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.

描述（由适用提供）：血管生成是癌症进展的重要过程。在没有血管支持的情况下，癌细胞将变性甚至凋亡。因此，抗血管生成疗法成为治疗癌症的有前途的策略。血管生成蛋白（ANG）是一种主要由癌细胞分泌的蛋白质。阻止其与内皮细胞表面上的ANG受体的相互作用可以禁用其功能诱导癌症血管生成，从而抑制癌症的进展。尽管已经开发了某些ANG抑制剂，甚至还被FDA批准，以阻止Ang及其受体之间治疗癌症的相互作用，但这些抑制剂缺乏肿瘤的能力，可能会导致严重的副作用，例如出血和高血压。为了解决这个问题，我们建议开发一种基于人类安全的噬菌体肿瘤抑制剂，以改善癌症的抗血管生成疗法。该应用程序的目标是（i）识别可以通过主要的外套噬菌体显示技术选择性地结合并干扰ANG的常规功能的人的脉络结合宠物；（ii）通过将最近发现的乳腺肿瘤毒性肽与尖端和同一纳米纤维侧壁上鉴定出的Ang结合肽构建双重功能重组噬菌体纳米纤维。预计其表面上的艾恩结合辣椒首先是乳腺肿瘤的家，然后与肿瘤内的ANG结合以抑制肿瘤血管生成。 Our hypotheses are that (1) Ang-binding pepperides 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 pepperides 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随后抑制肿瘤的生长。我们将执行两个目的来检验我们的假设：目标1：通过对ANG的生物群体从主要的涂层播放噬菌体图书馆中识别出昂的辣椒。我们将使用噬菌体展示技术对商业购买的ANG进行生物塑料，并选择可以从主要的涂层播放的噬菌体库中专门靶向并与Ang结合的ang结合辣椒。所选肽的人体结合特异性将通过噬菌体捕获ELISA，肽抑制测定和噬菌体相互作用测定来验证。 AIM 2：构建双重功能性乳腺肿瘤 - 肿瘤/ang结合噬菌体，并评估其在选择性抑制肿瘤生长中的使用。我们将使用我们已建立的双显示技术在单噬菌体纳米纤维上同时显示乳腺肿瘤 - 结合肽，并在体外评估其抗肿瘤活性。然后，我们将把噬菌体注入乳腺肿瘤模型中，以验证噬菌体可以回家肿瘤，与肿瘤细胞分泌的ANG结合以抑制血管生成并抑制肿瘤的生长。该项目将导致肿瘤 - 结合纳米纤维，这些纳米纤维可以作为纳米医学的选择性抑制癌症的血管生成和进展而不会引起副作用。