Alpha-Particle Emitter Radiopharmaceutical Therapy for Liver Cancer

摘要肝细胞癌是最常见的原发性肝癌，居第五位。 在全球范围内被诊断为癌症，以及癌症死亡的第二大常见原因。此外，肝脏 也是转移性癌症最常见的部位。大多数晚期疾病患者只提供非 外科姑息治疗的选择。肝肿瘤的血供来自肝动脉，而 正常肝组织的血供主要来源于门静脉。动脉内治疗，例如 化疗栓塞术和放射栓塞术，利用肝肿瘤经肝动脉的血供 有选择地提供对比和治疗。碘化油是FDA批准的一种用于肝脏的放射不透明造影剂。 动脉内治疗期间的肿瘤成像。在清除肿瘤的同时，碘油积聚并留在肿瘤内。 当通过肝动脉注射时，提供了一种载体来输送治疗剂，如 As、化疗药物和发射的放射性核素(188Re和131I)治疗肝脏肿瘤，但这些治疗方法有 限制，敦促需要开发新的治疗方法。阿尔法放射药物疗法 (DNARPT)是高度有效的，对靶细胞造成很大程度上不可修复的损伤。由于射程较短 阿尔法粒子，RPT将对附近健康细胞的损害降至最低。α粒子的高能转移 使rpt不受大多数抗性机制的影响，包括途径冗余和氧合状态， 这是治疗肝脏肿瘤的理想特征。碘化油有关于其药理的详细信息， 配方和毒性，由于其FDA批准的状态，以及它对RPT的重新用途可以建立在信息的基础上 从美国食品和药物管理局之前的研究中获得批准，以帮助将一种新型的RPT试剂--碘油乳剂快速转化为 诊所。拟议的工作重点是评估靶向RPT乳剂治疗不能切除的原发性肝 癌症与标准护理治疗的比较(目标1)。选定的RPT乳剂将在技术上进行测试 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，建议的工作集中在开发一种配套的显像剂或扩展 成像方案，以允许单一的治疗药物(目标1-3)。圆满完成拟议中的 研究表明，一种基于目前批准的碘油乳剂的FDA RPT试剂--碘油乳剂，可以 重新用于快速开发和评估，作为治疗或治疗原发和 转移性肝癌。

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.