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

使用多功能纳米液滴进行图像引导氧气增强光动力疗法可改善头颈癌的治疗效果

• 批准号: 10670377
• 负责人: Srivalleesha Mallidi
• 金额: $ 41.48万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670377
• 关键词: Acute; Address; Adjuvant; Adjuvant Chemotherapy; Adjuvant Radiotherapy; Aftercare; Appearance; Beds; Biodistribution; Biological; Biological Markers; Blood Vessels; Cancer Model; Cell surface; Cetuximab; Chemoresistance; Chemotherapy and/or radiation; Clinical; Contrast Media; Cosmetics; Data; Deglutition; Disease; Dose; Drug Kinetics; Dyes; Eating; Encapsulated; Environment; Epidermal Growth Factor Receptor; Equilibrium; Excision; FDA approved; Feedback; Fluorescence; Fluorocarbons; Food; Gases; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Health; Histopathology; Hypoxia; Image-Guided Surgery; In complete remission; Indocyanine Green; Invaded; Kinetics; Life; Light; Liquid substance; Localized Malignant Neoplasm; Mainstreaming; Mastication; Molecular; Monitor; Necrosis; Neoadjuvant Therapy; Normal tissue morphology; Operative Surgical Procedures; Oral mucous membrane structure; Organ; Outcome; Oxygen; PUVA Photochemotherapy; Pathologic; Patient-Focused Outcomes; Patients; Penetration; Pharmaceutical Preparations; Photosensitizing Agents; Phototherapy; Quality of life; Radiation therapy; Radio; Recurrence; Resected; Residual Neoplasm; Site; Solid Neoplasm; Speech; Surface; Surgeon; Surgical margins; Survival Rate; Therapeutic; Time; Tissues; Toxic effect; Treatment Efficacy; Treatment outcome; Tumor Burden; Tumor Volume; Tumor stage; Verteporfin; absorption; cancer therapy; chemotherapy; clinical translation; contrast imaging; cost; dosimetry; fluorescence imaging; fluorescence-guided surgery; healing; image guided; improved; in vivo; insight; irradiation; local drug delivery; loss of function; malignant mouth neoplasm; mouse model; nanoDroplet; nanodrug; nanotechnology platform; overexpression; patient population; phase change; photoacoustic imaging; psychologic; receptor expression; side effect; spatiotemporal; success; systemic toxicity; targeted treatment; tool; treatment response; treatment strategy; tumor; tumor eradication; uptake

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.

项目摘要 头部和颈部鳞状细胞癌（HNSCC），尤其是口腔癌（ORCA）是令人衰弱的 疾病在过去十年中没有总体存活率没有增加，患者经历了明显的身体 以及由于该地区关键器官的功能丧失和外观外观而导致的心理损失。目前 一线治疗是手术，其中> 5-12毫米的正常组织区域以外的肿瘤边缘以外的 达到明显的边缘并减少机车区域复发。辅助放疗和化学疗法是 根据肿瘤阶段进行管理，但是这些疗法具有严重的毒性，没有添加 益处。总体而言，迫切需要空间局部的治疗工具，可以帮助消除肿瘤 完全或减轻肿瘤负担充足，以减少正常组织切除，以最佳的手术切除。 光动力疗法（PDT）是一种有效的，空间局部的癌症治疗，对健康的损害极少 组织。尽管其低成本，在减轻肿瘤负担方面的成功以及口腔治疗后的良好康复 PDT粘膜尚未成为主流前线疗法，主要是因为实体瘤的PDT功效 取决于光敏剂（PS）在肿瘤部位的显着积累，在附近的氧气可用性 PS，以及PS-Light辐照组合的有效给药。我们的新纳米平台，Verosite，增强了所有 除了有助于图像引导的手术外，其中三个参数还可以显着改善HNSCC 患者的结果。 Verosite（Verteporfin，氧气和靶向平台）是全氟化合物（PFC） 基于光声（PAI）和荧光（FLI）含有吲哚苷绿（ICG）染料的基于纳米植物的染料 成像对比度，有效PDT的PS Verteporfin和氧气，将针对表皮生长因子 受体（EGFR），一种细胞表面生物标志物在逆戟鲸中显着过表达。一旦专门积累 在肿瘤下，ICG吸收光将触发液体对PFC的气相变化的目的 为时空传递PS和O2以进行有效的PDT。受我们有前途的初步数据的动机，我们 假设最好的治疗结果（减轻肿瘤负担，低复发和增强的生活质量 通过启用的图像引导的手术，将获得正常组织和功能的最小损失） 和氧气增强的PDT。我们以三个特定目的评估了该假设：AIM-1：合成，优化， 并描述了Verosite平台，AIM-2：建立Verosite NDS生物分布，药代动力学和 PDT的剂量需求在原位孔鼠模型中具有不同的EGFR表达和AIM-3： 证明启用氧气的氧气增强了PDT和荧光图像引导的手术将有助于 在各种原位孔模型中，最小的正常组织切除并增强了生存。总体而言，我们的 可自定义的多功能词素平台将增强PDT效力，并可以适应以减轻 许多氧依赖性疗法的缺氧，用于广泛的实体瘤。