Nanotechnology Platform for Targeting Solid Tumors

描述(由申请人提供)： 通过合理的设计在体内实现纳米粒(NP)介导的药物和显像剂的组织选择性递送的进展有限，部分原因是血管内皮细胞是体内这种治疗的强大屏障。实现纳米医学最终目标的两个基本障碍是缺乏合适的肿瘤/组织特异性靶点，以及缺乏关于血管内皮细胞与血载NP相互作用和处理的基本信息。我们使用了系统生物学方法与基于纳米技术的组织分离和亚分离蛋白质组学相结合，从而能够快速识别和验证新的癌症靶点(自然(2003)429：629-35)。在这里，我们建议使用这些靶点来将新的NPs导向体内的实体肿瘤。我们组建了一支独特的团队，在化学、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拥有关键专业知识。我们将整合我们现有的能力来研究各种新的内皮细胞(EC)靶向NPs的体内行为和相互作用。该项目的假设是，通过识别EC表面蛋白的特定抗体，NPs可以主动靶向实体肿瘤/选定的组织，而将NP靶向小窝可能不仅促进向ECs的转运，而且可能更重要的是，通过穿过内皮直接进入潜在的组织肿瘤细胞，从而进一步增强组织/肿瘤的穿透性。为此，我们提出了以下具体目标：1)制备和鉴定各种新的NPs，它们能够特异性地结合特定的肺泡和肿瘤诱导的EC表面蛋白；2)确定NP在培养的ECs中的细胞表面动力学和细胞内转运途径；3)研究抗体结合的NPs在体内的组织/肿瘤靶向和EC加工；4)通过体内生物有效性的评估，测试肿瘤靶向NPs在大鼠肿瘤模型中特异性递送药物的能力。通过实现这四个特定目标，我们将比目前所知的更好和更详细地了解NP靶向、内皮处理和组织/肿瘤穿透。这将通过创造用于诊断的新的体内成像剂以及能够绕过生物屏障直接输送到癌细胞的新的多功能疗法，促进NP技术从实验台到临床的转化。

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.