narrowing after cardiovascular interventions.