Optimization of targeted two-photon PDT triads for the treatment of head and neck cancers Charles W. Spangler* a , Jean R. Starkey a , Galyna Dubinina a , Carl Fahlstrom b , Joyce Shepard a,b a SensoPath Technologies, 920 Technology Blvd., Suite B, Bozeman, MT, USA 59718; b Department of Chemistry, Montana State University, Bozeman, MT, USA 59715 ABSTRACT Synthesis of new PDT triads that incorporate a tumor-killing porphyrin with large two-photon cross-section for 150 fs laser pulses (2000 GM) in the Near-infrared (NIR) at 840 nm, a NIR imaging agent, and a small peptide that targets over-expressed EGF receptors on the tumor surface. This triad formulation has been optimized over the past year to treat FADU Head and Neck SCC xenograft tumors in SCID mice. Effective PDT triad dose (1-10 mg/Kg) and laser operating parameters (840 nm, 15-45 min, 900 mW) have been established. Light, dark and PDT treatment toxicities were determined, showing no adverse effects. Previous experiments in phantom and mouse models indicate that tumors can be treated directly through the skin to effective depths between 2 and 5 cm. Treated mice demonstrated rapid tumor regression with some complete cures in as little as 15-20 days. No adverse effects were observed in any healthy tissue through which the focused laser beam passed before reaching the tumor site, and excellent healing occurred post treatment including rapid hair re-growth. Not all irradiation protocols lead to complete cures. Since two-photon PDT is carried out by rastering focused irradiation throughout the tumor, there is the possibility that as the treatment depth increases, some parts of the tumor may escape irradiation due to increased scattering, thus raising the possibility that tumor re-growth could be triggered by small islands of untreated cells, especially at the rapidly growing tumor margins, a problem we hope to alleviate by using image-guided two-photon PDT. Keywords: Two-photon PDT, head and neck tumors, EGF targeting, tumor regression, toxicities, treatment optimization 1. INTRODUCTION Photodynamic therapy (PDT) has made strides towards a more general clinical acceptance over the past decade, but still has not reached the stage where it is recognized as a first line or primary treatment for solid subcutaneous cancerous tumors, such as Head and Neck cancers, by most clinicians, including most surgeons and radiation oncologists. The use of targeted therapies has been garnering an increasing awareness in the clinical cancer community with the approval of such therapies as Avastin, Gleevec, Herceptin and Erbitux, not withstanding the recent decision of the FDA to remove approval of Avastin for the treatment of breast cancer. However, these therapies are often used in combination with surgery and radiation treatment, and their cost can be prohibitive, particularly for patients with no, or minimal health insurance. For example, Gleevec, for chronic myeloid leukemia, can cost more than $4,500 per month, while Avastin, for colon cancer, as much as $100,000/yr 1 . With ever increasing concern over the cost of health care delivery, we need more cost effective outpatient cancer treatments, such as PDT. Image-guided therapy can also play a major role in new cancer treatments, and is being studied in a number of academic laboratories 2-5 . A one-photon commercial instrument was briefly available on the market (QinetiQ N.A. – “See Treat PDT ) 6 but its’ clinical relevance suffered from a lack of approved photo-sensitizers that could treat tumors more than 1 cm below the skin surface. To address these and other issues we have designed, synthesized and tested a triad formulation that combines (1) a synthetic porphyrin that can be activated from 800-840 nm to produce cytotoxic singlet oxygen deep in the tissue transparency window, (2) a small peptide designed to direct the porphyrin to over-expressed EGF receptor sites, and (3) an imaging chromophore that can provide Near infrared (NIR) imaging of the targeted tumor to guide the PDT process. In this current project, using this triad, we have successfully treated HNSCC FADU tumor xenografts in SCID mice. Due to its potentially excellent 3D loco-regional control, targeted two-photon PDT (TPPDT) has many advantages for the noninvasive treatment of recurring refractory Head and Neck cancers that are resistant to further chemotherapy and radiation. The low 5-year survival rate for these cancers has not changed in 30 years, and is largely explained by the Photonic Therapeutics and Diagnostics VIII, edited by Nikiforos Kollias, et al., Proc. of SPIE Vol. 8207, 820720 © 2012 SPIE · CCC code: 1605-7422/12/$18 · doi: 10.1117/12.909640 Proc. of SPIE Vol. 8207 820720-1 Downloaded from SPIE Digital Library on 21 Mar 2012 to 153.90.194.26. Terms of Use: http://spiedl.org/terms