Nanotechnology Platform for Targeting Solid Tumors

靶向实体瘤的纳米技术平台

• 批准号: 7127277
• 负责人: Jan Eugeniusz Schnitzer
• 金额: $ 67.78万
• 依托单位: SIDNEY KIMMEL CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7127277
• 关键词: aminopeptidase; annexins; athymic mouse; biotechnology; caveolins; diagnosis design /evaluation; disease /disorder model; drug vehicle; fluorescent dye /probe; glioblastoma multiforme; green fluorescent proteins; intracellular transport; intravenous administration; intravital microscopy; ionophores; laboratory rat; monoclonal antibody; nanotechnology; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplasm /cancer diagnosis; nonhuman therapy evaluation; particle; therapy design /development; tissue /cell culture; transcytosis; vascular endothelium

DESCRIPTION (provided by applicant): Limited progress in achieving nanoparticle (NP)-mediated tissue-selective delivery of drugs and imaging agents in vivo by rational design exists in part because the vascular endothelium is a formidable barrier to this type of therapy in vivo. Two fundamental roadblocks to achieving the ultimate goals of nanomedicine are the lack of appropriate tumor/tissue specific targets and a lack of basic information regarding the interaction and processing of blood-borne NP by the endothelium. We have used a systems biology approach coupled with nanotechnology-based tissue fractionation and subfractionation proteomics to enable the rapid identification of and validation of new cancer targets (Nature (2003) 429:629-35). Here, we propose to use these targets toward directing new NPs to solid tumors in vivo. We have assembled a unique team with key expertise in chemistry, nanotechnology, immunology, tumor biology, molecular imaging, membrane trafficking, and vascular cell biology. We will integrate our existing capabilities to investigate the in vivo behavior and interactions of a variety of new endothelial cell (EC)-targeted NPs. This project's hypothesis is that NPs can be actively targeted to solid tumors/select tissues via specific antibodies recognizing EC surface proteins and that targeting NP to caveolae may further enhance tissue/tumor penetration by facilitating transport not only into the ECs but perhaps more importantly across the endothelium for direct access to underlying tissue tumor cells. To this end, we propose the following specific aims: 1) To generate and characterize various new NPs that specifically bind select lung- and tumor-induced EC surface proteins in caveolae; 2) To define cell surface dynamics and intracellular trafficking pathways of NP specifically targeting caveolae in ECs grown in culture; 3) To investigate tissue/tumor targeting and EC processing of antibody-conjugated NPs in vivo after intravenous administration; 4) To test the ability of tumor-targeting NPs to deliver drugs specifically in rat tumor models by assessing their bioefficacy in vivo. By accomplishing these four specific aims, we will gain a better and much more detailed understanding of NP targeting, endothelial processing, and tissue/tumor penetration than is known at present. This will facilitate translation of NP technology from bench to clinic by creating new in vivo imaging agents for diagnostics as well as new multifunctional therapeutics capable of bypassing biological barriers for direct delivery to cancer cells.

描述（由申请人提供）： 通过合理的设计在体内实现纳米颗粒（NP）介导的药物和成像剂的组织选择性递送的有限进展部分地存在，因为血管内皮是这种类型的体内治疗的强大屏障。实现纳米医学最终目标的两个基本障碍是缺乏适当的肿瘤/组织特异性靶点，以及缺乏关于内皮细胞对血液传播的NP的相互作用和处理的基本信息。我们已经使用系统生物学方法结合基于纳米技术的组织分级分离和亚分级分离蛋白质组学，以使得能够快速鉴定和验证新的癌症靶标（Nature（2003）429：629-35）。在这里，我们建议使用这些靶点将新的NP引导到体内实体瘤。我们组建了一支独特的团队，拥有化学、纳米技术、免疫学、肿瘤生物学、分子成像、膜运输和血管细胞生物学方面的关键专业知识。我们将整合我们现有的能力，研究各种新的内皮细胞（EC）靶向纳米粒子的体内行为和相互作用。该项目的假设是，NP可以通过识别EC表面蛋白的特异性抗体主动靶向实体瘤/选择组织，并且将NP靶向小窝可以通过促进转运不仅进入EC，而且可能更重要的是穿过内皮直接进入下层组织肿瘤细胞来进一步增强组织/肿瘤渗透。为此，我们提出了以下具体目标：1）产生和表征各种新的NP，其特异性结合选择的肺和肿瘤诱导的EC表面蛋白在小窝中; 2）确定NP特异性靶向在培养中生长的EC中的小窝的细胞表面动力学和细胞内运输途径; 3）研究静脉内施用后抗体缀合的NP的体内组织/肿瘤靶向和EC加工; 4）通过评估肿瘤靶向纳米颗粒在体内的生物功效来测试肿瘤靶向纳米颗粒在大鼠肿瘤模型中特异性递送药物的能力。通过实现这四个具体目标，我们将获得比目前已知的更好和更详细的了解NP靶向，内皮加工和组织/肿瘤渗透。这将通过创造新的用于诊断的体内成像剂以及能够绕过生物屏障直接递送至癌细胞的新的多功能治疗剂来促进NP技术从实验室到临床的转化。