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

描述(申请人提供)：由于一般健康状况不佳或情况混乱，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，当与有效的化疗相结合时，可以提供有希望的结果。不幸的是，大多数化疗方案都与高全身毒性有关，因此当需要微创方法时，不是理想的策略。在这些病例中，局部注射给药系统提供了系统治疗的替代方案，因为它们可以在图像指导下给药，并且可以将大部分释放的药物直接集中在肿瘤侧，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的局部平台药物输送系统，用于实体肿瘤的治疗，该系统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。拟议的递送系统将使用独特的压力驱动药物扩散概念来增强药物对肿瘤组织的渗透，并将通过在配方中加入癌症选择性增敏剂和活性物质来降低有效药物浓度。扩散增加和有效药物剂量减少的协同结合，应该会导致一个在治疗肿瘤方面明显更有效的系统。这项工作将分四个目标进行。首先，将对压力诱导阿霉素释放的概念进行测试和优化。同时，将检查化学增敏剂的局部共给药情况。在第三节 目的：测定给药系统的局部定位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给药系统的治疗效果，肝癌是最难通过全身化疗或手术切除治疗的肿瘤之一。根据获得的数据设计的可注射局部给药配方将在治疗实体肿瘤方面更加有效，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.