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: 10521642
• 负责人: Srivalleesha Mallidi
• 金额: $ 49.16万
• 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/10521642
• 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; Clinical; Contrast Media; Cosmetics; Data; Deglutition; Disease; Dose; Drug Delivery Systems; 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; 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; Radio; Recurrence; Resected; Residual Tumors; 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; base; cancer therapy; chemoradiation; chemotherapy; clinically translatable; contrast imaging; cost; density; dosimetry; fluorescence imaging; healing; image guided; improved; in vivo; insight; irradiation; loss of function; malignant mouth neoplasm; mouse model; nanoDroplet; nanodrug; nanotechnology platform; overexpression; patient population; phase change; psychologic; receptor expression; response; side effect; success; systemic toxicity; targeted treatment; tool; 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.

项目概要 头颈鳞状细胞癌 (HNSCC)，特别是口腔癌 (OrCa) 是一种使人衰弱的癌症 过去十年来，这种疾病的总生存率没有增加，并且患者经历了显着的身体不适 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损失。目前 一线治疗是手术，切除肿瘤边缘之外 > 5-12 毫米的正常组织区域 实现清晰的切缘并减少局部区域复发。辅助放疗和化疗是 根据肿瘤分期进行给药，但是这些疗法具有严重的毒性并且没有提供任何附加作用 益处。总体而言，迫切需要能够帮助根除肿瘤的空间局部治疗工具 完全或充分减少肿瘤负荷，以实现最佳手术切除，同时减少正常组织的切除。 光动力疗法（PDT）是一种有效的、空间局部的癌症治疗方法，对健康的损害最小 组织。尽管其成本低廉，但在减少肿瘤负荷方面取得了成功，并且口腔治疗后愈合良好 粘膜，PDT尚未成为主流的一线治疗，主要是因为PDT在实体瘤中的疗效 取决于光敏剂（PS）在肿瘤部位的显着积累，肿瘤附近氧气的可用性 PS，以及 PS-光照射组合的有效剂量。我们的新纳米平台 Verosite 增强了所有 其中三个参数除了有助于图像引导手术之外，还可以显着改善 HNSCC 患者的结果。 Verosite（维替泊芬、氧气和传感靶向平台）是一种全氟化碳 (PFC) 基于纳米平台，包含用于光声 (PAI) 和荧光 (FLI) 的吲哚菁绿 (ICG) 染料 成像对比、PS 维替泊芬和氧气进行有效的 PDT，并将针对表皮生长因子 受体 (EGFR)，一种在 OrCa 中显着过度表达的细胞表面生物标志物。一旦专门积累 在肿瘤处，ICG 吸收光将触发 PFC 的液相到气相变化，从而达到目的 时空输送 PS 和 O2，以实现有效的 PDT。受到我们有希望的初步数据的激励，我们 假设最佳治疗结果（减少肿瘤负荷、低复发和提高生活质量） 正常组织和功能损失最小）将通过 Verosite 启用的图像引导手术获得 和氧气增强 PDT。我们以三个具体目标评估该假设：目标 1：综合、优化、 并描述 Verosite 平台的特征，目标 2：建立 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 小鼠模型中 PDT 的剂量要求： 证明 Verosite 启用氧气增强 PDT 和荧光图像引导手术将有助于 最小限度的正常组织切除并提高各种原位 OrCa 模型的存活率。总体而言，我们的 可定制的多功能 Verosite 平台将增强 PDT 功效，并可适应缓解 多种实体瘤的许多氧依赖性疗法中的缺氧。