Interstitial Chemophototherapy with Light-Activated Nanoparticulate Doxorubicin

光激活纳米颗粒阿霉素间质化学光疗

基本信息

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
项目类别：
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

项目摘要

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.

概括我们的目标是将间质性化学光疗 (I-CPT) 商业化，作为局部治疗的新治疗选择晚期肝癌。阿霉素 (Dox) 可以主动加载到长循环、血清稳定、卟啉- 磷脂 (PoP) 脂质体并用 665 nm 激光 (PhotoDox) 释放。这种方法导致极大增强药物在受照射组织中的积累，从而实现超强的肿瘤消融。在第一阶段 STTR 中，我们利用这个剂量测定治疗计划平台来指导使用 PhotoDox 进行 I-CPT 的光管理。我们证明了这种利用光剂量测定的治疗计划对于消融大的原位是有效的大鼠肝细胞癌肿瘤。在本次STTR第二阶段申请中，我们建议进一步推进I-CPT 与 PhotoDox 一起开展 IND 工作，以支持未来的临床研究。为此，我们建议完成以下目标：目标 1：使用 PhotoDox 优化 I-CPT，以实现大自发性的持久完整响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背景下自发性局部晚期肝细胞癌 (HCC) 和肝癌，如乙型肝炎患者所见。在试点研究中，我们已安全地将 PhotoDox 注射到土拨鼠身上，确认了 PhotoDox 的长循环特性并应用了基于 FEM 的治疗计划以及用 I-CPT 安全治疗土拨鼠 HCC (~50 cm3) 的剂量测定。我们将解决关键问题：什么 I-CPT 与 PhotoDox 治疗大型 HCC 的最佳光照设置是什么？目标 2：产生 IND- 使用 PhotoDox 提供有关 I-CPT 毒性的数据。 POP BIO 之前已生成非 GLP 毒性数据 PhotoDox 在大鼠中的应用，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) 途径对以下成分的适用性： PhotoDox 并提供了有关首次人体研究之前所需毒理学研究的指导。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 项目将通过提供与以下相关的有价值的信息来提供向 FDA 提交 IND 所需的数据了解人类肝癌患者的 I-CPT 治疗。如果成功，使用 PhotoDox 进行 I-CPT 将使大多数患有无法手术且有问题的原发肿瘤的新肝癌患者受益。