Alpha-Particle Emitter Radiopharmaceutical Therapy for Liver Cancer

肝癌的α粒子发射放射性药物治疗

• 批准号: 10305102
• 负责人: Jessie Nedrow
• 金额: $ 63.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/10305102
• 关键词: 90Y; Address; Algorithms; Alpha Particle Emitter; Alpha Particles; Animals; Biodistribution; Calcium; Cancer Etiology; Cancer Model; 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; 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

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.

肝细胞癌是最常见的原发性肝癌，发病率居第五位 世界范围内诊断出的癌症，以及癌症死亡的第二大最常见原因。此外，肝脏 也是转移癌最常见的部位。大多数晚期疾病患者只提供非- 手术姑息治疗方案。肝肿瘤的血供来源于肝动脉， 正常肝组织的血供主要来自门静脉。动脉内治疗，例如 化疗栓塞和放射栓塞，通过肝动脉利用肝肿瘤的血液供应， 选择性地输送造影剂和治疗。碘油是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。碘油在清除肿瘤时积聚并保留在肿瘤中 当通过肝动脉注射时，正常肝组织的组织，提供了递送治疗剂的载体， 放射性核素（188 Re和131 I）治疗肝肿瘤，但这些治疗方法 这些限制，迫切需要开发新的治疗方法。α放射性药物治疗 （CCRPT）是非常有效的，对靶细胞造成很大程度上无法修复的DNA损伤。由于距离短， α粒子，将对附近健康细胞的损害降至最低。α粒子的高能转移 使EMPRPT不受大多数耐药机制的影响，包括途径冗余和氧合状态， 这是治疗肝肿瘤的理想特征。碘油有其药理学的详细信息， 配方和毒性，由于其FDA批准的状态，以及它的重新用途为CMPRPT可以建立在信息 从先前的研究中获得FDA批准，以帮助快速将一种新型的可重复使用的RPT药物-碘油乳剂转化为 诊所拟议的工作重点是评估靶向的CRARPT乳剂用于不可切除的原发性肝脏 与标准护理治疗相比的癌症（目标1）。将在技术试验中测试所选的BARRPT乳液。 兔VX 2肝癌模型，使我们能够评估这些药物通过肝动脉的分布（目的2）。 最后，所提出的工作集中在开发伴随成像剂或扩大 成像方案，以允许单一治疗诊断剂（目的1-3）。成功完成拟议的 研究表明，基于目前FDA批准的碘油乳剂， 重新用于快速开发和评估作为治疗或治疗诊断剂的原发性和 转移性肝癌