Engineered Nanoparticles to Radioprotect Salivary Tissue

工程纳米颗粒可辐射保护唾液组织

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：头颈癌每年影响 40,000 人，占恶性肿瘤的 6%。放射治疗是主要治疗方法，通常会对唾液腺造成不可逆转的损伤，导致这些患者出现永久性口干或口干。有口腔和全身感染的风险，并且生活质量也明显下降。我们目前的治疗只是姑息治疗（例如人工唾液/口香糖），并且我们实验室的最新结果表明，在临床前小鼠模型中，纳米颗粒 (NP) 介导的 siRNA 递送至受辐射的唾液组织具有治疗功效，这可以短暂调节细胞对辐射的反应，以促进生存。然而，这种辐射防护策略和其他辐射防护策略的长期可行性，特别是在评估细胞静止的潜力或继发性恶性肿瘤的风险方面，要研究辐射防护组织的长期命运，这是临床所需的一步。翻译起来，我们是一个共同递送 siRNA 和活性雌激素激动剂的纳米颗粒系统（目标 1），当将这种药物 4-羟基他莫昔芬 (4-OHT) 递送至发育中的适当转基因组织时，将诱导荧光报告基因的表达。此外，由于生物组织的大部分辐射损伤来自活性氧 (ROS)，因此我们感兴趣的是抑制最初的辐射损伤。 FDA 批准的口干症预防剂是氨磷汀，一种静脉注射的自由基清除剂，治疗窗窄，并且可能产生包括肿瘤保护在内的全身副作用。使用新型纳米颗粒制剂对腺体进行预处理，旨在通过活性氨磷汀的持续细胞内释放为唾液组织提供抗氧化剂（目标 2），完成这些目标将确定辐射防护的目标和后遗症，同时确定哪些目标。本申请还详细介绍了两种治疗策略，以补充研究培训。两位申办者都致力于申请人作为临床医生科学家的发展，并将继续对申请人进行实验设计、科学写作和演示方面的培训。申请人还将与医生一起追求四项纵向临床经验。致力于癌症治疗，以更好地了解他的研究的临床背景。最后，申请人将在医学培训期间继续参与未来实验研究的开发。