Enhancing Liver Cancer Treatment With Image-Guided Magnetic Hyperthermia

 描述（由申请人提供）：原发性肝癌是全球癌症相关死亡的第三大常见原因。据估计，由于发病率和死亡率预计都将增加，因此死于这一疾病的人数正在上升。死亡通常发生在局部疾病进展导致的器官衰竭之后。通常，患者在疾病被诊断时已经进展到晚期和不可切除的肿瘤，主要是因为早期疾病没有表现出症状。在这种情况下，只有非手术姑息治疗的选择。图像引导的干预已经成为有效的微创手术，提供个性化的肿瘤靶向，能够解决局部疾病和最大限度地减少全身毒性。然而，这些手术只能适度提高患者的生存率，因此需要新技术。非消融性热疗或热疗（HT）作为其他疗法的补充，对于不可切除的癌症的有效性已得到充分证实。HT广泛影响肿瘤生物学，并且它可以以增强化疗剂效力的方式显著影响肿瘤结构和生理学。有效实施HT用于癌症治疗的关键障碍一直是将热量瞄准肿瘤并提供适当的热剂量。磁性氧化铁纳米颗粒（MION）提供了克服这些障碍的能力，因为它们提供了加热和成像能力，以增强靶向治疗。当暴露于交变磁场（AMF）时，MION在肿瘤内产生热量。这种热量在整个肿瘤中传导，以增强其他治疗剂的递送和有效性。图像引导的方法提供了MION分布的实时可视化的潜力，并提供了有效肿瘤靶向的反馈和必要的信息来制定稳健的治疗计划，从而为个性化治疗创造了潜力。我们最近开发了一种MION配方，可提供双重成像（X射线和磁共振），用低功率磁场加热，并可与标准化疗药物共同配制。该制剂包含包埋在油状介质中的MION。我们假设X射线图像引导的磁热疗将使癌细胞对化疗敏感，从而与单独化疗相比具有上级疗效。将在肝细胞癌的异种移植小鼠模型中评估在图像引导递送MION-曲洛多制剂后的治疗效果。将在兔肝脏原位VX 2肿瘤模型（介入性图像引导肝脏手术的首选动物模型）中评估成像和图像引导输送、MION的生物分布以及加热前后MION分布的定量测量。该项目的成功完成将提供必要的数据和工具，以推动这项技术更接近于不可切除的原发性肝癌的临床治疗。

 DESCRIPTION (provided by applicant): Primary liver cancer is the third most common cause of cancer-related death worldwide. Estimates predict that death from this disease is on the rise because both incidence and mortality are projected to increase. Death usually follows organ failure from progression of local disease. Often patients have already progressed to advanced and unresectable tumors at the time the disease is diagnosed, largely because early stage disease exhibits no symptoms. In such cases, only non-surgical palliative treatment options are available. Image- guided interventions have emerged as potent minimally invasive procedures that offer individualized tumor targeting, with ability to address local disease and minimize systemic toxicities. Yet, these procedures only modestly improve patient survival, creating a need for new technology. The effectiveness of non-ablative heat therapy or hyperthermia (HT) as a complement for other therapies is well-established for unresectable cancers. HT broadly affects tumor biology and it can dramatically affect tumor structure and physiology in ways that enhance the potency of chemotherapeutic agents. The critical barriers to effectively implementing HT for cancer therapy have been targeting the heat to the tumor and delivering the proper heat dose. Magnetic iron oxide nanoparticles (MIONs) offer the capability to overcome these barriers because they provide both heating and imaging capability to enhance targeted delivery of therapy. MIONs produce heat within the tumor when exposed to alternating magnetic fields (AMFs). This heat conducts throughout the tumor to enhance delivery and effectiveness of other therapeutic agents. An image-guided approach offers the potential of real-time visualization of MION distribution with feedback on effective tumor targeting and the necessary information to develop robust treatment planning, creating the potential for individualized therapy. We have recently developed a MION formulation that provides dual imaging (x-ray and magnetic resonance), heating with low- power magnetic fields, and that enables co-formulation with standard chemotherapy agents. This formulation comprises MIONs, embedded in the oily medium of lipiodol. We hypothesize that x-ray image-guided magnetic hyperthermia will sensitize cancer cells to chemotherapy leading to superior efficacy when compared to chemotherapy alone. The effects of therapy, following image-guided delivery of the MION-lipiodol formulation will be assessed in xenograft mouse models of hepatocellular carcinoma. Imaging and image-guided delivery, biodistribution of MIONs, and quantitative measures of MION distribution before and after heating will be assessed in the orthotopic VX2 tumor model in rabbit livers, a preferred animal model for interventional image- guided liver procedures. Successful completion of the proposed project will provide the necessary data and tools to advance this technology closer to clinical treatment of unresectable primary liver cancer.