Nanotechnology Platform for Targeting Solid Tumors

靶向实体瘤的纳米技术平台

基本信息

批准号：
7676083
负责人：
MARK A TALAMINI
金额：
$ 75.82万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-29 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7676083
关键词：
Address Adverse effects Aminopeptidase P Animal Model Annexin A1 Antibodies Antibody Formation Antineoplastic Agents Area Behavior Binding Biochemical Biological Biology Biomedical Research Blood Blood Vessels Bypass Candidate Disease Gene Caveolae Cell Fractionation Cell Surface Proteins Cell membrane Cell physiology Cell surface Cells Cellular biology Chemistry Chronic Clinic Clinical Cloning Coupled Data Diagnosis Diagnostic Diagnostic Imaging Disease Distant Doctor of Medicine Dose Doxorubicin Drug Delivery Systems Drug Formulations Endocytosis Endothelial Cells Endothelium Engineering Equipment Event Excision Figs - dietary Fractionation Generations Genes Genetic Genomics Goals Heating Heterogeneity Human Image Immunology Individual Intravenous Label Laboratories Location Lung Lung Neoplasms Malignant Neoplasms Mediating Medicine Membrane Protein Traffic Micrometastasis Modeling Molecular Molecular Profiling Monitor Nanotechnology Neoplasm Metastasis Neoplastic Stromal Cell Organ Oxygen Pathway interactions Penetration Pharmaceutical Preparations Pharmacologic Substance Physics Physiological Physiological Processes Positioning Attribute Primary Neoplasm Principal Investigator Process Property Proteins Proteomics Radioimmunoconjugate Radioisotopes Rattus Reagent Receptor Cell Reporter Research Research Personnel Resolution Sampling Silicon Dioxide Site Solid Neoplasm Surface Surgeon Systems Biology Technology Testing Therapeutic Therapeutic Agents Therapeutic antibodies Time Tissues Translations Treatment Efficacy Tumor Biology Tumor Cell Biology Tumor Tissue Validation Vascular Endothelial Cell Vascular Endothelium Work antibody conjugate base cancer cell cancer therapy design gene therapy human disease in vivo innovation interest intravenous administration intravenous injection lymph nodes molecular imaging multidisciplinary nanocarrier nanolabel nanomedicine nanoparticle nanoscale nanotherapeutic neoplastic neoplastic cell novel strategies polyacrylamide pre-clinical prevent programs response targeted delivery tissue processing tool trafficking transcytosis treatment duration tumor uptake whole body imaging

项目摘要

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）：通过合理设计在体内实现纳米颗粒（NP）介导的在体内的组织选择性输送的组织选择性递送的进展有限，部分原因是血管内皮是这种体内这种疗法的强大障碍。实现纳米医学的最终目标的两个基本障碍是缺乏适当的肿瘤/组织特定靶标，以及缺乏有关内皮细胞血液传播NP的相互作用和处理的基本信息。我们已经使用了一种系统生物学方法，再加上基于纳米技术的组织分级和亚分型蛋白质组学来快速鉴定和验证新的癌症靶标（Nature（2003）429：629-35）。在这里，我们建议将这些靶标用于将新的NP引导到体内实体瘤。我们已经组建了一个独特的团队，具有化学，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。我们将整合现有的功能，以研究各种新的内皮细胞（EC）靶向的NP的体内行为以及相互作用。该项目的假设是，可以通过识别EC表面蛋白的特定抗体将NP主动地靶向实体瘤/选择组织，并且将NP靶向Caveolae可能会进一步增强组织/肿瘤的渗透，这不仅可以促进进入EC，而且更重要的是，在整个内皮中更重要的是，可以直接访问下皮，以直接进入下皮细胞。为此，我们提出了以下特定目的：1）生成和表征各种新的NP，这些NP专门结合了小窝中选择的肺和肿瘤诱导的EC表面蛋白； 2）定义NP的细胞表面动力学和细胞内运输途径，该培养物在培养物中生长的EC中有针对性的小窝； 3）研究静脉内给药后体内抗体偶联的NP的组织/肿瘤靶向和EC处理； 4）通过评估其体内的生物效能，测试靶向肿瘤NP在大鼠肿瘤模型中专门提供药物的能力。通过实现这四个特定目标，我们将对NP靶向，内皮加工和组织/肿瘤穿透比目前所知更好，更详细地了解。这将通过创建用于诊断剂的新型体内成像剂以及新的多功能治疗剂，能够绕开生物学障碍以直接递送到癌细胞，从而促进NP技术从长凳到诊所的转化。