PROJECT SUMMARY Pancreatic cancer (PaCa) has the poorest prognosis amongst all major cancer types and claimed the lives of over 41,000 Americans in 2016. Upon clinical presentation, most patients are diagnosed with locally advanced disease without good treatment options, either to delay progression or for palliation. Chemotherapy is generally ineffective due to hypovascular nature of the tumor. Tumor removal is often unfeasible due to the proximity of major blood vessels, which also complicate thermal ablative procedures. We seek to develop chemophototherapy as a novel ablative modality for PaCa. This approach combines phototherapy and chemotherapy using a single agent, based on light-activated liposomes. Recently, long-circulating liposomal irinotecan (IRI) was approved for treating PaCa. We have found that when small amounts of porphyrin-phospholipid (i.e. 2 molar percent) are incorporated into conventional stealth liposomes, stability and long blood-circulating properties are retained. In prior work using doxorubicin, circulation was >25 hours in rodents, but the liposomes rapidly release their contents (in a couple of minutes) upon exposure to clinically relevant red light. This results in an order of magnitude greater drug deposition in the tumor, leading to potent ablation. We will adapt this approach to develop a long-circulating, light-activated form of irinotecan. We will also apply recent methodology to develop and assess an ultrafast light-triggered release version, by incorporating small amounts of unsaturated lipids, together with the PoP. We will assess the IRI PoP formulations in patient derived xenografts that mimic feathers of the clinical disease, as well as in an orthotopic model derived from a genetically engineered mouse model of the disease. Treatment parameters such as the drug dose, light dose, and drug-light interval will be assessed. We will develop and assess interstitial phototreatment and computer-aided treatment planning of optical fiber placement, based on MR scans with light propagation modeling that will be required to apply chemophototherapy in clinical studies. We will characterize the depth of ablation measurements and treatment with multiple interstitial fibers in large rat tumors. Finally, in order to asses the applicability of this technique near the critical vessels found in many PaCa tumors, we will characterize drug and light dose functional responses in large veins in rodents in vivo, in sheep carotid arteries ex vivo and in acellular collagen vessels.