Nanoparticles for targeting drug delivery to the injured vascular wall

用于将药物递送至受损血管壁的纳米颗粒

• 批准号: 7569399
• 负责人: Kytai Truong Nguyen
• 金额: $ 17.62万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569399
• 关键词: Adhesions; Adhesives; Angioplasty; Antibodies; Area; Arteries; Binding; Binding Sites; Blood Cells; Blood Platelets; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cell Communication; Cell Culture Techniques; Deposition; Development; Dexamethasone; Drug Carriers; Drug Delivery Systems; Effectiveness; Emulsions; Endothelial Cells; Endothelium; Figs - dietary; Glycoprotein Ib; Goals; In Vitro; Inflammation; Injury; Intervention; Methods; Modeling; Outcome Study; P-Selectin; Pharmaceutical Preparations; Physiological; Property; Rattus; Recruitment Activity; Research Project Grants; Site; Smooth Muscle Myocytes; Surface; System; Therapeutic Agents; Thrombosis; VWF gene; Vascular Diseases; base; cell motility; cell type; clinical application; design; drug efficacy; effective therapy; in vivo; injured; innovation; migration; nanoparticle; novel; particle; prevent; restenosis; shear stress; surface coating; uptake

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.

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，可以在心血管介入（如血管成形术）后将治疗剂靶向并递送至受损血管壁。我们的策略是模拟血小板（一种血细胞类型）的糖蛋白Ib（GPIb）通过受损内皮细胞（EC）中表达的P-选择素或沉积在受损内皮下的vWF的结合，这对于循环血小板在高剪切条件下与受损血管壁的初始相互作用至关重要。在我们的提议中，与包括抗P-选择素抗体的当前靶向策略相比，使用GPIb-纳米颗粒用于靶向药物递送的主要优点是GPIb特异性结合在受损EC上表达的P-选择素和沉积在受损内皮下的vWF两者，从而将更多的纳米颗粒作为药物载体累积到受损壁位点以进行有效的药物递送。为了实现我们的目标，三个具体目标是：（1）使用标准的双乳液方法开发药物（地塞米松）负载的可生物降解GPIb-纳米颗粒。(2)使用平行流板系统、用P-选择素或vWF包被的表面和活化的EC研究这些纳米颗粒的体外靶向活性和有效性。(3)使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功效。这些特定目标的评估参数包括GPIb的结合位点和稳定性、纳米颗粒性质的变化、流动条件下GPIb-纳米颗粒在活化内皮细胞中的粘附和摄取以及这些纳米颗粒在发炎EC和损伤大鼠动脉中的药理活性。心血管介入治疗经常损伤血管壁，导致晚期病理状况的发展，如炎症和再狭窄。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，可以快速靶向并递送治疗剂至受损的EC和内皮下，尽管存在剪切影响，以获得治疗这些并发症的更有效疗法。