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.

项目总结 头颈部鳞状细胞癌(HNSCC)，尤其是口腔癌(Orca)是一种令人衰弱的疾病。 在过去十年中总体存活率没有增加的疾病，并且患者接受了显著的身体检查 以及因区域关键器官功能丧失和外表美观而造成的心理损失。目前， 一线治疗是手术，切除肿瘤边缘以外5-12毫米的正常组织区域，以 实现清晰的利润率，减少区域复发。辅助放射治疗和化疗是 然而，根据肿瘤分期进行治疗，这些疗法有严重的毒性，并且没有提供额外的 利益。总体而言，迫切需要能够帮助根除肿瘤的空间定位治疗工具。 完全或充分减轻肿瘤负担，以减少正常组织切除的最佳手术切除。 光动力疗法(PDT)是一种有效的、空间定位的癌症治疗方法，对健康的损害最小 纸巾。尽管其成本低，但成功地减轻了肿瘤负担，并在口腔治疗后获得了良好的愈合 对于黏膜，PDT尚未成为一种主流的一线治疗方法，主要是因为PDT对实体瘤的疗效 取决于光敏剂(PS)在肿瘤部位的显著积累，附近氧气的可获得性 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 这些参数中的三个，除了有助于图像引导手术外，还使其能够显著改善HNSCC 病人的结果。Verosite(维替普芬、氧气和传感靶向平台)是一种全氟碳化合物(PFC) 基于纳米平台，含有用于光声(PAI)和荧光(FLI)的吲哚青绿(ICG)染料 成像对比度、PS维替普芬和氧气用于有效的PDT，并将靶向于表皮生长因子 受体(EGFR)是一种细胞表面生物标志物，在虎鲸中显著过度表达。一旦专门积累起来 在肿瘤处，icg对光的吸收会触发PFC的液-气相转变，从而达到这一目的 以时空递送PS和O2以实现有效的PDT。在我们充满希望的初步数据的激励下，我们 假设最佳治疗结果(减少肿瘤负担、降低复发率和提高生活质量 以最小的正常组织和功能损失)将通过启用Verosite的图像引导手术获得 以及氧气增强型光动力疗法。我们从三个具体目标对该假设进行评估：目标1：综合、优化、 和表征Verosite平台，Aim-2：建立Verosite NDS的生物分布、药代动力学和 在不同EGFR表达和AIM-3的原位虎鲸小鼠模型中PDT的剂量要求： 证明Verosite支持的氧气增强型PDT和荧光图像引导手术将有助于 在各种原位虎鲸模型中，最小限度地切除正常组织并提高存活率。总的来说，我们的 可定制的多功能Verosite平台将增强PDT疗效，并可调整以缓解 许多氧依赖疗法中的低氧适用于多种实体肿瘤。