Liver cancer incidence is on the rise in the United States and worldwide. Since the majority of patients with hepatic malignancies are not candidates for invasive surgical resection, there is a strong demand for alternative therapies. Local, minimally invasive, image-guided approaches such as tumor ablation offer promising outcomes for liver cancer patients, 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. Accordingly, the overarching goal of our research is to develop an effective local, ultrasound-guided platform drug delivery system for treatment of solid tumors that can be administered, monitored, and controlled by utilizing existing interventional radiology techniques. Within the scope of this larger project, one of the crucial elements is development of the appropriate base matrix that will carry the drug. This matrix needs to be biocompatible and injectable and yet be able to carry a high amount of drug for an extended time. In addition, the drug released from the delivery system needs to overcome the limited penetration distance problem faced by most implantable chemotherapy systems. The goal of the proposed project is thus to engineer and evaluate a new injectable delivery system that meet the above design criteria. The proposed system will incorporate a unique polymer shown to prolong the release rate of doxorubicin to clinically therapeutic rates, through use of reversible, high-affinity molecular interactions. The polymer is also capable of enhancing drug penetration into tumor tissue using a unique concept of pressure-driven drug diffusion. The synergistic combination of minimal invasiveness, therapeutic release rates, and increased diffusion should result in a system that is significantly more effective in treatment of tumors. The work will be carried out in three aims. First an injectable formulation of these affinity-based polymers will be synthesized and characterized. These polymers will then be evaluated and optimized for pressure-induced doxorubicin release in a novel in vitro tissue mimicking phantom. Finally, in this last aim, the optimal implant formulation, developed in the first two aims with the effective concentration at the highest penetration distance, will be tested in vivo in an orthotopic wildtype rat model of HCC. The injectable local drug delivery formulations designed based on the acquired data will be more effective in treatment of liver tumors and could be the driving force behind a shift in minimally invasive management of primary hepatocellular carcinomas as well as secondary liver cancers resulting from metastasis.