Multifunctional Hollow Gold Nanospheres for Concurrent Photothermal-Chemotherapy

 描述（由申请人提供）：原发性和转移性肝肿瘤患者的治疗是一个具有挑战性的未解决问题。只有5-20%的肝脏肿瘤患者是手术候选者，并且已经证明单独的全身化疗在治疗肝细胞癌和肝转移方面的疗效有限。微创影像引导介入技术，包括经动脉介入和经皮介入（例如，射频消融术、激光消融术）已被引入临床 用于治疗肝肿瘤患者。然而，这些技术受到癌细胞不完全消除的限制，这可能导致局部肿瘤复发。因此，迫切需要开发创新的肝脏肿瘤局部治疗方法。我们相信，动脉内递送的纳米颗粒提供了一个独特的机会，高度集中的局部递送热和化疗剂，从而可以显着提高治疗肝肿瘤的疗效。我们开发了一种创新的专有技术，能够同时介导近红外激光触发光热消融（PTA）和阿霉素（DOX）的局部释放。我们的DOX负载的聚乙二醇包覆的中空金纳米球（DOX@PEG-HAuNS）在正常体温下表现出较低的全身毒性，并且当与高温和消融温度下的激光暴露相结合时，显着增强了抗肿瘤功效。在这个SBIR计划中，我们组建了一个多学科团队，以实施连贯的战略来应对发展和翻译挑战。我们的具体目标是：1）在良好实验室规范（GLP）生产条件下大规模合成和表征高质量的DOX@PEG-HAuNS，2）测定大鼠IA注射后DOX@PEG-HAuNS的药代动力学（PK）和生物分布，并在原位大鼠肝癌模型和临床相关的大型动物肝癌模型中证明同时PTA和DOX化疗的可行性（兔VX 2模型）。我们相信，所提出的双模式治疗策略将提供上级局部肿瘤控制，同时减少不良反应的可能性。 事件拟议工作的成功将为DOX@PEG-HAuNS未来的临床试验铺平道路。

 DESCRIPTION (provided by applicant): Treatment of patients with primary and metastatic liver tumors is a challenging unsolved problem. Only 5-20% of patients with tumors in the liver are surgical candidates, and systemic chemotherapy alone has been demonstrated to be of limited efficacy in treating hepatocellular carcinoma and liver metastases. Minimally invasive image-guided interventional techniques, including transarterial interventions and percutaneous interventions (e.g., radiofrequency ablation, laser ablation), have been introduced into the clinic for the treatment of patients with liver tumors. However, these techniques are limited by incomplete elimination of cancer cells, which can lead to local tumor recurrence. Therefore, there is an urgent need to develop innovative local treatment approaches for liver tumors. We believe that intraarterially delivered nanoparticles offers a unique opportunity for highly concentrated local delivery of heat and chemotherapeutic agents and thus may significantly improve the efficacy of treatment for liver tumors. We have developed an innovative proprietary technology that is capable of mediating simultaneous near-infrared laser-triggered photothermal ablation (PTA) and local release of doxorubicin (DOX). Our DOX-loaded, polyethylene glycol-coated hollow gold nanospheres (DOX@PEG-HAuNS) have demonstrated low systemic toxicity under normal body temperatures and significantly enhanced antitumor efficacy when combined with laser exposure under hyperthermia and ablative temperatures. In this SBIR program, we have assembled a multidisciplinary team to implement a coherent strategy to address developmental and translational challenges. Our specific aims are: 1) To synthesize and characterize high-quality DOX@PEG-HAuNS in large scale and under Good laboratory Practice (GLP) production conditions, 2) To determine the pharmacokinetics (PK) and biodistribution of DOX@PEG-HAuNS after IA injection in rats, and to demonstrate the feasibility of concurrent PTA and DOX chemotherapy in an orthotopic rat liver cancer model and a clinically relevant large animal liver cancer model (rabbit VX2 model). We believe that the proposed dual-modality treatment strategy will offer superior local tumor control while reducing the likelihood of adverse events. Success of the proposed work will pave the way for future clinical trials of DOX@PEG-HAuNS.