Engineered Nanoparticles to Radioprotect Salivary Tissue

工程纳米颗粒可辐射保护唾液组织

• 批准号: 9121660
• 负责人: Jomy Jo Varghese
• 金额: $ 4.36万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121660
• 关键词: 4-Hydroxy-Tamoxifen; Accounting; Acinar Cell; Acute; Address; Adverse effects; Affect; Agonist; Amifostine; Antioxidants; Apoptotic; Artificial nanoparticles; Biological; Biological Preservation; Cell Death; Cells; Characteristics; Chemistry; Chewing Gum; Clinical; Complement; Complex; Development; Diagnosis; Dose; Drug Delivery Systems; Eating; Ensure; Estrogens; Experimental Designs; FDA approved; FarGo; Figs - dietary; Food; Formulation; Future; Generations; Genetic; Gland; Goals; Head and Neck Cancer; Homeostasis; In Vitro; Individual; Injury; Intervention; Label; Laboratories; Life; Long-Term Effects; Longitudinal Studies; Malignant Neoplasms; Mediating; Medical; Methods; Modeling; Outcome; Pathology; Patients; Pharmaceutical Preparations; Physicians; Population; Prophylactic treatment; Protective Agents; Proteins; Quality of life; Radiation; Radiation therapy; Radioprotection; Reactive Oxygen Species; Reporter; Reporter Genes; Reporting; Research; Research Training; Risk; Safety; Saliva; Salivary; Salivary Gland Tissue; Salivary Glands; Scientist; Second Primary Cancers; Secondary to; Sleep; Small Interfering RNA; Supporting Cell; System; Systemic infection; Technology; Testing; Therapeutic; Time; Tissue Survival; Tissues; Tooth structure; Training; Transgenic Organisms; Translations; Treatment Efficacy; Work; Writing; Xerostomia; antioxidant therapy; arm; base; cancer therapy; cell injury; clinical application; controlled release; daughter cell; drug distribution; experience; improved; in vivo; insight; interest; irradiation; mouse model; nanoparticle; novel; oral infection; palliative; pre-clinical; prevent; prophylactic; public health relevance; radiation response; radioprotected; research study; systemic toxicity; therapeutic target; treatment effect; tumor

 DESCRIPTION (provided by applicant): Head and neck cancers affect 40,000 individuals each year, accounting for 6% of malignancies. Radiation therapy, a mainstay of treatment, often causes irreversible damage to the salivary glands resulting in permanent xerostomia or dry mouth. These patients are at risk for oral and systemic infection and also experience significantly diminished quality of life. Our current treatments are only palliative (e.g. artificil saliva / chewing gum) and do not address the underlying pathology. Recent results from our laboratory have demonstrated therapeutic efficacy of nanoparticle (NP) mediated siRNA delivery to irradiated salivary tissue in a preclinical murine model. This transiently modulates th cellular response to radiation to favor survival. What remains unclear, however, is long term viability of this and other radioprotective strategies, particularly in evaluating the potential fo cellular quiescence or the risk of secondary malignancy. To investigate long term fate of radioprotected tissue, a needed step towards clinical translation, we are developing a nanoparticle system to co-deliver siRNA and an active estrogen agonist (Aim 1). This agent, 4-hydroxytamoxifen (4-OHT), when delivered to the appropriate transgenic tissues, will induce expression of a fluorescent reporter protein that will persist in treated cells and daughter cells beyond the transient effect of siRNA. Additionally, because the majority of radiation damage to biological tissues is from reactive oxygen species (ROS), we are interested in dampening the initial radiation insult. The only FDA-approved xerostomia prophylactic agent is amifostine, an intravenously administered radical scavenger, with a narrow therapeutic window, and the potential for systemic side effects including tumor protection. Our proposed strategy is to locally pre-treat the gland with a novel nanoparticle formulation aimed at arming salivary tissues with an antioxidant supply via the sustained intracellular release of active amifostine (Aim 2). Completion of these aims will identify targets and sequellae of radioprotection, while simultaneously determining which of the two therapeutic strategies is more effective. Also detailed within this application are clinical activities to complement the research training of the applicant. Both sponsors are committed to the applicant's development as a clinician-scientist and will continue to train the applicant in experimental design, scientific writing, and presentation. The applicant will also pursue four longitudinal clinical experiences with physicians working in cancer treatment to gain a better understanding of the clinical context of his research. Finally, the applicant will continue involvement in the development of future experimental studies during his medical training.

 描述(申请人提供)：头颈部癌症每年影响40,000人，占恶性肿瘤的6%。放射治疗是治疗的主要手段，通常会对唾液腺造成不可逆转的损害，导致永久性口干或口干。这些患者面临口腔和全身感染的风险，生活质量也显著下降。我们目前的治疗只是姑息性的(例如人工唾液/口香糖)，没有解决潜在的病理问题。我们实验室的最新结果证明了纳米颗粒(NP)介导的siRNA在临床前小鼠模型中对受照射的唾液组织的治疗效果。这会短暂地调节细胞对辐射的反应，从而有利于生存。然而，尚不清楚的是，这种和其他放射防护策略的长期可行性，特别是在评估细胞静止的可能性或继发性恶性肿瘤的风险方面。为了研究辐射保护组织的长期命运，这是临床转化的必要步骤，我们正在开发一种纳米颗粒系统，以共同传递siRNA和活性雌激素激动剂(目标1)。这种药物，4-羟基他莫昔芬(4-OHT)，当传递到适当的转基因组织时，将诱导一种荧光报告蛋白的表达，这种蛋白将在处理的细胞和子细胞中持续存在，而不是siRNA的瞬时效应。此外，由于生物组织的大部分辐射损伤是由活性氧物种(ROS)造成的，我们有兴趣减少最初的辐射伤害。FDA批准的唯一干口症预防药物是氨磷汀，一种静脉注射的自由基清除剂，治疗窗口很窄，可能会产生包括肿瘤保护在内的全身副作用。我们建议的战略是在当地 用一种新的纳米颗粒制剂对腺体进行预处理，目的是通过细胞内持续释放活性氨磷汀来为唾液组织提供抗氧化剂(目标2)。完成这些目标将确定放射防护的靶点和后遗症，同时确定两种治疗策略中哪一种更有效。这项申请中还详细介绍了临床活动，以补充 申请人。两个赞助商都致力于申请者作为临床科学家的发展，并将继续培训申请者在实验设计、科学写作和陈述方面的能力。申请者还将与医生一起学习四种纵向临床经验。 从事癌症治疗工作，以更好地了解他的研究的临床背景。 最后，申请者将在他的医学培训期间继续参与未来实验研究的发展。