Pressure-Driven Local Drug Delivery System for Treatment of Liver Cancer

描述（由申请人提供）：由于一般健康状况不佳或混杂因素，许多肝脏恶性肿瘤患者不适合进行侵入性手术切除。在这些患者中，局部、微创、图像引导的方法（如肿瘤消融术）与有效的化疗相结合时，可提供有希望的结局。不幸的是，大多数化疗方案与高全身毒性相关，因此当需要微创方法时不是理想的策略。在这些情况下，局部可注射药物递送系统提供了全身治疗的替代方案，因为它们可以在图像引导下施用，并且可以将释放的药物的大部分直接集中在肿瘤侧，避免全身副作用。该项目的总体目标是开发一种有效的图像引导局部平台药物递送系统，用于治疗实体瘤，可以通过利用现有的介入放射学技术进行管理，监测和控制。所提出的递送系统将使用压力驱动药物扩散的独特概念来增加药物渗透到肿瘤组织中，并且将通过将癌症选择性敏化剂与活性剂一起沿着掺入制剂中来降低有效药物浓度。增加的扩散和降低的有效药物剂量的协同组合应导致在肿瘤治疗中显著更有效的系统。这项工作将在四个目标下进行。首先，压力诱导的阿霉素释放的概念将被测试和优化。同时，将检查化疗增敏剂的局部共递送。第三 目的是确定给药系统的局部部位特异性药代动力学和药效学。最后，在最后一个目标中，将在肝癌的实验模型中评估最佳递送系统的治疗功效，肝癌是最难用全身化疗或手术切除治疗的癌症之一。根据所获得的数据设计的可注射局部给药制剂将更有效地治疗实体瘤，并可能成为癌症微创治疗转变的驱动力。

DESCRIPTION (provided by applicant): Many patients with hepatic malignancies are not candidates for invasive surgical resection due to poor general health or confounding conditions. In these patients local, minimally invasive, image-guided approaches such as tumor ablation offer promising outcomes when combined with effective chemotherapy. Unfortunately most chemotherapeutic regimens are associated with high systemic toxicities and thus are not the ideal strategy when a minimally invasive approach is desired. Local, injectable drug delivery systems offer an alternative to systemic therapy in these cases, since they can be administered under image guidance, and can focus the bulk of released drug directly at the tumor side avoiding systemic side effects. The overarching goal of this project is to develop an effective image-guided local platform drug delivery system for treatment of solid tumors that can be administered, monitored and controlled by utilizing existing interventional radiology techniques. The proposed delivery system will augment drug penetration into tumor tissue using a unique concept of pressure- driven drug diffusion and will lower the effective drug concentration by incorporating a cancer-selective sensitizer into the formulation along with the active agent. The synergistic combination of increased diffusion and decreased effective drug dose should result in a system that is significantly more effective in treatment of tumors. The work will be carried out in four aims. First, the concept of pressure-induced doxorubicin release will be tested and optimized. In parallel, the local co-delivery of the chemosensitizer will be examined. In the third aim, the local site-specific pharmacokinetics and pharmacodynamics of the delivery system will be determined. Finally, in the last aim the therapeutic efficacy of the optimal delivery system wil be assessed in an experimental model of liver cancer, one of the most difficult to treat with systemic chemotherapy or surgical removal. Injectable local drug delivery formulations designed based on the acquired data will be more effective in treatment of solid tumors and could be the driving force behind a shift in minimally invasive management of cancer.