Interstitial Chemophototherapy with Light-Activated Nanoparticulate Doxorubicin

光激活纳米颗粒阿霉素间质化学光疗

• 批准号: 10010747
• 负责人: GAL SHAFIRSTEIN
• 金额: $ 39.99万
• 依托单位: POP BIOTECHNOLOGIES, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-06 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010747
• 关键词: Address; Adverse event; Animals; Benchmarking; Biotechnology; Blood Circulation; Blood Vessels; Buffaloes; Cancer Patient; Clinic; Clinical Research; Combination Drug Therapy; Comprehensive Cancer Center; Computer Models; Data; Dose; Doxorubicin; Drug Delivery Systems; Drug Kinetics; Drug vehicle; Effectiveness; Elements; Encapsulated; Formulation; Goals; Half-Life; HepG2; Hour; Human; In Vitro; Lasers; Licensing; Light; Lighting; Liposomes; Liver neoplasms; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of liver; Methods; Modeling; Mus; Nanotechnology; National Cancer Institute; Neck; Oryctolagus cuniculus; PUVA Photochemotherapy; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phospholipids; Phototherapy; Porphyrins; Pre-Clinical Model; Primary Neoplasm; Primary carcinoma of the liver cells; Property; Rattus; Rodent; Roswell Park Cancer Institute; Safety; Serum; Small Business Technology Transfer Research; Survival Rate; System; Testing; Therapeutic; Toxic effect; Translating; Ultrasonography; Woodchuck; anti-cancer; base; clinically relevant; commercialization; dosimetry; effective therapy; hepatic necrosis; image guided; improved; in vivo; interstitial; light dosimetry; nanoparticulate; novel; outcome forecast; phase 2 study; preclinical study; primary endpoint; response; safety testing; secondary endpoint; subcutaneous; success; treatment planning; tumor; tumor ablation; tumor growth

SUMMARY Our goal is to advance the commercialization of interstitial chemo-phototherapy (I-CPT) as a potent antitumor therapeutic option for locally advanced tumors. This application will focus on providing a proof of concept for the benefit of I-CPT in the treatment locally advanced hepatocellular carcinoma (HCC). Patients with inoperable locally advanced HCC have a poor prognosis with a 5-year survival rate of just 31%. The combination of chemotherapy and phototherapy (CPT) involves administering a single agent such as PhotoDox, a novel long-circulating, doxorubicin in porphyrin-phospholipid liposome formulation. The major advantages of PhotoDox are: 1) it is thermally independent; 2) has rapid drug release upon 665-nm light administration; 3) is long-circulating (~22 hour half-life), serum stable, and otherwise like DOXIL®; and 4) has been demonstrated to be effective in multiple tumor models. PhotoDox was tested by the National Cancer Institute Nanotechnology Characterization Lab, and was found to be similar to DOXIL® in in vitro toxicity and in vivo pharmacokinetic studies. POP Biotechnologies, Inc. has an exclusive license for PhotoDox. Dr. Shafirstein's team at Roswell Park Cancer Institute (RPCI) has developed and validated a novel system to provide specific light dosimetry in large tumors. In this STTR application, POP Biotechnologies will combine PhotoDox with Dr. Shafirstein’s treatment planning approach to optimize and guide I-CPT for effective therapy of locally advanced liver tumors by accomplishing the following aims: Aim 1: To define light irradiance and fluence for effective I-CPT in subcutaneous HepG2 tumors. The PI validated finite element method approach will be used to guide a light dose finding study to define a safe and effective intratumoral light irradiance and fluence for I-CPT with PhotoDox. We will address the key question: What is the optimal intratumoral light irradiance and fluence for I-CPT with PhotoDox? Aim 2: Demonstrate the effectiveness of I-CPT in an orthotopic liver cancer rat model. We will use the FEM to translate the optimal interstitial light delivery determined in murine tumors (Aim 1) to larger orthotopic liver cancer in rats. We will address the key question: Can we deliver an effective I-CPT with PhotoDox to an orthotopic model of liver tumor? This translational Phase I project will provide required data to guide a Phase II study where our teams will test and study I-CPT with PhotoDox in a spontaneous woodchuck HCC (available at RPCI) that is relevant to understanding I-CPT treatment in the context of human liver cancer patients. If successful, I-CPT with PhotoDox stands to benefit the majority of new liver cancer patients, who have inoperable and problematic primary tumors.

概括 我们的目标是推进间质化疗光疗 (I-CPT) 作为一种有效抗肿瘤药物的商业化 局部晚期肿瘤的治疗选择。该应用程序将重点提供概念证明 I-CPT 在治疗局部晚期肝细胞癌 (HCC) 中的益处。患者患有 无法手术的局部晚期HCC预后较差，5年生存率仅为31%。这 化疗和光疗的组合（CPT）涉及使用单一药物，例如 PhotoDox，一种新型长循环阿霉素，采用卟啉-磷脂脂质体制剂。主要 PhotoDox 的优点是： 1）它是热独立的； 2) 在665 nm光下快速释放药物 行政; 3) 循环长（半衰期约 22 小时）、血清稳定，其他方面与 DOXIL® 相似；和 4) 有 已被证明在多种肿瘤模型中有效。 PhotoDox 已通过国家癌症中心测试 研究所纳米技术表征实验室，发现其体外毒性和体内毒性与DOXIL®相似 体内药代动力学研究。 POP Biotechnologies, Inc. 拥有 PhotoDox 的独家许可。 Shafirstein 博士在罗斯威尔公园的团队 癌症研究所 (RPCI) 开发并验证了一种新颖的系统，可在以下情况下提供特定的光剂量测定： 大肿瘤。在此 STTR 应用中，POP Biotechnologies 将 PhotoDox 与 Shafirstein 博士的技术相结合 优化和指导 I-CPT 有效治疗局部晚期肝脏肿瘤的治疗计划方法 通过实现以下目标： 目标 1：定义皮下 HepG2 肿瘤中有效 I-CPT 的光辐照度和注量。 PI 验证的有限元方法将用于指导光剂量发现研究，以定义 使用 PhotoDox 为 I-CPT 提供安全有效的瘤内光辐照度和注量。我们将解决关键问题 问题：使用 PhotoDox 进行 I-CPT 的最佳瘤内光辐照度和注量是多少？ 目标 2：证明 I-CPT 在原位肝癌大鼠模型中的有效性。 我们将使用 FEM 将小鼠肿瘤中确定的最佳间质光传递（目标 1）转化为 大鼠中较大的原位肝癌。我们将解决关键问题：我们能否提供有效的 I-CPT PhotoDox 用于肝肿瘤原位模型？ 这个转化性第一阶段项目将提供所需的数据来指导第二阶段研究，我们的团队将在该研究中进行测试 并在自发土拨鼠 HCC 中使用 PhotoDox 研究 I-CPT（可在 RPCI 上获得），这与 了解人类肝癌患者的 I-CPT 治疗。如果成功，I-CPT PhotoDox 将使大多数无法手术且有问题的新肝癌患者受益 原发性肿瘤。