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.
This proposal aims to improve the design of local injectable drug delivery systems for minimally invasive, image-guided cancer chemotherapy. To achieve this goal, the proposed approach will use a dual approach. First, the drug penetration will be improved beyond what is currently feasible with local implants. Second, the therapeutic drug levels will be lowered by delivering a chemosensitizer with the same implant. If properly developed and successfully applied these techniques have the potential to advance the development and translation of such systems into clinical practice. Benefiting from this minimally-invasive chemotherapeutic approach would be the substantial patient population who cannot undergo other generally more invasive and demanding procedures such as tumor surgical resection due to confounding factors in their condition. Specifically, in this application we will test the proposed approach in treatment of experimental hepatocellular carcinoma.