Alpha-Particle Emitter Radiopharmaceutical Therapy for Liver Cancer

肝癌的α粒子发射放射性药物治疗

基本信息

批准号：
10394421
负责人：
Jessie Nedrow
金额：
$ 62.59万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394421
关键词：
90Y Address Algorithms Alpha Particle Emitter Alpha Particles Animals Biodistribution Calcium Cancer Etiology Cancer Patient Cells Cessation of life Chemoembolization Clinic Companions Complex Contrast Media DNA Damage Data Daughter Development Disseminated Malignant Neoplasm Distributional Activity Dose Doxorubicin Drug Kinetics Drug Monitoring Emulsions Energy Transfer Evaluation FDA approved Formulation Glass Goals Hep3B HepG2 Hepatic artery Human Image Injections Interventional radiology Linear Energy Transfer Liver Liver neoplasms Malignant neoplasm of liver Malignant neoplasm of prostate Metastatic Neoplasm to the Bone Metastatic Neoplasm to the Liver Metastatic Prostate Cancer Methods Microspheres Modeling Mus Organ Oryctolagus cuniculus Palliative Care Pathway interactions Patients Pharmacology Portal vein structure Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Property Protocols documentation Radio-Opaque Radioembolization Radiofrequency Interstitial Ablation Radioisotopes Radiopharmaceuticals Regimen Research Resistance Roentgen Rays Route Site Source Testing Therapeutic Therapeutic Agents Therapeutic Embolization Time Tissues Toxic effect Translating Treatment Efficacy Tumor-Derived Unresectable Vascular blood supply Visualization Work X-Ray Computed Tomography Xenograft Model advanced disease anti-PSMA base cancer diagnosis cancer imaging cell killing chemotherapy clinically relevant cytotoxicity dosimetry experience image guided imaging agent improved liver cancer model mimetics molecular imaging mouse model neoplastic cell novel novel therapeutics particle therapy preclinical evaluation reconstruction resistance mechanism response single photon emission computed tomography small molecule standard of care success systemic toxicity targeted treatment theranostics therapy outcome treatment effect treatment strategy tumor tumor growth tumor vascular supply

项目摘要

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fifth most frequently diagnosed cancer worldwide, as well as the second most frequent cause of cancer death. Furthermore, the liver is also the most common site for metastatic cancer. Most patients with advanced disease are offered only non- surgical palliative treatment options. Hepatic tumors derived their blood supply from the hepatic artery whereas normal liver tissue’s blood supply is mainly sourced from the portal vein. Intra-arterial therapies, such as chemoembolization and radioembolization, exploit the hepatic tumors’ blood supply via the hepatic artery to selectively deliver contrast and therapies. Lipiodol is an FDA approved radio-opaque contrast agent used in liver tumor imaging during intra-arterial therapies. Lipiodol accumulates and remains in the tumor while clearing out of normal liver tissue when injected via the hepatic artery, providing a vehicle to deliver therapeutic agents, such as, chemotherapeutics and -emitting radionuclides (188Re and 131I) to liver tumors, but these treatments have limitations, urging the need for development of new therapies. Alpha-emitting radiopharmaceutical therapy (RPT) is highly potent, causing largely irreparable DNA damage to targeted cells. Due to the short range of alpha particles, RPT minimizes damage to nearby healthy cells. The high-energy transfer of alpha particles makes RPT impervious to most resistance mechanisms including pathway redundancy and oxygenation status, a desirable feature for treatment of liver tumors. Lipiodol has detailed information on its pharmacology, formulation and toxicity, due to its FDA-approved status, and its repurposing for RPT can build upon information from previous studies for FDA approval to help rapidly translate a novel RPT agent-Lipiodol emulsion to the clinic. The proposed work is focused on evaluating targeted RPT emulsions for unresectable primary liver cancer as compared to standard of care treatment (Aim 1). A selected RPT emulsion will be tested in a technical rabbit VX2 liver cancer model, allowing us to evaluate these agents’ distribution via the hepatic artery (Aim 2). Finally, the proposed work is focused on the development of a companion imaging agent or the expansion of imaging protocols to allow for a single theranostic agent (Aims 1-3). The successful completion of the proposed research is that an RPT agent-Lipiodol emulsion, based on current FDA approved Lipiodol emulsions, can be repurposed for quick development and evaluation as a therapeutic or theranostic agent for primary and metastatic liver cancer.

肝细胞癌 (HCC) 是最常见的原发性肝癌，也是第五大最常见的癌症全世界诊断出癌症，也是癌症死亡的第二常见原因。也是转移性癌症最常见的部位。大多数晚期疾病患者仅接受非治疗。手术姑息治疗方案肝肿瘤的血液供应来自肝动脉，而正常肝组织的血液供应主要来自门静脉，例如动脉内治疗。化疗栓塞和放射栓塞，利用肝动脉通过肝肿瘤的血液供应，选择性地提供造影剂和治疗剂是 FDA 批准的用于肝脏的不透射线造影剂。动脉内治疗期间的肿瘤成像在清除时碘油会积聚并保留在肿瘤中。当通过肝动脉注射时，正常肝组织会形成正常肝组织，提供传递治疗药物的载体，例如例如，化疗和发射  的放射性核素（188Re 和 131I）可治疗肝肿瘤，但这些治疗方法局限性，迫切需要开发新的α发射放射性药物疗法。 (RPT) 非常有效，由于作用范围短，会对目标细胞造成基本上无法修复的 DNA 损伤。 α 粒子，RPT 最大限度地减少对附近健康细胞的伤害 α 粒子的高能转移。使 RPT 不受大多数阻力机制的影响，包括通路冗余和氧合状态，碘化油是治疗肝脏肿瘤的一个理想功能，有其药理学的详细信息，由于其 FDA 批准的状态，其配方和毒性以及其重新用于 RPT 的用途可以建立在信息的基础上根据 FDA 批准之前的研究，帮助快速将新型 αRPT 剂 - 碘化油乳剂转化为拟议的工作重点是评估用于不可切除的原发性肝脏的靶向 αRPT 乳剂。与标准护理治疗相比的癌症（目标 1）将通过技术测试选定的 RPT 乳剂。兔 VX2 肝癌模型，使我们能够评估这些药物通过肝动脉的分布（目标 2）。最后，拟议的工作重点是开发伴随成像剂或扩展允许单一治疗诊断剂的成像协议（目标 1-3）成功完成。研究表明，基于目前 FDA 批准的碘油乳液，可以使用 RPT 剂 - 碘油乳液重新用于快速开发和评估，作为原发性和转移性肝癌。