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

项目摘要 HCC是世界上第五大最常见的恶性肿瘤，也是美国第四大癌症死亡原因。 切除和移植是肝癌唯一可能治愈的治疗方法，但只有10-15%的患者 是候选人。索拉非尼和阿霉素（DOX）-经导管动脉化疗栓塞（TACE） 组合可以提供有效的组合，通过抑制 血管生成，同时诱导细胞凋亡。最近的临床结果显示， 索拉非尼和DOX-TACE组的总生存率和进展或死亡风险显著改善 组合.然而，索拉非尼目前以口服片剂制剂全身给药。 同时全身暴露和缺乏肿瘤特异性导致副作用，包括皮疹， 手足综合症、腹泻和高血压。考虑到这些方面通常无法容忍的严重性- 由于药物的副作用，通常必须减少药物剂量或完全停止给药（>30%的患者）。 我们的MRI-可见pH缓冲剂药物洗脱微球（pH-DEM）平台提供了 提高肝靶向治疗HCC的疗效，同时通过以下途径降低全身暴露 导管引导的递送。索拉非尼和DOX负载的pH-DEM递送至肝脏的定量成像 肿瘤将是关键，允许纵向反应的早期预测，从而促进调整 根据需要调整个体治疗方案（额外给药或采用替代疗法）。 通过一个建立在我们在纳米医学，材料，介入 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抑制索拉非尼 以及向肝肿瘤递送细胞毒性DOX。本项目将在一个完善的 肝癌的啮齿动物模型： 目的1：表征MRI可见pH触发药物合成方案之间的关系 洗脱微球（pH-DEM）和所得到的索拉非尼和DOX药物负载和释放速率。 目的2：确定这些MRI可见索拉非尼和DOX负载的pH-DEM的成像特征， 证实MRI允许经导管输送至肝脏肿瘤后的体内定量。 目的3：证实索拉非尼和阿霉素负载pH-DEM抑制血管生成和肿瘤生长， pH-DEM递送的体内测量可预测肿瘤反应。

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.