Development of a Novel Nanoconstruct Based Photothermal Therapy for Tumor Hypoxia

开发基于新型纳米结构的肿瘤缺氧光热疗法

基本信息

批准号：
8337539
负责人：
Huan Xie
金额：
$ 11.33万
依托单位：
TEXAS SOUTHERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8337539
关键词：
3T3 Cells Ablation Academia Animals Antibodies Area Binding Biodistribution Biological Markers Biomedical Research Blood Vessels Blood specimen Caliber Cell Death Cells Clinical Collaborations Colon Carcinoma Colonic Neoplasms Competence Coupled Data Development Drug Kinetics Effectiveness Environment Extracellular Protein Fostering Future Gold HT29 Cells Heating Human Hypoxia Image In Vitro Injection of therapeutic agent Institutes Lasers Malignant Neoplasms Mass Spectrum Analysis Measures Medical Microscopy Minority Modality Mus Neoplasm Metastasis Normal Cell Normal tissue morphology Nude Mice Optics Organ Outcome Performance Plasma Polyethylene Glycols Radiation Radio Recurrence Recurrent tumor Relative (related person)Research Residual Tumors Resistance Resolution Saline Sampling Series Solid Neoplasm Solutions Students Survival Rate System Techniques Temperature Testing Texas Time Training Treatment Efficacy Tumor Volume Universities Xenograft procedure base cancer cell cancer therapy cancer type carbonate dehydratase career chemotherapy improved in vivo injured insight interest killings nanoparticle nanorod neoplastic cell novel overexpression targeted delivery therapy development three-dimensional modeling traditional therapy tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Hypoxia is a common feature of solid tumors that occurs across a wide variety of malignancies and significantly reduces tumor sensitivity to radiation and chemotherapy. Therefore, it is of great importance to develop therapies that target specifically to hypoxic microenvironments and effectively eliminate tumors without damage of normal tissue and recurrence of cancer cells. Nanoparticle-based photothermal ablation therapy assisted by near infrared (NIR) laser has arisen as one of most promising new medical strategies for this endeavor. Gold nanorods (GNR) are of particular interest in this regard because of their small and adjustable size, strong optical tunability as well as inertness. Base on that, we performed a series of preliminary studies that successfully prepared and characterized a novel nanoconstruct composed of GNR and anti-carbonic anhydrase IX (CAIX) antibody, which is a viable biomarker for tumor hypoxia. Herein we propose to test our hypothesis that this nanoconstruct-based photothermal ablation will effectively eliminate tumors in hypoxic microenvironments without damage to normal tissue. The first aim is to conduct in vitro cellular binding, uptake and photothermal destruction studies. It will determine if this approach will have specific binding to CAIX-overexpressed human colon tumor HT29 cells and will effectively destruct cancer cells at the laser condition that normal cells remain intact. The second aim is to study pharmacokinetics and biodistribution of targeted and nontargeted GNR (with and without anti-CAIX) in animals bearing HT29 xenografts. It will elucidate if higher accumulation of GNR at tumor hypoxia can be achieved with the aid of anti-CAIX antibody. The third aim is to perform in vivo photothermal ablation on animals bearing HT29 xenografts. It will reveal whether this therapy can target on hypoxic regions, effectively kill cancer cells and improve the survival rate of tumored animals. In general, these studies will validate the feasibility of applying this GNR/anti-CAIX-based photothermal ablation therapy to treat tumor hypoxia and improve clinical outcome. PUBLIC HEALTH RELEVANCE: The proposed GNR/anti-CAIX nanoconstruct-based photothermal therapy could serve as an alternative or complementary approach for standard cancer treatment to eliminate residual or recurrent tumor cells, especially within the hypoxic areas that are resistant to traditional therapies. This therapy can have widespread utilization in many different cancer types that overexpress CAIX. Such a class solution to the vexing problem of hypoxic therapy resistance would likely be a significant contribution to cancer treatment.

描述（由申请人提供）：缺氧是实体瘤的常见特征，发生在各种恶性肿瘤中，并显着降低了肿瘤对放射和化学疗法的敏感性。因此，开发专门针对缺氧微环境的疗法并有效消除肿瘤而没有正常组织损害和癌细胞复发，这一点非常重要。基于纳米颗粒的光热消融疗法在近红外（NIR）激光辅助疗法已成为这项努力最有前途的新医疗策略之一。金纳米棒（GNR）在这方面特别感兴趣，因为它们的尺寸较小且可调节性强，可调性和惰性。在此基础上，我们进行了一系列初步研究，这些研究成功地制备并表征了由GNR和抗钙质酸酐酶IX（CAIX）抗体组成的新型纳米结构，该抗体是肿瘤缺氧的可行生物标志物。在此，我们建议测试我们的假设，即这种基于纳米结构的光热消融将有效地消除低氧微环境中的肿瘤，而不会损害正常组织。第一个目的是进行体外细胞结合，摄取和光热破坏研究。它将确定这种方法是否将与CAIX过表达的人结肠肿瘤HT29细胞具有特异性结合，并在正常细胞保持完整的激光条件下有效地破坏癌细胞。第二个目的是研究具有HT29异种移植物的动物的靶向和非目标GNR（有和没有抗球的）的药代动力学和生物分布。如果借助于抗Caix抗体，可以阐明GNR在肿瘤缺氧下的较高积累。第三个目的是对带有HT29异种移植物的动物进行体内光热消融。它将揭示该疗法是否可以靶向低氧区域，有效地杀死癌细胞并提高肿瘤动物的存活率。通常，这些研究将验证应用此GNR/抗抗糖基的光热疗法的可行性，以治疗肿瘤缺氧并改善临床结果。公共卫生相关性：拟议的GNR/抗CAIX纳米结构的光热疗法可以作为标准癌症治疗的替代或互补方法，以消除残留或复发性肿瘤细胞，尤其是在对传统疗法具有抗性的缺氧区域内。这种疗法可以在过表达Caix的许多不同癌症类型中广泛使用。这种针对低氧治疗抗性问题的类别解决方案可能对癌症治疗有重要贡献。