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

项目摘要 头颈部鳞状细胞癌（HNSCC），特别是口腔癌（OrCa）是一种使人衰弱的癌症。 在过去的十年中，总生存率没有增加，并且患者经历了显著的身体检查。 以及由于该区域关键器官的功能丧失和美容外观而造成的心理创伤。目前 一线治疗是手术，其中切除肿瘤边缘以外> 5 - 12 mm的正常组织区域， 实现清晰的边缘和减少局部区域复发。辅助放疗和化疗是 然而，这些疗法具有严重的毒性，并且没有提供额外的治疗。 效益总的来说，迫切需要空间定位的治疗工具，可以帮助肿瘤根除 完全或充分减少肿瘤负荷，以实现最佳手术切除，同时减少正常组织切除。 光动力疗法（PDT）是一种有效的、空间定位的癌症治疗方法，对健康人的损害最小。 组织中尽管其成本低，成功地减少了肿瘤负担，并在治疗后的口腔 虽然PDT在粘膜中的疗效不高，但PDT尚未成为主流的一线治疗方法，主要是因为PDT在实体瘤中的疗效 取决于光敏剂（PS）在肿瘤部位的显著积累，肿瘤附近的氧气可用性， PS和PS-光照射组合的有效剂量。我们的新纳米平台Verosite， 这些参数中的三个，除了辅助图像引导手术，平衡它，以显着改善HNSCC 患者结局。Verosite（Verteporfin，氧气和传感靶向平台）是一种全氟化碳（PFC） 基于纳米平台，其含有用于光声（PAI）和荧光（FLI）的吲哚菁绿色（ICG）染料 成像对比剂，PS维替泊芬和氧气用于有效的PDT，并将靶向表皮生长因子 受体（EGFR），一种在OrCa中显著过表达的细胞表面生物标志物。一旦特别积累 在肿瘤处，ICG对光的吸收将触发PFC的液相到气相的变化， 以时空输送PS和O2用于有效的PDT。基于我们有希望的初步数据，我们 假设最佳治疗结果（降低肿瘤负荷、降低复发率和提高生活质量 正常组织和功能损失最小）将通过Verosite enabled图像引导手术获得 和氧增强PDT。我们在三个具体目标中评估假设：目标1：综合，优化， 并表征Verosite平台，目的-2：确定Verosite ND的生物分布、药代动力学和 具有不同EGFR表达和Aim-3的原位OrCa鼠模型中PDT的剂量要求： 证明Verosite启用氧增强PDT和荧光图像引导手术将有助于 最小的正常组织切除和提高各种原位OrCa模型的存活率。总体而言，我们 可定制的多功能Verosite平台将增强PDT疗效，并可适用于缓解 缺氧在许多实体瘤的氧依赖性治疗中的应用。

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.