Development of a Novel Nanoconstruct Based Photothermal Therapy for Tumor Hypoxia

描述（由申请人提供）：缺氧是实体肿瘤的共同特征，发生在各种恶性肿瘤中，显著降低肿瘤对放疗和化疗的敏感性。因此，开发专门针对缺氧微环境的治疗方法，在不损伤正常组织和癌细胞复发的情况下有效消除肿瘤具有重要意义。基于纳米粒子的近红外激光辅助光热消融治疗已成为这方面最有前途的新医疗策略之一。金纳米棒（GNR）由于其小而可调的尺寸、强的光学可调性和惰性而在这方面受到特别关注。在此基础上，我们进行了一系列初步研究，成功制备并表征了一种由GNR和抗碳酸酐酶IX （CAIX）抗体组成的新型纳米结构，该结构是一种可行的肿瘤缺氧生物标志物。在此，我们提出验证我们的假设，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与cax过表达的人类结肠肿瘤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。第二个目的是研究靶向和非靶向GNR（含或不含抗caix）在HT29异种移植动物体内的药代动力学和生物分布。这将阐明抗caix抗体是否能在肿瘤缺氧时实现更高的GNR积累。第三个目标是对携带HT29异种移植物的动物进行体内光热消融。这将揭示该疗法是否能靶向缺氧区，有效杀死癌细胞，提高肿瘤动物的存活率。总之，这些研究将验证这种基于GNR/抗caix的光热消融治疗肿瘤缺氧的可行性，改善临床预后。

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.