Catheter-Directed Image-Guided Delivery of Cytostatic and Cytotoxic Combination Therapy to Liver Tumors

项目总结 肝癌是世界上第五大常见恶性肿瘤，也是美国癌症死亡的第四大原因。 切除和移植是唯一有可能治愈肝癌的治疗方法，但只有10%-15%的患者 都是候选人。索拉非尼联合多柔比星肝动脉化疗栓塞术(TACE) 联合可能提供有效的组合，通过抑制抑制来最大化治疗结果 血管生成，同时诱导细胞凋亡。最近的临床结果显示，中位数 索拉非尼和DOX-TACE的总体存活率和进展或死亡风险显著改善 组合。然而，索拉非尼目前是以口服片剂的形式系统地给药。 随之而来的全身暴露和缺乏肿瘤特异性会导致副作用，包括皮疹， 手足综合征、腹泻和高血压。考虑到这些方面通常无法容忍的严重程度- 为了提高疗效，通常必须减少药物剂量或完全停止给药(30%的患者)。 我们的磁共振可见pH触发药物洗脱微球(pH-DEM)平台提供了潜在的 通过以下途径提高肝细胞癌定向治疗的有效性，同时减少全身暴露 导尿管定向输液。索拉非尼和多柔比星pH-DEM肝内给药的定量成像 肿瘤将是早期预测纵向反应的关键，从而促使调整 根据需要对个别治疗方案进行调整(额外给药或采用替代疗法)。 通过一个合作项目，利用我们在纳米医学、材料、介入方面的优势 肿瘤学和放射学，我们寻求开发一种强大的新方法，用于图像引导的细胞静态索拉非尼 和肝肿瘤的细胞毒性DOX递送。该项目将解决以下目标，在一个完善的 肝癌啮齿动物模型： 目的1：表征我们的磁共振可见pH触发药物的合成方案之间的关系 洗脱微球(pH-DEM)以及由此产生的索拉非尼和多柔比星的载药量和释放率。 目的2：确定这些MRI可见的索拉非尼和DOX的pH-DEM和DEM的成像特性 验证在经导管给药至肝脏肿瘤后，磁共振成像允许体内定量。 目的3：验证索拉非尼和多柔比星pH-DEM对血管生成和肿瘤生长的抑制作用 体内pH-DEM释放的测量可以预测肿瘤的反应。

PROJECT SUMMARY HCC is the 5th most common malignancy in the world and the 4th leading cause of cancer death in the US. Resection and transplantation are the sole potentially curative treatments for HCC, but only 10-15% of patients are candidates. Sorafenib and doxorubicin (DOX)-transcatheter arterial chemoembolization (TACE) combination may offer a potent combination maximizing therapeutic outcomes by inhibiting angiogenesis and simultaneously inducing apoptosis. Recent clinical results showed that the median overall survival and the risk of progression or death were significantly improved in sorafenib and DOX-TACE combination. However, sorafenib is currently administered systemically in an oral tablet formulation. Consequent systemic exposures and a lack of tumor specificity leads to side-effects including skin rashes, hand and foot syndrome, diarrhea, and hypertension. Given the commonly intolerable severity of these side- effects, drug dose often must be reduced or administration discontinued altogether (>30% of patients). Our MRI-visible pH triggerd drug eluting microsphere (pH-DEM) platforms offer the potential to increase the efficacy of liver-directed therapies for HCC while reducing systemic exposures via catheter-directed delivery. Quantitative imaging of sorafenib and DOX loaded pH-DEM delivery to liver tumors will be critical to permit early prediction of longitudinal response thus prompting adjustments to individual treatment regimens as needed (additional administrations or adoption of alternative therapies). Through a collaborative project building upon our strengths in nanomedicine, materials, interventional oncology, and radiology, we seek to develop a powerful new approach for image-guided cytostatic sorafenib and cytotoxic DOX delivery to liver tumors. This project will address the following Aims in a well-established rodent model of liver cancer: Aim 1: Characterize the relationship between the synthesis protocols for our MRI-visible pH triggered drug eluting microspheres (pH-DEM) and resulting sorafenib and DOX drug loading and release rates. Aim 2: Determine imaging characteristics of these MRI visible sorafenib and DOX loaded pH-DEM and validate that MRI permits in vivo quantification following transcatheter delivery to liver tumors. Aim 3: Validate that sorafenib and DOX loaded pH-DEM inhibit angiogenesis and tumor growth and that in vivo measurements of pH-DEM delivery are predictive of tumor responses.