SUMMARY Our goal is to advance the commercialization of interstitial chemo-phototherapy (I-CPT) as a potent antitumor therapeutic option for locally advanced tumors. This application will focus on providing a proof of concept for the benefit of I-CPT in the treatment locally advanced hepatocellular carcinoma (HCC). Patients with inoperable locally advanced HCC have a poor prognosis with a 5-year survival rate of just 31%. The combination of chemotherapy and phototherapy (CPT) involves administering a single agent such as PhotoDox, a novel long-circulating, doxorubicin in porphyrin-phospholipid liposome formulation. The major advantages of PhotoDox are: 1) it is thermally independent; 2) has rapid drug release upon 665-nm light administration; 3) is long-circulating (~22 hour half-life), serum stable, and otherwise like DOXIL®; and 4) has been demonstrated to be effective in multiple tumor models. PhotoDox was tested by the National Cancer Institute Nanotechnology Characterization Lab, and was found to be similar to DOXIL® in in vitro toxicity and in vivo pharmacokinetic studies. POP Biotechnologies, Inc. has an exclusive license for PhotoDox. Dr. Shafirstein's team at Roswell Park Cancer Institute (RPCI) has developed and validated a novel system to provide specific light dosimetry in large tumors. In this STTR application, POP Biotechnologies will combine PhotoDox with Dr. Shafirstein’s treatment planning approach to optimize and guide I-CPT for effective therapy of locally advanced liver tumors by accomplishing the following aims: Aim 1: To define light irradiance and fluence for effective I-CPT in subcutaneous HepG2 tumors. The PI validated finite element method approach will be used to guide a light dose finding study to define a safe and effective intratumoral light irradiance and fluence for I-CPT with PhotoDox. We will address the key question: What is the optimal intratumoral light irradiance and fluence for I-CPT with PhotoDox? Aim 2: Demonstrate the effectiveness of I-CPT in an orthotopic liver cancer rat model. We will use the FEM to translate the optimal interstitial light delivery determined in murine tumors (Aim 1) to larger orthotopic liver cancer in rats. We will address the key question: Can we deliver an effective I-CPT with PhotoDox to an orthotopic model of liver tumor? This translational Phase I project will provide required data to guide a Phase II study where our teams will test and study I-CPT with PhotoDox in a spontaneous woodchuck HCC (available at RPCI) that is relevant to understanding I-CPT treatment in the context of human liver cancer patients. If successful, I-CPT with PhotoDox stands to benefit the majority of new liver cancer patients, who have inoperable and problematic primary tumors.