Endovascular Filtration to Change Drug Biodistribution (ELOCUTION)

PROJECT SUMMARY We are developing novel minimally invasive catheter-based devices placed under real-time x-ray angiography guidance: functional endovascular filters that remove chemotherapy from the blood in order to reduce systemic toxicity during locoregional infusion therapy. The fundamental challenge of eliminating a specific agent from the blood in veins draining an organ undergoing intraarterial chemotherapy (IAC)—after the agent has its therapeutic effect in the treated organ and before it causes a systemic toxic effect—can be met by capture strategies based on physicochemical properties of the target agent. Preclinical ChemoFilter devices containing ion exchange resins (IER) that reduce doxorubicin (Dox) deposition in the heart of a hepatic IAC swine model by 46% are now being commercialized through startup company Filtro. We will use advanced imaging to quantify the degree to which venous drug filtration changes the biodistribution of target drugs infused into the hepatic artery and the carotid artery (with and without blood brain barrier disruption), simulating the treatment of liver tumors and brain tumors, respectively. Prototype ChemoFilters will be modeled, built, validated in vitro for efficacy, and tested in vivo for efficacy and safety. Experienced teams from UCSF, Penn State, and Purdue will undertake the following specific aims: (SA1) mathematically model drug capture by ChemoFilters, (SA2) synthesize radiolabeled chemotherapeutic analog tracers, (SA3) validate ChemoFilter designs in vitro for capacity to capture drugs, and (SA4) assess safety and efficacy of optimized filters in vivo in small and large animal models. Achievement of these aims will create a family of minimally invasive medical devices that could markedly increase the efficacy of image-guided locoregional intraarterial chemotherapy by lowering systemic drug concentrations and reducing systemic toxicities, thus permitting dose escalation in any given IAC procedure and better local tumor control in fewer IAC sessions. The imaging techniques developed herein will enable superior drug distribution monitoring, providing insight into modifying biodistribution clinically.