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

摘要 据世界卫生组织估计，2010年早产（PTB）的年发生率超过10%。 大多数国家。早产是生命第一年死亡的主要原因， 包括终身认知挑战的发病率。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，对社会来说代价高昂。虽然PTB是一个 多因素疾病，最常见的单一原因是炎症。不幸的是，目前没有食物， 药物管理局批准的预防肺结核的药物。努力开发药物治疗， 候选药物的低疗效和潜在的致畸性阻碍了预防PTB的进展。几 多年前，我们偶然发现，广泛使用的药用赋形剂N，N- 在我们的小鼠模型中，二甲基乙酰胺（DMA）可以预防PTB并拯救幼崽免于自然流产。 我们实验室的进一步研究表明，DMA抑制核转位和核转录激活。 因子κ B（NF-κ B B），一种调节免疫细胞介导的炎症的转录因子。另外我们 已经表明DMA减弱了培养的人滋养层细胞和人胎盘细胞的细胞因子分泌， 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- 纳米乳化药物递送系统（SNEDDS），其利用第一次子宫/宫颈通过效应， 将引入阴道腔的药物直接输送到子宫颈和子宫，从而最大限度地降低 全身毒性和致畸性。父母补助金的主要目的是检验我们的阴道 (pv)DMA负载的SNEDDS将直接向宫颈靶组织递送有效浓度的DMA， 预防PTB而不引起致畸作用。此次资助提供的Cellcyte X活细胞分析仪 补充将使我们能够研究DMA加载SNEDDS和纯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具体目标是 补助金补充是1）检验DMA促进M1至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。Cellcyte X活细胞分析仪将 放置在PD/PI的实验室中，并放入标准细胞培养箱中。年轻的调查员， 来自世界上资源不足的地区，那里的肺结核发病率很高，当他们发展到 训练有素的生物医学科学家这一建议将提供重要信息， 了解两种不同DMA制剂对宫颈巨噬细胞的影响， 并将有助于完善预防PTB的理想DMA制剂的开发。

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.