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Selective tumor inhibition by tumor-homing angiogenesis-suppressing nanofibers

通过肿瘤归巢血管生成抑制纳米纤维选择性抑制肿瘤

基本信息

批准号：
9110918
负责人：
Chuanbin Mao
金额：
$ 19.66万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9110918
关键词：
Address Adverse effects Affinity Angiogenesis Inhibitors Antibodies Apoptotic Arteries Bacteriophages Binding Biological Assay Blood Vessels Breast Cancer Model Breast Cancer Treatment Capsid Proteins Cell surface Coagulation Process DNA Data Disease Endothelial Cells Enzyme-Linked Immunosorbent Assay Excision FDA approved Fetal Development Fiber Funding Generations Genetic Engineering Goals Health Hemorrhage Home environment Homing Human Hypertension Immune response In Vitro Lead Libraries Malignant Neoplasms Mammary Neoplasms Methods Minor Mus Necrosis Neoplasm Metastasis Nutrient Oxygen Peptides Phage Display Pharmaceutical Preparations Process Proteins Publishing Random Peptide Libraries Recombinants Reporting Ribonucleases Side Site Specificity Surface Techniques Testing Tetanus Helper Peptide Toxic effect Tubulin Tumor Angiogenesis United States National Institutes of Health Virus Waste Products Wound Healing angiogenesis angiogenin angiogenin receptor antiangiogenesis therapy antitumor effect base blood vessel development cancer cell cancer therapy design heart function improved in vitro activity in vivo inhibitor/antagonist nanofiber nanomedicine nanoscale neoplastic cell neutralizing monoclonal antibodies novel prevent receptor small molecule tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Angiogenesis is an important process in the progression of cancer. In the absence of vascular support, cancer cells will become necrotic or even apoptotic. Therefore, antiangiogenic therapy becomes a promising strategy for treating cancers. Angiogenin (Ang) is a protein predominantly secreted by cancer cells for angiogenesis. Blocking its interaction with Ang receptors on endothelial cell surface can disable its function of inducing cancer angiogenesis and thus inhibit the progression of cancers. Although some Ang inhibitors have been developed and even approved by the FDA for blocking the interactions between Ang and its receptors to treat cancer, these inhibitors lack the tumor-homing capability and may lead to serious side effects, such as bleeding and hypertension. To address this problem, we propose to develop a human-safe phage-based tumor-homing Ang inhibitor for improved cancer antiangiogenic therapy. The objectives of this Application are (i) to identify Ang- binding peptides that can selectively bind to and interfere with the regular functions of Ang by major coat phage display technique; and (ii) to construct a dual-functional recombinant phage nanofiber by double-displaying our recently discovered breast tumor-homing peptide at the tip and the identified Ang-binding peptide on the side- walls of the same nanofiber. The resultant phage nanofiber displaying both tumor-homing and Ang-binding peptides on its surface is expected to first home to breast tumors and then bind to the Ang within the tumors to inhibit the tumor angiogenesis. Our hypotheses are that (1) Ang-binding peptides can be identified from a major coat-displayed phage library, and (2) the dual-functional tumor-homing/Ang-binding phage nanofibers double- displaying Ang-binding and tumor-homing peptides can serve as a smart angiogenic inhibitor to selectively home to and retain within breast tumors, and bind Ang to block the tumor angiogenesis and subsequently inhibit the tumor growth. We will carry out two aims to test our hypothesis: Aim 1: Identify Ang-binding peptides from a major coat-displayed phage library by biopanning against Ang. We will use phage display technique to conduct biopanning against commercially purchased Ang and select Ang-binding peptides that can specifically target and bind to Ang from the major coat-displayed phage library. The Ang-binding specificity of the selected peptides will be verified by phage capture ELISA, peptide inhibition assay, and phage-Ang interaction assay. Aim 2: Construct dual functional breast tumor-homing/Ang-binding phage and evaluate its use in selectively inhibiting tumor growth. We will use our established double display technique to display both the breast tumor-homing and Ang- binding peptides on the single phage nanofiber and evaluate its antitumor activity in vitro. We will then inject the phage into the breast tumor models to verify that the phage can home to tumor, bind to Ang secreted by tumor cells to suppress angiogenesis and inhibit tumor growth. This project will lead to tumor-homing Ang-binding nanofibers that can serve as nanomedicines for selectively inhibiting cancer angiogenesis and progression without causing the side effects.