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: 10384796
• 负责人: GAL SHAFIRSTEIN
• 金额: $ 100.14万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384796
• 关键词: Address; Animals; Benchmarking; Biotechnology; Buffaloes; Cancerous; Canis familiaris; Characteristics; Chronic viral hepatitis; Clinic; Clinical; Clinical Research; Computer Models; Data; Dose; Doxorubicin; Elements; Encapsulated; Experimental Animal Model; Formulation; Future; Goals; Hepatitis B; Human; In complete remission; Lasers; Licensing; Light; Lighting; Lipids; Liposomes; Liver neoplasms; Locally Advanced Malignant Neoplasm; Magnetic Resonance Imaging; Malignant neoplasm of liver; Maximum Tolerated Dose; Measures; Methods; Modeling; Monitor; Mus; Nature; Oryctolagus cuniculus; PUVA Photochemotherapy; Patients; Persons; Pharmaceutical Preparations; Phase; Phospholipids; Phototherapy; Pilot Projects; Porphyrins; Primary Neoplasm; Primary carcinoma of the liver cells; Rattus; Reporting; Rodent; Route; Safety; Serum; Small Business Technology Transfer Research; Surface; Survival Rate; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Translating; Vaccines; Vascular Permeabilities; Woodchuck; Work; absorption; base; blood perfusion; contrast enhanced; dosimetry; first-in-human; interstitial; light dosimetry; liver cancer patient; meetings; nanoparticulate; novel; novel therapeutics; primary endpoint; response; secondary endpoint; success; treatment planning; tumor; tumor ablation

Summary Our goal is to commercialize interstitial chemo-phototherapy (I-CPT) as a new therapeutic option for locally advanced liver cancers. Doxorubicin (Dox) can be actively loaded into long circulating, serum-stable, porphyrin- phospholipid (PoP) liposomes and be released with 665-nm laser light (PhotoDox). This approach leads to vastly enhanced drug accumulation in irradiated tissues, resulting in ultrapotent tumor ablation. In the phase I STTR, we employed this dosimetry-treatment planning platform to guide light administration of I-CPT with PhotoDox. We demonstrated that this treatment planning with light dosimetry is effective in ablating large orthotopic hepatocellular carcinoma tumors in rats. In this phase II STTR application we propose to further advance I-CPT with PhotoDox towards an IND for enabling future clinical studies. To that end we propose to complete the following aims: Aim 1: Optimizing I-CPT with PhotoDox for a durable complete response of large spontaneous hepatocellular carcinoma in a woodchuck model. The woodchuck model is the largest experimental animal model with spontaneous locally advanced hepatocellular carcinoma (HCC) in the context of chronic viral hepatitis and liver cancer, as seen in people with hepatitis B. In pilot studies, we have safely dosed PhotoDox to woodchucks, confirmed the characteristic long-circulating nature of PhotoDox and applied the FEM based treatment planning and dosimetry to safely treat HCC (~50 cm3) with I-CPT in woodchucks. We will address the key question: What are the optimal light settings for I-CPT with PhotoDox in the treatment of large HCC? Aim 2: Generate IND- enabling data on the toxicity of I-CPT with PhotoDox. POP BIO has previously generated non-GLP toxicity data of PhotoDox in rats including cursory establishment of the maximum tolerated dose. Since then, POP BIO has held a pre-IND meeting with the FDA, who confirmed the suitability of the 505(b)(2) route for components of PhotoDox and provided guidance about the required toxicological studies required prior to first-in-human studies. We will address the key question: What is the toxicity of PhotoDox under GLP studies? This translational Phase II project will provide required data for an IND submission to the FDA by providing valuable 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.

总结 我们的目标是商业化间质化学光疗（I-CPT）作为一种新的治疗选择， 晚期肝癌多柔比星（Dox）可以主动装载到长循环的、血清稳定的卟啉受体中。 脂质体中，并且用665-nm激光（PhotoDox）释放。这种方法导致了巨大的 增强的药物在照射组织中的积累，导致超强效肿瘤消融。在第一阶段STTR中， 我们采用该剂量测定-治疗计划平台来指导I-CPT与PhotoDox的光管理。 我们证明，这种治疗计划与光剂量是有效的消融大原位 大鼠肝癌肿瘤。在第二阶段STTR应用中，我们建议进一步推进I-CPT 与PhotoDox一起申请IND，以实现未来的临床研究。为此，我们建议完成 目的1：优化I-CPT与PhotoDox，以获得大的自发性 土拨鼠模型中的肝细胞癌。土拨鼠模型是最大的实验动物模型 慢性病毒性肝炎背景下的自发性局部晚期肝细胞癌（HCC）， 肝癌，见于B型肝炎患者。在试点研究中，我们已经安全地给土拨鼠服用了PhotoDox， 证实了PhotoDox的特征性长循环性质，并应用了基于FEM的治疗计划 和剂量测定，以安全地治疗土拨鼠肝癌（~50立方厘米）与I-CPT。我们将解决关键问题：什么 I-CPT联合PhotoDox治疗大肝癌的最佳光照设置是什么？目标2：生成IND- 使I-CPT与PhotoDox的毒性数据成为可能。POP BIO之前已生成非GLP毒性数据 包括粗略确定最大耐受剂量。从那时起，POP BIO 与FDA举行了IND前会议，FDA确认了505（B）（2）途径对成分的适用性 PhotoDox，并提供了关于首次人体研究之前所需毒理学研究的指南。 我们将解决关键问题：GLP研究中PhotoDox的毒性是什么？这个转化阶段 II项目将通过提供以下有价值的相关信息，为向FDA提交IND申请提供所需数据： 了解I-CPT治疗人类肝癌患者的背景。如果成功，I-CPT与PhotoDox 这将使大多数新的肝癌患者受益，他们患有无法手术和有问题的原发性肿瘤。