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情况，许多肝脏恶性肿瘤患者不适合进行有创伤性手术切除。在这些患者中，局部、微创、图像引导的方法，如肿瘤消融，与有效的化疗相结合，提供了有希望的结果。不幸的是，大多数化疗方案与高系统性毒性有关，因此当需要微创方法时，不是理想的策略。在这些情况下，局部注射给药系统提供了全身治疗的替代方案，因为它们可以在图像指导下给药，并且可以将释放的大部分药物直接集中在肿瘤一侧，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输送系统，用于治疗实体肿瘤，该系统可以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利用压力驱动药物扩散的独特概念增强药物对肿瘤组织的渗透，并将通过将癌症选择性敏化剂与活性剂结合到制剂中来降低有效药物浓度。增加扩散和减少有效药物剂量的协同组合应该导致一个系统在治疗肿瘤时显着更有效。这项工作将分四个目标进行。首先，对压力诱导阿霉素释放的概念进行测试和优化。同时，将检查局部化学增敏剂的共同递送。在第三个

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.