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: 10700814
• 负责人: GAL SHAFIRSTEIN
• 金额: $ 99.86万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10700814
• 关键词: Ablation; Animals; Benchmarking; Biotechnology; Cancerous; Canis familiaris; Characteristics; Chronic viral hepatitis; Clinic; Clinical; Clinical Research; Computer Models; Data; Dose; Doxorubicin; Elements; Encapsulated; Experimental Animal Model; 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; blood perfusion; commercialization; contrast enhanced; dosimetry; first-in-human; interstitial; light dosimetry; liposomal formulation; liver cancer patient; nanoparticulate; novel; novel therapeutics; pre-Investigational New Drug meeting; 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.

摘要 我们的目标是将间质化疗-光疗(i-cpt)商业化，作为一种新的局部治疗方案。 晚期肝癌。阿霉素(Dox)可以主动地负载到长循环、血清稳定、卟啉- 磷脂(POP)脂质体，并用665 nm激光(PhotoDox)释放。这种方法极大地导致了 增强了辐射组织中的药物积累，导致了超强的肿瘤消融。在第一阶段STTR中， 我们利用这个剂量-治疗计划平台来指导PhotoDox的I-CPT的光管理。 我们证明，这种光剂量学治疗计划在消融大型原位手术中是有效的。 大鼠肝细胞癌肿瘤模型。在这个第二阶段的STTR应用中，我们建议进一步推进I-CPT 与PhotoDox合作开发IND，使未来的临床研究成为可能。为此，我们建议完成 以下目标：目标1：用PhotoDox优化I-CPT，以获得持久的大自发完全反应 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。 慢性病毒性肝炎和自发性局部进展性肝细胞癌 肝癌，就像在乙肝患者身上看到的那样。在初步研究中，我们已经安全地给土拨鼠注射了Photodox， 确定了Photodox的长循环特性，并应用基于有限元的治疗计划 用I-CPT在土拨鼠体内安全地治疗肝癌(~50 cm~3)的剂量学。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条件是什么？目标2：生成Ind- 使用PhotoDox提供有关I-CPT毒性的数据。POP Bio之前生成了非GLP毒性数据 包括粗略地确定大鼠的最大耐受量。从那时起，流行音乐传记 与FDA举行了IND前会议，FDA确认了505(B)(2)路线对以下组件的适用性 PhotoDox，并就首次人体研究之前所需的毒理学研究提供了指导。 我们将解决关键问题：在GLP研究中，PhotoDox的毒性是什么？此翻译阶段 II项目将提供向FDA提交IND所需的数据，方法是提供有价值的相关信息 在人类肝癌患者的背景下理解I-CPT治疗。如果成功，则使用PhotoDox进行I-CPT 有利于大多数新的肝癌患者，他们有无法手术和有问题的原发肿瘤。