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

标题：用于头颈部鳞状细胞的影像引导干预的可变形放射治疗药物 癌症 摘要/摘要 这个第二阶段SBIR提案的总体目标是将我们高效无毒的可变型 纳米热像仪(TNTs)用于头颈部鳞状细胞癌精确影像引导介入的临床试验 细胞癌(HNSCC)。HNSCC是全球第六大常见癌症。大约有55万个新的 全球每年都有病例，仅美国就有65,630例。HNSCC的总体存活率保持不变 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。 复发或转移的HNSCC患者的中位总生存期仅为10个月。即使是在 加强手术、放疗和化疗，这些患者的预后仍然令人沮丧。完整的外科手术 去除(带负边距)是处理的目标，但由于渗透，可能很难实现 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，而且可以在保留肿瘤的同时消灭任何残留的癌症 重要的器官结构和功能。此外，可以检测和消除的治疗药物的开发 早期HNSCC病变，特别是侵袭性亚型，可能会对生存和功能产生巨大影响 对很多病人来说。我们最近开发了一套高度创新的TNTs，它具有出色的能力 绕过通常阻碍向肿瘤输送药物的连续生物障碍，包括 HNSCC。在我们的第一阶段SBIR赠款中，我们优化了TNT，并展示了1)智能Dual 肿瘤普遍存在的特征(如肿瘤酸中毒)对TNTs大小/电荷转化的影响 酸性胞外pH，Phe)显著增加肿瘤积聚和TNTs在HNSCC中的穿透 2)TNTs能够有效地显示肿瘤、药物输送和 近红外荧光成像(NIRFI)和磁共振成像(MRI)的疗效；3) 在原位HNSCC小鼠模型中，通过TNTs进行的协同三模式治疗获得了100%的完全治愈率。 这些有希望的成果为我们推进SBIR第二阶段项目奠定了坚实的基础，在该项目中，我们 计划1)合成规模化的GMP级TNTs，2)进行研究 在两个物种(狗和啮齿动物)中进行药理学和毒理学研究的新药(IND)，以及3)草案IND 应用和设计HNSCC患者I期临床试验，确定各期剂量 我们的长期目标是开发安全、高效和低成本的治疗药物 HNSCC。这项研究的成功完成将使拟议的TNTs准备好进行临床试验。这个 建议的可转化的肿瘤标志物靶向但易于制造的纳米治疗药物 能够克服向HNSCC输送药物的重要障碍为以下方面提供了巨大的机会 因此，精确图像引导介入治疗HNSCC具有很大的药理、临床和商业价值 可能导致一种有市场的纳米制剂来改善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.