Transformable Theranostics for imaging-guided interventions in head and neck squamous cell carcinoma

标题：头颈部鳞状细胞成像引导介入治疗的可变形治疗诊断学 癌 摘要/摘要 该第二阶段SBIR提案的总体目标是将我们高效且无毒的Transformable Nano-Theranostics（TNT）用于头颈部鳞状细胞癌的精确图像引导干预的临床试验 细胞癌（HNSCC）。HNSCC是全球第六大常见癌症。约有55万新 全球每年有65，630例，仅在美国就有65，630例。HNSCC的总生存率仍然是 在过去的25年里没有变化。肿瘤复发和转移是导致死亡的主要原因。 复发性或转移性HNSCC患者的中位总生存期仅为10个月。即使有 这些患者的预后仍然很差。完全手术 去除（具有负边缘）是治疗的目标，但由于渗透而难以实现 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，而且可以在保留肿瘤的同时摧毁任何残留的肿瘤。 关键器官的结构和功能。此外，开发治疗诊断剂，可以检测和消除 早期HNSCC病变，特别是侵袭性亚型，可能对生存和功能产生巨大影响 对于许多患者来说。我们最近开发了一套高度创新的TNT，具有出色的能力， 绕过通常阻碍药物递送至肿瘤的连续生物屏障，包括 HNSCC。在我们的第一阶段SBIR赠款中，我们优化了TNT，并证明了1）智能双 尺寸/电荷-响应于肿瘤的普遍存在的标志（例如，肿瘤酸中毒诱导）的TNT的转化 酸性细胞外pH，pHe）显著增加了HNSCC中TNT的肿瘤积聚和渗透 组织，并促进在癌细胞中的摄取; 2）TNT能够有效地可视化肿瘤、药物递送和 通过近红外荧光成像（NIRFI）和磁共振成像（MRI）观察治疗效果; 在原位HNSCC小鼠模型中，通过TNT的协同三模式疗法实现了100%的完全治愈率。 这些令人鼓舞的结果为我们推进SBIR第二阶段项目奠定了坚实的基础， 计划1）合成大规模良好的制造业生产（GMP）级TNT，2）进行调查 在两个种属（犬和啮齿动物）中进行药理学和毒理学研究的新药（IND），以及3）IND草案 应用并设计HNSCC患者的I期首次人体临床试验，以确定阶段剂量 二.我们的长期目标是开发安全，高效和具有成本效益的治疗诊断剂， HNSCC。这项研究的成功完成将使拟议的TNT为临床试验做好准备。的 提出了可转化的，肿瘤标志性靶向但易于制造的纳米治疗诊断剂， 能够克服向HNSCC递送药物的重要障碍，为以下方面提供了巨大的机会： 精确的图像引导HNSCC的干预，因此具有很大的药理，临床和商业价值。 潜在的导致可销售的纳米制剂，以改善HNSCC的治疗。

Title: Transformable Theranostics for imaging-guided interventions in head and neck squamous cell carcinoma Summary/Abstract The overall goal of this Phase II SBIR proposal is to translate our highly effective and non-toxic Transformable Nano-Theranostics (TNTs) into clinical trials for precision image-guided intervention of head and neck squamous cell carcinoma (HNSCC). HNSCC is the sixth most common cancer worldwide. There are around 550,000 new cases worldwide annually and 65,630 cases in the U.S. alone. The overall survival rate of HNSCC remains unchanged over the past 25 years. Tumor recurrence and metastasis are the leading causes of mortality. Patients with recurrent or metastatic HNSCC have a median overall survival of only 10 months. Even with intensive surgery, radiotherapy and chemotherapy, prognosis for these patients is still dismal. Complete surgical removal (with negative margins) is the goal of the treatment, but can be 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 can not only guide surgery but also destroy any residual cancer while sparing critical organ structure and function. Moreover, development of theranostic agents that can detect and eliminate early HNSCC lesions, particularly aggressive sub-types, could have tremendous impact in survival and function for many patients. We recently developed a set of highly innovative TNTs that possess outstanding capability to circumvent the sequential biological barriers which have generally hindered drug delivery to tumors, including HNSCC. In our Phase I SBIR grant, we have optimized TNTs and demonstrated that 1) the smart dual size/charge- transformation of TNTs in response to ubiquitous hallmarks of tumors (e.g. tumor acidosis induced acidic extracellular pH, pHe) dramatically increased the tumor accumulation and penetration of TNTs in HNSCC tissue, and facilitated uptake in cancer cells; 2) TNTs enabled effective visualization of tumor, drug delivery and therapeutic effect by near infrared fluorescence imaging (NIRFI) and magnetic resonance imaging (MRI); 3) the synergistic trimodal therapy via TNTs achieved a 100% complete cure rate in orthotopic HNSCC mouse models. Those promising results built a solid foundation for us to move forward to the SBIR Phase II project, in which we plan to 1) synthesize large scale Good Manufactory Production (GMP) grade TNTs, 2) perform Investigation New Drug (IND) enabling pharmacology and toxicology studies in two species (dog and rodent), and 3) draft IND application and design a phase I first-in-human clinical trial for HNSCC patients to determine the dose for phase II. Our long-term goal is to develop safe, highly efficacious and cost-effective theranostic agents for human HNSCC. The successful completion of this research will make the proposed TNTs ready for clinical trials. The proposed transformable, tumor hallmark targeting yet easy-to-make nano-theranostic agents that are highly capable of overcoming the important barriers for drug delivery to HNSCC offer tremendous opportunities for precision image-guided intervention of HNSCC, therefore have great pharmacological, clinical and commercial potentials to lead to a marketable nano-formulation to improve the treatment of HNSCC.