N N-Dimethylacetamide Vaginal Self-nanoemulsifying Drug Delivery System for the Prevention or Preterm Birth

摘要 世界卫生组织估计，年早产率(PTB)超过10%。 大多数国家。早产是导致出生第一年死亡的主要原因，与 发病率包括终生认知挑战。与早产相关的急性和长期护理费用 生育对家庭有深远的影响，对社会也是巨大的代价。尽管PTB是一种 多因素障碍，最常见的单一原因是炎症。可悲的是，目前没有食物和 药品监督管理局批准了预防肺结核的药物。努力开发药物疗法以延缓或 候选药物的低效和潜在的致畸作用一直阻碍着结核病的预防。几个 几年前，我们偶然发现，广泛使用的药用辅料N，N- 在我们的小鼠模型中，二甲基乙酰胺(DMA)可以预防肺结核并挽救幼鼠的自然流产。 我们实验室的进一步研究表明，DMA抑制核移位和核激活 KappaB因子(NF-B)，一种调节免疫细胞介导的炎症反应的转录因子。此外，我们 研究表明，DMA可减少培养的人滋养层细胞和人胎盘的细胞因子分泌 外植体。最近，我们的实验室与我们的合作者合作开发了一种阴道(PV)自我 纳米乳化给药系统(SNEDDS)，它利用第一次子宫/宫颈通过效应来 将引入阴道的药物直接输送到宫颈和子宫，从而将感染风险降至最低 全身毒性和致畸性。家长资助的主要目标是检验这样一个假设：我们的阴道 (PV)加载DMA的SNEDDS将直接将有效浓度的DMA输送到宫颈靶组织，以 在不引起致畸作用的情况下预防肺结核。这项资助提供的Cellcell X活细胞分析仪 补充内容将使我们能够调查加载DMA的SNEDDS和整齐DMA如何影响 宫颈巨噬细胞在炎症驱动早产发病机制中的作用。这样做的具体目的是 GRANT补充剂是1)检验DMA促进M1向M2巨噬细胞表型转换的假设 2)检测DMA对巨噬细胞吞噬功能的影响。Cellcell X活细胞分析仪将是 放置在PD/PI的实验室中，并适合标准的细胞培养孵化器。年轻的调查员，他们来了 来自世界上结核病发病率高的资源不足地区的人，将经常使用它，因为他们发展成 训练有素的生物医学科学家。这项建议将提供重要的信息，将使我们的 了解两种不同的DMA制剂对宫颈巨噬细胞的影响 并将有助于完善用于预防肺结核的理想的甲氧基苯丙胺配方的开发。

ABSTRACT The World Health Organization estimates that the annual rate of preterm birth (PTB) is greater than 10% in most countries. Premature birth is the leading cause of mortality in the first year of life and is associated with morbidity that includes life-long cognitive challenges. Acute and long-term care costs associated with preterm birth have far reaching effects on families and are enormously expensive for society. Although PTB is a multifactorial disorder, the single most common cause is inflammation. Sadly, there is currently no Food and Drug Administration approved drug for the prevention of PTB. Efforts to develop drug therapy to delay or prevent PTB have been hampered by the low efficacy and potential teratogenicity of candidate drugs. Several years ago, we made the fortuitous discovery that the widely used pharmaceutical excipient, N,N- dimethylacetamide (DMA), prevents PTB and rescues pups from spontaneous abortion in our mouse model. Further studies in our laboratory revealed that DMA suppresses nuclear translocation and activation of nuclear factor kappa B (NF-B), a transcription factor that regulates immune cell-mediated inflammation. In addition, we have shown that DMA attenuates cytokine secretion from cultured human trophoblasts and from human placental explants. Recently, our laboratory has teamed up with our collaborator’s to develop a vaginal (pv) self- nanoemulsifying drug delivery system (SNEDDS), which takes advantage of the first uterine/cervix pass effect to deliver drugs introduced into the vaginal cavity directly to the cervix and uterus, thereby minimizing risk of systemic toxicity and teratogenicity. The major goal of the parent grant is to test the hypothesis that our vaginal (pv) DMA loaded SNEDDS will deliver efficacious concentrations of DMA directly to cervix target tissue to prevent PTB without causing teratogenic effects. The Cellcyte X live cell analyzer provided by this grant supplement will allow us to investigate how DMA loaded SNEDDS and neat DMA affect the function of cervical macrophages in the pathogenesis of inflammation driven preterm birth. The specific aims of this grant supplement are 1) to test the hypothesis that DMA promotes M1 to M2 macrophage phenotype switching and 2) to test the effect of DMA on macrophage phagocytic function. The Cellcyte X live cell analyzer will be housed in the PD/PI’s laboratory and fits into a standard cell culture incubator. Young investigators, who come from under-resourced parts of the world where rates of PTB are high, will use it routinely, as they develop into well-trained biomedical scientists. This proposal will provide important information that will sharpen our understanding of the effect of two different DMA formulations on cervical macrophages that play a key role in PTB and will help refine the development of the ideal DMA formulation for the prevention of PTB.