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

摘要 根据世界卫生组织的估计，早产（PTB）的年发生率高于 在大多数国家，这一比例超过10%。妊娠37周前早产 是生命第一年死亡的主要原因， 终身认知后果。与早产相关的急性和终身护理费用 对家庭产生广泛和持续的影响，对社会造成巨大的代价。原因 PTB的病因是多因素的，但PTB最常见的单一病因是炎症。可悲的是， 目前，美国食品和药物管理局还没有批准用于 预防PTB。这方面的转化研究和药物开发的障碍之一是， 领域是影响胎儿的药物相关毒性的风险。几年前，我们制作了 一个偶然的发现，安全的药物溶剂，N，N-二甲基乙酰胺（DMA），防止 在我们的小鼠模型中，PTB和拯救自发流产的幼崽。在我们的进一步研究 实验室发现，DMA抑制核转位和核因子激活 κ B（NF-κ B），一种调节免疫细胞介导的炎症的转录因子。在 此外，我们已经表明，DMA减弱细胞因子分泌从培养的人， 滋养层和来自人胎盘外植体。最近，我们的实验室与我们的 合作者开发阴道（pv）自纳米乳化药物递送系统（SNEDDS）， 其利用第一次通过子宫/子宫颈的效果来输送引入到子宫内的药物 阴道腔直接到子宫颈和子宫，从而最大限度地减少全身毒性的风险， 致畸性本项目的具体目标是：1）测试我们的pv DMA的效果 SNEDDS对小鼠模型宫颈组织形态学和炎症反应的影响; 2） 确定DMA抑制NF-κ B转录活性的分子机制;以及3） 比较DMA SNEDDS与腹膜内给药 DMA。为了实现这些目标，我们组建了一个PTB，宫颈组织形态学专家团队， 和药物制剂。这个多学科团队将与我们的学生一起工作，他们 都来自于一个多元化的、缺乏服务的群体。虽然肺结核是一个全球性的公共卫生问题， 在得不到充分服务的人群中，肺结核的发病率明显较高。重新利用的新奇 一种容易获得且廉价的预防PTB的常用药物赋形剂， 设计可由远离诊所的患者施用的阴道制剂，或 医院，解决了PTB药物开发领域的关键差距。

ABSTRACT Based on World Health Organization estimates, the annual rate of preterm birth (PTB) is greater than 10% in the majority of countries. Premature birth before 37 completed weeks of gestation is the leading cause of mortality in the first year of life and is associated with morbidity that has life-long cognitive consequences. Acute and lifespan care costs associated with preterm births have broad and sustained effects on families and are enormously expensive for society. Causes of PTB are multifactorial, but the single most common cause of PTB is inflammation. Sadly, there is currently no United States Food and Drug Administration approved drug for the prevention of PTB. One of the hurdles in translational research and drug development in this field is the risk of drug related toxicity affecting the fetus. Several years ago, we made the fortuitous discovery that the safe pharmaceutical solvent, 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-kB), 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 specific aims of the current project are to 1) test the effects of our pv DMA SNEDDS on histomorphology and inflammatory responses in the cervix in a murine model; 2) determine the molecular mechanism whereby DMA inhibits NF-kB transcriptional activity; and 3) compare toxic and teratogenic effects of a DMA SNEDDS to intraperitoneal administration of DMA. To accomplish these aims, we assembled a team of experts in PTB, cervix histomorphology and drug formulation. This multidisciplinary team will be working alongside our students, who come from a diverse and underserved population. Although PTB is a global public health problem, rates of PTB are significantly higher among underserved populations. The novelty of re-purposing a readily available and inexpensive common drug excipient to prevent PTB, together with designing a vaginal formulation that can be administered by patients remote from clinics or hospitals, addresses a critical gap in the field of drug development for PTB.