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: 10325367
• 负责人: Tzu-yin Lin
• 金额: $ 48.03万
• 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/10325367
• 关键词: Acidosis; Acids; Alcohol consumption; Aminolevulinic Acid; Animal Model; Antineoplastic Agents; Biological; Canis familiaris; Cell Line; Charge; Chemistry; Clinical; Clinical Trials; 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; Investigational Drugs; Investigational New Drug Application; Lead; Lesion; Light; Lighting; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of nasopharynx; Malignant neoplasm of urinary bladder; Multimodal Imaging; Nature; Near-infrared optical imaging; Neoplasm Metastasis; Operative Surgical Procedures; Organ; PUVA Photochemotherapy; Patients; Penetration; Pharmacology; Pharmacology and Toxicology; Phase; Photosensitizing Agents; Phototherapy; Procedures; Production; Prognosis; Protocols documentation; Publishing; Quality Control; Quality of life; Radiation therapy; Rattus; Recurrence; Research; Research Contracts; Residual Cancers; Residual Tumors; Risk Factors; Rodent; Safety; Sensitivity and Specificity; Site; Small Business Innovation Research Grant; Solid; Solid Neoplasm; Structure; Surgical margins; Survival Rate; System; Therapeutic Effect; Tissues; Tobacco use; Translating; Translations; Virus Diseases; Visualization; Work; anti-cancer; bench to bedside; cGMP production; cancer cell; cancer type; chemotherapy; clinical translation; commercialization; cost effective; design; experience; extracellular; first-in-human; image guided; image guided intervention; image visualization; image-guided drug delivery; improved; innovation; large scale production; malignant oropharynx neoplasm; monomer; mortality; mouse model; nanoformulation; nanoparticle; nanotechnology platform; nanotheranostics; novel; 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：可转换的疗法用于成像引导的干预干预措施 癌 摘要/摘要 这一II阶段SBIR提案的总体目标是翻译我们的高效和无毒的转化 纳米骨静脉曲张（TNT）进入临床试验，用于精确的图像引导的头颈部鳞状干预 细胞癌（HNSCC）。 HNSCC是全球第六大癌症。大约有550,000个新 仅在美国，全球案件每年在全球范围内和65,630例案件。 HNSCC的总生存率仍然存在 在过去的25年中，没有变化。肿瘤复发和转移是死亡率的主要原因。 复发性或转移性HNSCC的患者的总生存期中位数仅10个月。即使有 这些患者的强化手术，放疗和化学疗法，预后仍然很沮丧。完整的手术 去除（负边缘）是治疗的目标，但由于渗透而难以实现 重要结构。由于阳性手术边缘与预后不良有关，因此很有必要 开发新的治疗方法，不仅可以指导手术，还可以在保留期间破坏任何残留癌症 关键器官结构和功能。此外，开发可以检测和消除的治疗剂 早期的HNSCC病变，尤其是侵略性的子类型，可能对生存和功能产生巨大影响 对于许多患者。我们最近开发了一套高度创新的TNT，具有出色的能力 规避一般阻碍药物输送到肿瘤的顺序生物屏障，包括 HNSCC。在我们的第I阶段SBIR赠款中，我们已经优化了TNT并证明了1）智能双重 肿瘤无处不在的TNT的尺寸/电荷转化（例如肿瘤酸中毒引起的肿瘤标志 酸性细胞外pH，PHE）显着增加了TNT在HNSCC中的肿瘤积累和渗透 组织，并促进癌细胞的摄取； 2）TNT有效地可视化肿瘤，药物输送和 近红外荧光成像（NIRFI）和磁共振成像（MRI）的治疗作用； 3） 通过TNTS的协同三链疗法在原位HNSCC小鼠模型中实现了100％的完全治愈率。 那些有希望的结果为我们迈向SBIR II期项目奠定了坚实的基础，我们在其中 计划至1）合成大型良好的制造生产（GMP）级TNT，2）进行调查 新药（IND）在两个物种（狗和啮齿动物）中启用药理学和毒理学研究，3） 用于HNSCC患者的应用和设计I期第一阶段的临床试验，以确定相位的剂量 ii。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剂 HNSCC。这项研究的成功完成将使拟议的TNT准备临床试验。这 提议的可转换的肿瘤标志性靶向但易于制造的纳米骨抗剂剂高度高度 能够克服向HNSCC吸毒的重要障碍，为 因此，HNSCC的精确图像引导干预措施具有很好的药理，临床和商业 导致可销售的纳米配置以改善HNSCC治疗的潜力。