权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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（由申请人提供）：血管生成是癌症进展中的重要过程。在缺乏血管支持的情况下，癌细胞会坏死甚至凋亡。因此，抗血管生成疗法成为治疗癌症的一种有前途的策略。血管生成素（Ang）是一种主要由癌细胞分泌的用于血管生成的蛋白质。阻断其与内皮细胞表面血管紧张素受体的相互作用可以使其功能丧失诱导癌症血管生成，从而抑制癌症的进展。尽管一些Ang抑制剂已经被开发出来，甚至被FDA批准用于阻断Ang及其受体之间的相互作用来治疗癌症，但这些抑制剂缺乏肿瘤归巢能力，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，我们建议开发一种人类安全的基于噬菌体的肿瘤归巢血管紧张素抑制剂，以改善癌症抗血管生成治疗。本申请的目的是(i)通过主外壳噬菌体展示技术鉴定能够选择性结合并干扰Ang的常规功能的Ang结合肽； (ii)通过在同一纳米纤维的尖端双重展示我们最近发现的乳腺肿瘤归巢肽和在同一纳米纤维的侧壁上鉴定的血管紧张素结合肽来构建双功能重组噬菌体纳米纤维。由此产生的噬菌体纳米纤维在其表面展示肿瘤归巢肽和血管紧张素结合肽，预计首先归巢于乳腺肿瘤，然后与肿瘤内的血管紧张素结合以抑制肿瘤血管生成。我们的假设是（1）可以从主要的涂层展示噬菌体文库中鉴定出血管紧张素结合肽，（2）双重展示血管紧张素结合和肿瘤归巢肽的双功能肿瘤归巢/血管紧张素结合噬菌体纳米纤维可以作为智能血管生成抑制剂，选择性地归巢并保留在乳腺肿瘤内，并结合血管紧张素以阻断肿瘤血管生成和随后抑制肿瘤生长。我们将实现两个目标来检验我们的假设：目标 1：通过针对 Ang 进行生物淘选，从主要外壳展示噬菌体库中识别 Ang 结合肽。我们将使用噬菌体展示技术对商业购买的 Ang 进行生物淘选，并从主要外壳展示噬菌体库中选择能够特异性靶向并结合 Ang 的 Ang 结合肽。所选肽的 Ang 结合特异性将通过噬菌体捕获 ELISA、肽抑制测定和噬菌体-Ang 相互作用测定进行验证。目标 2：构建双功能乳腺肿瘤归巢/Ang 结合噬菌体并评估其在选择性抑制肿瘤生长中的用途。我们将使用我们已建立的双重展示技术在单噬菌体纳米纤维上展示乳腺肿瘤归巢肽和血管紧张素结合肽，并评估其体外抗肿瘤活性。然后我们将噬菌体注射到乳腺肿瘤模型中，以验证噬菌体能够归巢到肿瘤，与肿瘤细胞分泌的Ang结合，抑制血管生成并抑制肿瘤生长。该项目将产生肿瘤归巢的血管紧张素结合纳米纤维，它可以作为纳米药物，选择性地抑制癌症血管生成和进展，而不引起副作用。