Image-guided oxygen enhanced photodynamic therapy with multi-functional nanodroplets to improve head and neck cancer treatment outcomes

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PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC), particularly the oral cavity cancer (OrCa) is a debilitating disease with no increase in overall survival rate for the past decade and the patients undergo significant physical and psychological toll due to function loss of key organs in the region and cosmetic appearance. Currently the frontline treatment is surgery, where >5-12 mm of normal tissue region beyond tumor margins are resected to achieve clear margins and reduce loco-regional recurrence. Adjuvant radiotherapy and chemotherapy are administered based on the tumor stage, however these therapies had severe toxicity and provided no added benefit. Overall, there is a dire need for spatially localized therapeutic tools that can aid in tumor eradication entirely or reduce the tumor burden sufficiently for optimal surgical resection with reduced normal tissue removal. Photodynamic Therapy (PDT) is an effective, spatially localized cancer treatment with minimal damage to healthy tissues. Despite its low-cost, success in reducing tumor burden, and excellent healing post-treatment of the oral mucosa, PDT has yet to become a mainstream frontline therapy primarily because PDT efficacy in solid tumors depends on significant accumulation of the photosensitizer (PS) at the tumor site, availability of oxygen near the PS, and effective dosing of the PS-light irradiation combination. Our new nano-platform, Verosite, enhances all three of these parameters, in addition to aiding image-guided surgery, poising it to significantly improve HNSCC patient outcomes. Verosite (Verteporfin, Oxygen and Sensing Targeted platform) is a perfluorocarbon (PFC) based nanoplatform that contains Indocyanine green (ICG) dye for photoacoustic (PAI) and fluorescence (FLI) imaging contrast, PS verteporfin and oxygen for effective PDT, and will be targeted to Epidermal Growth Factor Receptor (EGFR), a cell surface biomarker significantly overexpressed in OrCa. Once specifically accumulated at the tumor, absorption of light by ICG will trigger a liquid to gas phase change of the PFC serves the purpose to spatio-temporally deliver PS and O2 for effective PDT. Motivated by our promising preliminary data, we hypothesize that best treatment outcomes (reduced tumor burden, low recurrence and enhanced quality of life with minimal loss of normal tissue and function) will be obtained with Verosite enabled image-guided surgery and oxygen enhanced PDT. We evaluate the hypothesis in three specific aims: Aim-1: Synthesize, optimize, and characterize the Verosite platform, Aim-2: Establish Verosite NDs biodistribution, pharmacokinetics and dose requirements for PDT in orthotopic OrCa murine models with varying EGFR expression and Aim-3: Demonstrate that Verosite enabled oxygen enhanced PDT and fluorescence image-guided surgery will aid in minimal normal tissue resection and enhance survival in various orthotopic OrCa models. Overall, our customizable multi-functional Verosite platform will enhance PDT efficacy and can be adapted to alleviate hypoxia in many oxygen-dependent therapies for a broad array of solid tumors.