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

用于头颈鳞状细胞癌成像引导干预的可转换治疗诊断学

• 批准号: 10467033
• 负责人: Tzu-yin Lin
• 金额: $ 84.98万
• 依托单位: THERANOSTEC, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467033
• 关键词: Acidosis; Acids; Alcohol consumption; Animal Model; Antineoplastic Agents; Biological; Canis familiaris; Cell Line; Charge; Chemistry; Chemotherapy and/or radiation; Clinical; Clinical Trials; Communication; Comprehensive Cancer Center; Consultations; Data; Detection; Development; Disease; Doctor of Philosophy; Dose; Doxorubicin; Drug Compounding; Drug Delivery Systems; Early Diagnosis; Epstein-Barr Virus Infections; Excision; FDA approved; Foundations; Generations; Goals; Grant; Head and Neck Squamous Cell Carcinoma; Human; Human papilloma virus infection; Image; Image-Guided Surgery; Immunomodulators; Immunotherapy; In Vitro; Infiltration; Investigation; Lesion; Light; Lighting; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of nasopharynx; Malignant neoplasm of urinary bladder; Modality; Multimodal Imaging; Nature; Near-infrared optical imaging; Neoplasm Metastasis; Operative Surgical Procedures; Organ; PUVA Photochemotherapy; Patients; Penetration; Pharmacology and Toxicology; Phase; Photosensitizing Agents; Phototherapy; Procedures; Production; Prognosis; Protocols documentation; Publishing; Quality Control; Quality of life; Radiation therapy; Rattus; Recommendation; Recurrence; Recurrent tumor; Research; Research Contracts; Residual Cancers; Residual Neoplasm; Risk Factors; Rodent; Safety; Sensitivity and Specificity; Site; Small Business Innovation Research Grant; Solid; Solid Neoplasm; Structure; Surgical margins; Survival Rate; System; Therapeutic; Therapeutic Effect; Tissues; Tobacco use; Translating; Virus Diseases; Visualization; Work; anti-cancer; bench-to-bedside translation; cGMP production; cancer cell; cancer type; chemotherapy; clinical translation; clinical trial readiness; commercialization; cost effective; design; experience; extracellular; first-in-human; fluorescence imaging; image guided; image guided intervention; image visualization; image-guided drug delivery; improved; innovation; large scale production; malignant oropharynx neoplasm; manufacture; monomer; mortality; mouse model; nanoformulation; nanoparticle; nanotechnology platform; nanotheranostics; novel; novel therapeutics; patient prognosis; pharmacologic; phase I trial; pheophorbide a; photothermal therapy; response; stability testing; subcutaneous; theranostics; tumor; uptake

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.

标题：用于头颈部鳞状细胞成像引导干预的可转换治疗诊断学 癌 摘要/摘要 第二阶段 SBIR 提案的总体目标是将我们高效且无毒的 Transformable 纳米治疗诊断学 (TNT) 进入临床试验，用于头颈部鳞状细胞的精确图像引导干预 细胞癌（HNSCC）。 HNSCC 是全球第六大常见癌症。新增约55万个 全球每年有 65,630 例病例，仅美国就有 65,630 例。 HNSCC 的总体生存率仍然 过去25年没有变化。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。即使与 密集的手术、放疗和化疗，这些患者的预后仍然很惨淡。完成手术 去除（边缘为负）是治疗的目标，但由于渗透而很难实现 的重要结构。由于手术切缘阳性与预后不良相关，因此非常需要 开发新的治疗方法，不仅可以指导手术，还可以消灭任何残留的癌症，同时保留 关键器官的结构和功能。此外，开发能够检测和消除的治疗诊断剂 早期 HNSCC 病变，尤其是侵袭性亚型，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，它们具有出色的能力 规避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 资助中，我们优化了 TNT 并证明了 1) 智能双 TNT 的大小/电荷转变响应肿瘤普遍存在的特征（例如肿瘤酸中毒引起 酸性细胞外 pH (pHe) 显着增加 HNSCC 中 TNT 的肿瘤积累和渗透 组织，并促进癌细胞的摄取； 2) TNT 能够有效地可视化肿瘤、药物输送和 通过近红外荧光成像（NIRFI）和磁共振成像（MRI）检测治疗效果； 3） 通过 TNT 协同三联疗法在原位 HNSCC 小鼠模型中实现了 100% 的完全治愈率。 这些可喜的成果为我们推进 SBIR 二期项目奠定了坚实的基础。 计划 1) 大规模合成良好制造厂生产 (GMP) 级 TNT，2) 进行调查 新药 (IND) 能够在两个物种（狗和啮齿动物）中进行药理学和毒理学研究，以及 3) IND 草案 应用并设计针对 HNSCC 患者的 I 期首次人体临床试验，以确定第一阶段的剂量 二.我们的长期目标是为人类开发安全、高效且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。这 提出了可转化的、肿瘤标志性靶向且易于制造的纳米治疗剂，其高度 能够克服 HNSCC 药物输送的重要障碍，为 HNSCC 提供了巨大的机会 影像引导精准干预HNSCC，因此具有良好的药理、临床和商业价值 有望开发出一种可销售的纳米制剂，以改善 HNSCC 的治疗。