Nanoparticle Targeting to Control Angiogenesis

纳米颗粒靶向控制血管生成

• 批准号: 7084418
• 负责人: Jeffrey M. Davidson
• 金额: $ 30.04万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7084418
• 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（由申请方提供）：本项目的目标是实现血管生成抑制剂靶向递送至新生血管形成部位。这是一种被广泛接受的策略，但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），作为一种手段，提供持续的，有针对性的血管生成抑制剂的血管生成部位：伤口和肿瘤。递送系统的关键要素是低毒性和组成灵活性，基于带电聚合物对的相互作用。作为一个模型系统，我们已经利用了新的肽类似物的血小板反应蛋白-1（TSP-1）先前显示具有血管抑制性能。为了提供NP内的保留，将这些肽制备为保留肝素结合和生物活性的聚乙二醇缀合物。用TSP-1肽缀合物制备的NP显示出与空NP明显不同的生物分布和对新血管形成部位的定位。该提案旨在实现三个目标：（1）NP制剂的优化，包括剂量设定和其他靶向剂的掺入;（2）使用成像和示踪剂技术来确定靶向NP在小鼠中的生物分布;（3）验证将含有血管抑制剂的NP靶向递送至伤口和肿瘤的功效。在进一步的研究中，将载脂蛋白E衍生的肽序列掺入纳米颗粒中以增强内皮细胞的选择性靶向。肿瘤递送和靶向将通过使用荧光素酶生物发光的非侵入性成像、123 I-荧光成像和使用钆造影剂的磁共振成像进行测试。传统的示踪技术和荧光标记的NP的显微镜定位也将被应用。在体内，肿瘤血管分布的实时图像分析将通过能量多普勒超声确定，肿瘤质量将通过磁共振成像确定。此外，传统的形态学和组织学技术将被用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，将专门针对病理性血管生成，对正常血管系统的影响最小。

项目成果

Nanovehicular intracellular delivery systems.

纳米细胞内输送系统。

• DOI: 10.1002/jps.21270
• 发表时间: 2008-09
• 期刊: JOURNAL OF PHARMACEUTICAL SCIENCES
• 影响因子: 3.8
• 作者: Prokop, Ales;Davidson, Jeffrey M.
• 通讯作者: Davidson, Jeffrey M.

Nanoparticulate system for efficient gene transfer into refractory cell targets.

用于将基因有效转移至难治性细胞靶标的纳米颗粒系统。

• DOI: 10.1021/bm0492531
• 发表时间: 2005
• 期刊: Biomacromolecules.
• 作者: Carlesso,Gianluca;Kozlov,Eugene;Prokop,Ales;Unutmaz,Derya;Davidson,JeffreyM
• 通讯作者: Davidson,JeffreyM

Development of improved nanoparticulate polyelectrolyte complex physicochemistry by nonstoichiometric mixing of polyions with similar molecular weights.

通过具有相似分子量的聚离子的非化学计量混合来开发改进的纳米颗粒聚电解质复合物物理化学。

• DOI: 10.1021/bm0604754
• 发表时间: 2007
• 期刊: Biomacromolecules
• 影响因子: 6.2
• 作者: Hartig,SeanM;Carlesso,Gianluca;Davidson,JeffreyM;Prokop,Ales
• 通讯作者: Prokop,Ales