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图像引导干预自发性猫头颈癌

基本信息

批准号：
10614437
负责人：
Yuanpei Li
金额：
$ 60.27万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/10614437
关键词：
Acidosis Acids Advanced Development Affinity Alcohol consumption Biodistribution Biological Blood Circulation Cell Line Charge Chemotherapy and/or radiation Clinical Communication 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 Surgery 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 Neoplasm 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 Veterinary Surgery Virus Diseases Visualization Xenograft Model anti-cancer cancer cell chemotherapy clinical development cost effective extracellular fluorescence imaging 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 nano 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 translational barrier tumor uptake

项目摘要

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.

项目摘要/摘要头颈部鳞状细胞癌（HNSCC）是全球第七个最常见的癌症。即使有强化手术，放疗和化学疗法，预后仍然令人沮丧。完全去除（负手术是手术的目标是治疗的目标，但是由于渗透而难以实现重要结构。由于阳性手术边缘与预后不良有关，因此很有必要开发新的治疗方法，不仅可以指导手术，还可以破坏残留肿瘤保留具有重要功能的正常组织。此外，可以检测到的治疗剂的开发并消除早期的HNSCC病变，尤其是侵略性子类型，将对许多HNSCC患者。我们最近开发了一套高度创新的可转换纳米 - 具有出色的能力来规避顺序生物屏障的疗法（TNT）通常阻碍了包括HNSCC在内的肿瘤的药物输送。我们已经证明了1）聪明响应肿瘤酸中毒的双重大小/电荷转化可能会大大增加肿瘤 TNT在HNSCC组织中的积累和渗透，并促进癌细胞摄取； 2）启用了TNT 通过磁共振成像（MRI）和近红外荧光成像（NIRFI）； 3）通过TNTS的协同三型疗法达到100％在原位HNSCC小鼠模型中完全治愈速率。这些极为令人鼓舞的数据表明这样纳米平台可以转化为早期检测和消除HNSCC病变，很容易可以用光照明。该建议的目的是应对生物障碍和通过开发高效，无毒且易于制造的疗法剂的翻译障碍靶向可转换的纳米触角学（T-TNTS），用于使用与伴侣猫一起进行图像引导的干预措施自发的HNSCC。在AIM 1中，具有HNSCC靶向配体的一组强大的T-TNT纳米结构将为开发，优化和充分表征。在AIM 2中，生物分布和肿瘤靶向特性在原位HNSCC模型中，将使用光学成像和MRI研究选定的T-TNT。体内毒性顶部T-TNT的抗肿瘤功效将在包括PDX模型的HNSCC异种移植模型中评估。从AIM 2中选择的最佳T-TNT纳米结构将用于图像引导的治疗研究，在AIM 3中猫与自发的hnscc。成功开发这种治疗剂将显着增强 HNSCC的成像剂和协同疗法的交付，而治疗过程可以在各种空间和时间分辨率量表下进行监控。这项研究的结果将不大仅在推进下一代纳米触角的发展以进行有效的成像和治疗 HNSCC，但同时也为使用可转换的纳米固定剂来创建新的基本知识克服各种生物学障碍，以提高癌症中图像引导的药物递送的效率。