Tumor-penetrating nano-theranostics for image-guided interventions in spontaneous feline head and neck cancer

肿瘤穿透纳米治疗学用于自发性猫颈癌的图像引导干预

• 批准号: 10183222
• 负责人: Yuanpei Li
• 金额: $ 57.89万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10183222
• 关键词: Acidosis; Acids; Advanced Development; Affinity; Alcohol consumption; Aminolevulinic Acid; Biodistribution; Biological; Blood Circulation; Cell Line; Charge; Cleaved cell; Clinical; Companions; Crosslinker; Data; Detection; Development; Dose; Doxorubicin; Drug Delivery Systems; Early Diagnosis; Epstein-Barr Virus Infections; Excision; FDA approved; Family Felidae; Felis catus; Fluorescence; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Human papilloma virus infection; Image; Immunotherapy; In Vitro; Infiltration; Knowledge; Lesion; Ligands; Light; Lighting; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of nasopharynx; Medical Oncology; Modality; Modeling; Monitor; Multimodal Imaging; Nature; Near-infrared optical imaging; Normal tissue morphology; Operative Surgical Procedures; PUVA Photochemotherapy; Patients; Penetration; Permeability; Pharmaceutical Preparations; Phase I Clinical Trials; Photosensitizing Agents; Phototherapy; Physiological; Porphyrins; Process; Prognosis; Property; Publishing; Radiation therapy; Recurrence; Residual Tumors; Risk Factors; Sensitivity and Specificity; Signal Transduction; Site; Stimulus; Structure; Surface; Surgical Oncology; Surgical margins; Therapeutic; Therapeutic Effect; Therapeutic Index; Therapeutic Use Study; Tissues; Tobacco use; Toxic effect; Translating; Virus Diseases; Visualization; Xenograft Model; anti-cancer; cancer cell; chemotherapy; clinical development; cost effective; extracellular; image guided; image guided intervention; image visualization; image-guided drug delivery; imaging agent; improved; in vivo; innovation; malignant mouth neoplasm; malignant oropharynx neoplasm; mouse model; mouth squamous cell carcinoma; nanotechnology platform; nanotheranostics; next generation; novel; optical imaging; patient derived xenograft model; pharmacokinetics and pharmacodynamics; pheophorbide a; photothermal therapy; premature; response; spatiotemporal; subcutaneous; temporal measurement; theranostics; tumor; uptake

Project Summary/Abstract Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide. Even with intensive surgery, radiotherapy and chemotherapy, the prognosis is still dismal. Completely removal (negative surgical margin) with surgery is the goal of the treatment, but it is difficult to achieve due to the infiltration of vital structures. Since positive surgery margin is associated with poor prognosis, there is a great need to develop novel treatments which could not only guide the surgery but also destroy the residual tumors while sparing normal tissues with important functions. Moreover, development of theranostic agents that can detect and eliminate early HNSCC lesions, particularly the aggressive sub-types, will have tremendous impact in many patients with HNSCC. We recently developed a set of highly innovative Transformable Nano- Theranostics (TNTs) that possess outstanding capability to circumvent the sequential biological barriers which have generally hindered drug delivery to tumors including HNSCC. We have demonstrated that 1) the smart dual size/charge- transformation of TNTs in response to tumor acidosis could dramatically increase the tumor accumulation and penetration of TNTs in HNSCC tissue, and facilitate uptake in cancer cells; 2) TNTs enabled effective visualization of tumor, drug delivery and therapeutic effect by magnetic resonance imaging (MRI) and near infrared fluorescence imaging (NIRFI); 3) the synergistic trimodal therapy via TNTs achieved a 100% complete cure rate in orthotopic HNSCC mouse models. These highly encouraging data suggest that such nano-platform can be translated into early detection and elimination of HNSCC lesions, which are readily accessible to illumination with light. The goal of this proposal is to tackle the biological barriers and translational barriers of theranostic agents via the development of highly effective, non-toxic yet easy-to-make targeting Transformable Nano-Theranostics (t-TNTs) for image-guided intervention using companion cats with spontaneous HNSCC. In aim 1, a robust set of t-TNT nanoconstructs with HNSCC targeting ligand will be developed, optimized and fully characterized. In aim 2, the biodistribution and tumor targeting properties of the selected t-TNTs will be studied with optical imaging and MRI in orthotopic HNSCC model. The in vivo toxicity and anti-tumor efficacy of the top t-TNTs will be evaluated in HNSCC xenograft models including PDX models. The best t-TNT nanoconstruct selected from aim 2 will be used for image-guided treatment studies in aim 3 in cats with spontaneous HNSCC. Successful development of such theranostic agents will significantly enhance the delivery of imaging agents and synergistic therapies of HNSCC while the therapeutic delivery process can be monitored at various spatial and temporal resolution scales. Results from this study will be significant not only in advancing the development of next-generation nano-theranostics for effective imaging & therapy of HNSCC, but also in generating new fundamental knowledge of using transformable nanotheranostics for overcoming a variety of biological barriers to enhance the efficiency of image-guided drug delivery in cancers.

项目概要/摘要 头颈鳞状细胞癌 (HNSCC) 是全球第七大常见癌症。即使与 密集的手术、放疗和化疗，预后依然惨淡。完全去除（阴性 手术切缘）是治疗的目标，但由于手术边缘的浸润而难以实现。 重要的结构。由于手术切缘阳性与预后不良相关，因此非常需要 开发新的治疗方法，不仅可以指导手术，还可以消灭残余肿瘤，同时 保护具有重要功能的正常组织。此外，开发可以检测的治疗诊断剂 消除早期 HNSCC 病变，特别是侵袭性亚型，将对 许多 HNSCC 患者。我们最近开发了一套高度创新的可变形纳米 治疗诊断学 (TNT) 具有出色的能力，能够绕过连续的生物屏障， 通常会阻碍药物向肿瘤（包括 HNSCC）的输送。我们已经证明：1）智能 TNT 响应肿瘤酸中毒的双尺寸/电荷转变可能会显着增加肿瘤 TNT在HNSCC组织中的积累和渗透，并促进癌细胞的摄取； 2) 启用 TNT 通过磁共振成像 (MRI) 有效可视化肿瘤、药物输送和治疗效果 近红外荧光成像（NIRFI）； 3）通过TNT的协同三联疗法达到了100% 原位 HNSCC 小鼠模型的完全治愈率。这些非常令人鼓舞的数据表明， 纳米平台可以转化为早期检测和消除 HNSCC 病变，这些病变很容易 可以用光照明。该提案的目标是解决生物障碍和 通过开发高效、无毒且易于制造的治疗诊断剂的转化障碍 针对可变形纳米治疗学 (t-TNT)，使用伴侣猫进行图像引导干预 自发性 HNSCC。在目标 1 中，将开发一组具有 HNSCC 靶向配体的强大 t-TNT 纳米结构。 开发、优化并充分表征。在目标 2 中，生物分布和肿瘤靶向特性 选定的 t-TNT 将在原位 HNSCC 模型中通过光学成像和 MRI 进行研究。体内毒性 顶级 t-TNT 的抗肿瘤功效将在 HNSCC 异种移植模型（包括 PDX 模型）中进行评估。 从目标 2 中选择的最佳 t-TNT 纳米结构将用于目标 3 中的图像引导治疗研究 患有自发性 HNSCC 的猫。此类治疗诊断剂的成功开发将显着增强 显像剂的递送和 HNSCC 的协同治疗，而治疗递送过程可以 以各种空间和时间分辨率尺度进行监测。这项研究的结果将具有重大意义 只致力于推进下一代纳米治疗学的开发，以实现有效的成像和治疗 HNSCC，而且还产生了使用可变换纳米治疗学的新基础知识 克服各种生物障碍，提高癌症中图像引导药物输送的效率。