Development of a Novel Nanoconstruct Based Photothermal Therapy for Tumor Hypoxia

描述(申请人提供)：缺氧是实体肿瘤的一个共同特征，它发生在各种恶性肿瘤中，并显著降低肿瘤对放射和化疗的敏感性。因此，开发针对低氧微环境的治疗方法，在不损害正常组织和癌细胞复发的情况下有效地清除肿瘤具有重要意义。近红外激光辅助的基于纳米粒子的光热消融治疗已经成为这一领域最有前途的新医学策略之一。金纳米棒(GNR)具有尺寸小、尺寸可调、光学可调性强以及惰性等特点，在这方面引起了人们的极大兴趣。在此基础上，我们进行了一系列的初步研究，成功地制备并表征了一种新型的由GNR和抗碳酸酐酶IX(CAIX)抗体组成的纳米结构，该抗体是一种有效的肿瘤缺氧生物标志物。在此，我们建议验证我们的假设，即这种基于纳米结构的光热消融将在不损害正常组织的情况下，有效地消除缺氧微环境中的肿瘤。第一个目标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会与CAIX过表达的人结肠癌HT29细胞具有特异性结合，并在正常细胞保持完好的激光条件下有效地摧毁癌细胞。第二个目的是研究靶向和非靶向GNR(有和没有抗CAIX)在荷HT29异种移植瘤动物体内的药代动力学和生物分布。它将阐明是否可以在抗CAIX抗体的帮助下在肿瘤缺氧时实现更高的GNR积聚。第三个目的是在体内对携带HT29异种移植瘤的动物进行光热消融。它将揭示这种疗法是否可以靶向缺氧区域，有效地杀死癌细胞，提高肿瘤动物的存活率。总的来说，这些研究将验证这种基于GNR/抗CAIX的光热消融疗法用于治疗肿瘤缺氧和改善临床结果的可行性。

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.