Photodynamic therapy (PDT) is a treatment modality for a range of diseases including cancer. We have developed a new class of non-porphyrin PDT agent, the BF2-chelated tetraaryl-azadipyrromethenes (ADPMs). Previously, we have demonstrated that the ADPM class of compounds displays excellent photochemical and photophysical properties for therapeutic application (1,2). In vivo studies now show that treatment of human tumor-bearing nude mice with ADPM06 and light (690nm) leads to eschar development, subsequent tumour ablation and lesion healing. Studies using the MDA-MB-231 GFP-expressing model of human breast cancer show tumour ablation in 86% of animals after I.V. delivery of ADPM06 (2 mg/kg) followed immediately by irradiation with 150 J/cm2 light. We have utilised inherent drug fluorescent properties to describe organ biodistribution patterns. Fluorescence images were acquired using an IVIS Spectrum imaging system (excitation/ emission wavelengths: 640nm/ 720nm respectively). Peak fluorescence intensity was observed in the lungs, liver, kidneys, heart and spleen within one hour following drug administration. Fluorescence approached baseline levels within 24 hours and appeared to be completely cleared from animal by 48 hours. Fluorescence from tumour tissue significantly declined 3 hours post administration and reached baseline levels by 48 hours. We have postulated that ADPM06 is predominantly retained in tumor vasculature within the first few minutes following administration. Thus, using a short drug-light interval, we have sought to elicit a tumor vascular targeting response. In order to test this hypothesis directly, dynamic PET with continuous I.V. infusion of 18F-FDG has been applied over a 2 hour period (3). After initial tracer uptake (~30 min), rats bearing 13762 mammary carcinoma tumors on both sides of the chest wall were treated by parenteral administration of ADPM06 (0.8 mg/kg), followed immediately by irradiation of one tumor with light. For comparison of effect, mice bearing two EMT-6 mammary tumors first received ADPM06 (2 mg/kg) and one tumor was then irradiated 30 min later while infusing FDG and imaging with PET. Dynamic list-mode PET data were sorted into 5 minute frames and kinetic profiles plotted. Immediate irradiation after ADPM06 administration generally resulted in decreased 18F-FDG tumor uptake over time. Such behaviour is compatible with a vascular targeting response to therapy. Delayed irradiation increased tumor uptake rate even above control. Our data continues to show the ADPM family of compounds to be an exciting new class of photosensitizer having significant potential for further translational development. This work was supported by Science Foundation Ireland and UCD Ad Astra Research Scholarships.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA