Nanoparticle Targeting to Control Angiogenesis

纳米颗粒靶向控制血管生成

• 批准号: 6917828
• 负责人: Jeffrey M. Davidson
• 金额: $ 30.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-22 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917828
• 关键词: SDS polyacrylamide gel electrophoresis; angiogenesis; apolipoprotein E; autoradiography; bioimaging /biomedical imaging; biomaterial development /preparation; biotechnology; cell line; drug delivery systems; drug vehicle; enzyme linked immunosorbent assay; fluorescence microscopy; imaging /visualization /scanning; immunocytochemistry; laboratory mouse; lung; magnetic resonance imaging; neoplasm /cancer; peptides; pharmacokinetics; thrombospondins; ultrasonography; wound

DESCRIPTION (provided by applicant): The goal of this project is to achieve targeted delivery of angiostatic agents to sites of neovascularization. This is a widely accepted strategy that is limited in part by technologies of delivery and validation. The proposed studies center around a novel, biocompatible delivery device, the nanoparticle (NP), as a means to provide sustained, targeted delivery of angiostatic agents to sites of angiogenesis: wounds and tumors. The key elements of the delivery system are low toxicity and compositional flexibility, based interactions of charged polymer pairs. As a model system, we have utilized novel peptide analogs of thrombospondin-l (TSP-1) previously shown to have angiostatic properties. To provide retention within NP, these peptides have been prepared as polyethylene glycol conjugates that retain both heparin binding and biological activity. NP prepared with TSP-1 peptide conjugates show a markedly different biodistribution than empty NP and localization to sites of neovascularization. This proposal sets out to accomplish three goals: (1) optimization of the NP formulation, including dose-setting and incorporation of other targeting agents; (2) use of imaging and tracer technologies to ascertain biodistribution of targeted NP in mice; (3) validation of the efficacy of targeted delivery of NP containing angiostatic agents to wounds and tumors. In further studies, a peptide sequence derived from apolipoprotein E will be incorporated into the nanoparticle to enhance selective targeting of endothelial cells. Tumor delivery and targeting will be tested by noninvasive imaging using luciferase bioluminescence, 123I-scintigraphic imaging, and magnetic resonance imaging with gadolinium contrast. Conventional tracer technologies and microscopic localization of fluorescently labeled NP will be applied as well. In vivo, real-time image analysis of tumor vascularity will be determined by power Doppler ultrasound, and tumor mass will be determined by magnetic resonance imaging. In addition, conventional morphometric and histological techniques will be used to quantify the efficacy of this novel drug delivery system. The objective is to design drug delivery systems that will specifically target pathological angiogenesis with minimal effects on the normal vasculature.

描述（由申请人提供）：该项目的目的是实现将血管抑制剂的目标递送到新血管形成部位。这是一种广泛接受的策略，部分受到交付和验证技术的限制。拟议的研究围绕一种新型的生物相容性递送装置纳米颗粒（NP），作为提供血管生成部位的持续，靶向靶向血管抑制剂的一种手段：伤口和肿瘤。输送系统的关键要素是低毒性和组成柔韧性，这是带电聚合物对的基于基于的相互作用。作为模型系统，我们利用了先前显示的血小板传播L（TSP-1）的新型肽类似物具有血管性特性。为了在NP内提供保留率，这些肽是作为保留肝素结合和生物学活性的聚乙烯乙二醇结合物制备的。用TSP-1肽偶联物制备的NP显示出明显不同的生物分布与空NP以及对新血管形成部位的定位。该提案旨在实现三个目标：（1）优化NP公式，包括设定和掺入其他靶向剂； （2）使用成像和示踪技术来确定小鼠靶向NP的生物分布； （3）验证含有血管抑制剂的NP靶向递送到伤口和肿瘤的疗效。在进一步的研究中，将源自载脂蛋白E的肽序列将纳入纳米颗粒中，以增强内皮细胞的选择性靶向。肿瘤的递送和靶向将通过使用荧光素酶生物发光，123i scintigraphic Imaging和Gadolinium对比度进行磁共振成像来测试肿瘤的递送和靶向。也将应用常规的示踪技术和荧光标记为NP的微观定位。在体内，肿瘤血管的实时图像分析将由功率多普勒超声确定，肿瘤质量将由磁共振成像确定。此外，将使用常规的形态计量学和组织学技术来量化这种新型药物输送系统的功效。目的是设计药物输送系统，该系统将专门针对病理血管生成，对正常脉管系统产生最小的影响。