Development of a Novel Nanoconstruct Based Photothermal Therapy for Tumor Hypoxia

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，并显著降低肿瘤对放疗和化疗的敏感性。 因此，开发特异性靶向低氧微环境并有效消除肿瘤而不损伤正常组织和癌细胞复发的疗法是非常重要的。基于纳米粒子的光热消融治疗辅助近红外（NIR）激光已经成为最有前途的新的医疗策略之一，这方面的奋进。金纳米棒（GNR）在这方面特别感兴趣，因为它们的小且可调节的尺寸，强的光学可调谐性以及惰性。在此基础上，我们进行了一系列的初步研究，成功地制备和表征了一种由GNR和抗碳酸酐酶IX（CAIX）抗体组成的新型纳米结构，这是一种可行的肿瘤缺氧生物标志物。在此，我们提出测试我们的假设，即这种基于纳米结构的光热消融将有效地消除缺氧微环境中的肿瘤，而不损伤正常组织。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会与CAIX过表达的人类结肠肿瘤HT 29细胞特异性结合，并在正常细胞保持完整的激光条件下有效破坏癌细胞。第二个目的是研究携带HT 29异种移植物的动物中靶向和非靶向GNR（有和没有抗CAIX）的药代动力学和生物分布。这将阐明是否可以在抗CAIX抗体的帮助下实现肿瘤缺氧时GNR的更高积累。第三个目的是对携带HT 29异种移植物的动物进行体内光热消融。它将揭示这种疗法是否能靶向缺氧区域，有效地杀死癌细胞，提高肿瘤动物的存活率。总的来说，这些研究将验证应用这种基于GNR/抗CAIX的光热消融疗法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.