Engineered Nanoparticles to Radioprotect Salivary Tissue

 描述（由申请人提供）：头颈部癌症每年影响40，000人，占恶性肿瘤的6%。放射治疗，治疗的主要手段，往往会造成不可逆转的损害，唾液腺导致永久性口腔干燥症或口干。这些患者有口腔和全身感染的风险，生活质量也显著下降。我们目前的治疗方法仅是姑息性的（例如人工唾液/口香糖），不能解决潜在的病理学。我们实验室的最新结果已经证明了纳米颗粒（NP）介导的siRNA递送至临床前小鼠模型中的照射唾液组织的治疗功效。这短暂地调节细胞对辐射的反应以有利于存活。然而，目前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或继发性恶性肿瘤风险的可能性方面。为了研究放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来共同递送siRNA和活性雌激素激动剂（Aim 1）。这种药剂4-羟基他莫昔芬（4-OHT）在递送至适当的转基因组织时将诱导荧光报告蛋白的表达，所述荧光报告蛋白将在经处理的细胞和子细胞中持续存在，超过siRNA的瞬时效应。此外，由于对生物组织的大多数辐射损伤来自活性氧（ROS），因此我们对抑制初始辐射损伤感兴趣。唯一FDA批准的口干症预防剂是氨磷汀，一种静脉给药的自由基清除剂，具有狭窄的治疗窗口，以及包括肿瘤保护在内的全身副作用的潜力。我们提出的战略是在当地 用一种新的纳米颗粒制剂预处理腺体，旨在通过活性氨磷汀的持续细胞内释放来武装唾液组织的抗氧化剂供应（Aim 2）。这些目标的完成将确定目标和辐射防护的后果，同时确定两种治疗策略中哪一种更有效。本申请中还详细介绍了临床活动，以补充 申请人。两个申办者都致力于申请人作为临床科学家的发展，并将继续培训申请人的实验设计，科学写作和演示。申请人还将追求四个纵向的临床经验与医生 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，申请人将在其医学培训期间继续参与未来实验研究的开发。

 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.