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

项目总结/摘要 头颈部鳞状细胞癌（HNSCC）是全球第七大常见癌症。即使有 经过密集的手术、放疗和化疗，预后仍然很差。完全清除（阴性 手术切缘）与手术是治疗的目标，但由于浸润性， 重要的结构。由于手术切缘阳性与预后不良有关，因此非常需要 开发新的治疗方法，不仅可以指导手术，而且可以破坏残留的肿瘤， 保留具有重要功能的正常组织。此外，开发治疗诊断剂，可以检测 并消除早期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，可以绕过连续的生物屏障， 通常阻碍了药物向包括HNSCC在内的肿瘤的递送。我们已经证明，1）聪明的人 肿瘤酸中毒时TNTs的双重大小/电荷转化可以显著增加肿瘤细胞的增殖， TNTs在HNSCC组织中的积累和渗透，并促进癌细胞中的摄取; 2）TNTs使 通过磁共振成像（MRI）有效地显示肿瘤、药物输送和治疗效果， 近红外荧光成像（NIRFI）; 3）通过TNT的协同三模式治疗达到100% 原位HNSCC小鼠模型中的完全治愈率。这些令人鼓舞的数据表明， 纳米平台可以转化为HNSCC病变的早期检测和消除， 容易被光照亮。该提案的目标是解决生物障碍， 通过开发高效、无毒但易于制造的治疗诊断剂， 靶向可变形纳米治疗诊断学（t-TNT），用于使用伴猫进行图像引导干预， 自发性HNSCC。在目标1中，将制备一组具有HNSCC靶向配体的稳健的t-TNT纳米构建体。 开发、优化和充分表征。在目的2中，研究了该化合物的生物分布和肿瘤靶向性质。 将在原位HNSCC模型中用光学成像和MRI研究选定的t-TNT。的体内毒性 并且将在包括PDX模型的HNSCC异种移植模型中评价最佳t-TNT的抗肿瘤功效。 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。这种治疗诊断剂的成功开发将显著提高 成像剂的递送和HNSCC的协同疗法，而治疗递送过程可 以各种空间和时间分辨率尺度进行监测。这项研究的结果将是显著的， 只有在推进下一代纳米治疗诊断学的发展，有效的成像和治疗， HNSCC，而且还产生了使用可转化纳米治疗诊断学的新的基础知识， 克服各种生物学障碍以提高癌症中图像引导药物递送的效率。

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.