Abstract B148: Ultrasound image guided combination therapies involving photodynamic therapy and irinotecan.

Introduction: The field of cancer therapeutics is moving towards attacking the pathology with mechanistically distinct or synergistic combination therapies. In addition to possessing distinct cytotoxicity mechanisms, factors such as dose and sequence of combination therapy needs to be determined for effective therapeutic outcome. Non-invasive imaging techniques play a major role in personalizing these therapies by providing quantitative information on tumor volume, perfusion, oxygenation status, drug concentration etc. In particular we utilized ultrasound imaging to gauge the efficacy of photodynamic therapy (PDT) and irinotecan combination therapy in orthotopic pancreatic tumors of different volume. The rationale behind choosing PDT and irinotecan combination is that Irinotecan intracellular concentrations are increased, as PDT is known to cause destruction of ABC transporters that are responsible for the efflux of the drug and its metabolites outside of the cells. Photoacoustic imaging (a technique that provides contrast based on optical absorption properties of the tissue) was utilized to monitor changes in blood volume and oxygen saturation post photodynamic therapy. Materials and Methods: Orthotopic or subcutaneous pancreatic tumor models were established using MIA PaCA-2 cell line in Swiss Nu/Nu mice (4-6 weeks old). Cells (1 × 106in 50 μL of Matrigel-containing media) were injected into the pancreas or subcutaneously using a 301/2-gauge needle. Orthotopic tumors were imaged to gauge the combination treatment efficacy while the subcutaneous tumors provided change in tumor blood volume post PDT. Ultrasound imaging was used to non-invasively monitor tumor volume in mice and treatment was initiated when the tumors reached ∼35 mm3or ∼70 mm3. Irinotecan and photosensitizer, Benzoporphyrin derivative (BPD) were encapsulated in liposomes and injected via tail vein at concentrations 0.25 mg/kg and 20 mg/kg respectively, 60 minutes prior to PDT light irradiation. Interstitial PDT (690 nm laser, 100mW/cm2, 75 J/cm2) was performed on the exteriorized pancreas of the anesthetized mice with orthotopic tumors. Subcutaneous tumors also received the same PDT dose. Ultrasound and photoacoustic imaging was performed using commercially available Vevo LAZR system. Results and Conclusions: The longitudinal non-invasive ultrasound monitoring of orthotopic tumor volume in response to combination therapy was carried out with appropriate controls. We observed that PDT significantly enhances the tumoricidal efficacy of irinotecan and significantly inhibited tumor growth up to at least 3 weeks post-treatment (p < 0.05). A second combination treatment given at this point did not yield a reduction in tumor volume. In addition we also observed the treatment was ineffective in larger tumors. Photoacoustic imaging of subcutaneous tumors showed decrease in oxygen saturation and blood volume post PDT. The findings of this study recognize the importance of longitudinally monitoring tumor volume, vasculature and blood oxygen status for success of combination treatments. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B148. Citation Format: Srivalleesha Mallidi, Huang-Chiao Huang, Zhiming Mai, Ruth Goldschmidt, Joyce Liu, Patrick Chiang, Dmitriy Timerman, Imran Rizvi, Bryan Spring, Akilan Palanisami, Tayyaba Hasan. Ultrasound image guided combination therapies involving photodynamic therapy and irinotecan. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B148.