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

项目摘要/摘要 头颈部鳞状细胞癌(HNSCC)是全球第七大常见癌症。即使是在 经过密集的手术、放疗和化疗，预后仍然很差。完全删除(否定 手术切缘)配合手术是治疗的目标，但由于肿瘤的浸润性很难达到 重要的结构。由于手术切缘阳性与预后不良有关，因此极有必要 开发新的治疗方法，不仅可以指导手术，而且可以在 保留具有重要功能的正常组织。此外，还开发了能够检测到 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- 基因治疗(TNTs)，它具有出色的能力来绕过顺序的生物障碍 通常会阻碍药物对包括HNSCC在内的肿瘤的输送。我们已经证明了1)聪明的 肿瘤酸中毒后TNTs的双重大小/电荷转化可显著增加肿瘤生长 TNTs在HNSCC组织中的积聚和穿透，并促进癌细胞的摄取；2)TNTs使能 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)经TNTs的协同三模治疗达到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，这样的 纳米平台可以转化为早期发现和消除HNSCC病变，这些病变很容易 可以用光照射的。这项提案的目标是解决生物障碍和 通过开发高效、无毒但易于制造的治疗药物来实现翻译障碍 靶向可变形纳米医疗器(t-TNTs)用于图像引导介入使用陪伴猫 自发性HNSCC。在目标1中，一组具有HNSCC靶向配体的t-TNT纳米结构将被 开发、优化和充分表征。在目标2中，生物分布和肿瘤靶向性 筛选出的t-TNTs将在原位HNSCC模型中进行光学成像和MRI研究。体内毒性 并将在包括PDX模型在内的HNSCC异种移植模型中评估顶级t-TNTs的抗肿瘤效果。 从Aim 2中选择的最好的t-TNT纳米结构将用于Aim 3中的图像引导治疗研究 患有自发性HNSCC的猫。这种治疗药物的成功开发将显著增强 HNSCC的显像剂和协同治疗的交付，而治疗过程可以 在不同的空间和时间分辨率尺度上进行监测。这项研究的结果将是有意义的 只有在推动下一代纳米治疗药物的发展，才能有效地进行肿瘤的成像和治疗 HNSCC，而且还在生成使用可变形纳米温差学用于 克服各种生物障碍，以提高癌症图像引导给药的效率。

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.