Nanomedicine approaches for prevention of inflammation-induced preterm birth

项目摘要 早产（PTB），或妊娠37周之前出生，是婴儿死亡的第二大原因， 2017年美国。每年，超过260亿美元用于治疗和护理早产儿，而不是 解释发展和认知障碍的终身影响。在这里，我们专注于最 肺结核的常见病因炎症母体炎症触发促炎细胞因子反应 这也可能导致胎儿炎症反应综合征和围产期脑损伤。脑损伤导致 一系列不良神经行为结果，包括脑瘫、自闭症、精神分裂症和认知功能障碍。 延迟等等。唯一被批准用于预防肺结核的药物是合成的抗结核药物 单胎妊娠妇女每周全身注射己酸羟孕酮（OHPC） 有单胎自发性PTB病史的妊娠，最近一项失败的确证性研究导致 要求FDA从市场上撤回该药物。对于已经处于早产期的女性， 宫缩抑制剂（抗宫缩药物）可用于减缓子宫收缩，但这通常只会延迟 出生几天。迫切需要预防PTB的新的有效治疗方法。此外，阴道 给药途径未被充分探索，但非常有前途;阴道吸收的药物优先 运送到子宫。我们已经证明，通过增加粘膜药物渗透和消除 可以使用引起局部毒性、增加药物递送至靶生殖组织的高渗赋形剂， 办妥了一批在子宫内炎症的情况下，我们观察到， (P4)与药物，有利于非劳动状态的P4受体和基因表达，如组蛋白， 脱乙酰酶抑制剂（HDACi）的使用显著增加了继续分娩活仔的母鼠。在 相比之下，全身给予相同的药物组合或注射批准的产品OHPC没有 治疗效果基因表达变化的分析表明，子宫肌层活动的静止是关键， 我们已经证实，阴道联合后测量的子宫肌层组织P4和HDACi水平 在小鼠中的递送在防止人子宫肌层细胞收缩性方面也是最有效的。重要的是， 对暴露于宫内炎症后出生的幼崽进行初步神经行为分析， 阴道P4/HDACi表明，发育发生类似于未暴露于 子宫内炎症在此，我们提出了使用体外试验来评估 激酶抑制剂作为一类药物用于PTB预防。将筛选候选药物， 人子宫肌层细胞培养物中子宫肌层收缩性的抑制以及对炎症的下游作用 信号将被评估。然后将最有效的药物配制用于阴道给药， 纳入炎症诱导小鼠模型中评估药代动力学和疗效的研究 关于PTB

PROJECT SUMMARY Preterm birth (PTB), or birth before 37 weeks of gestation, was the second leading cause of infant death in the US in 2017. Each year, more than $26 billion is spent on treatment and care of babies born prematurely, not accounting for the lifelong impact of developmental and cognitive impairments. Here, we focus on the most common cause of PTB, inflammation. Maternal inflammation triggers a pro-inflammatory cytokine response that can also lead to fetal inflammatory response syndrome and perinatal brain injury. Brain injury leads to a spectrum of adverse neurobehavioral outcomes, including cerebral palsy, autism, schizophrenia, and cognitive delay among others. The only approved drug for prevention of PTB is the synthetic progestin hydroxyprogesterone caproate (OHPC) dosed systemically as weekly injections in women with a singleton pregnancy with a history of singleton spontaneous PTB, and a recently failed confirmatory study has led to calls for the FDA to withdraw the drug from the market. For women that are already in preterm labor, off-label tocolytics (anti-contraction medications) may be given to slow uterine contractions, but this typically only delays birth for a few days. New, effective treatments for preventing PTB are desperately needed. Further, the vaginal route of administration is underexplored but highly promising; vaginally absorbed drug is preferentially transported to the uterus. We have demonstrated that by increasing mucosal drug penetration and eliminating hypertonic excipients that cause local toxicity, increased drug delivery to target reproductive tissues can be achieved. In the setting of intrauterine inflammation, we have observed that combining vaginal progesterone (P4) with drugs that favor non-laboring states of P4 receptor and gene expression, such as histone deacetylase inhibitors (HDACi), provides a significant increase in dams that go on to deliver live pups. In contrast, dosing the same drug combination systemically or injecting the approved product OHPC had no therapeutic effect. Analysis of gene expression changes suggest that quiescing myometrial activity was key, and we have confirmed that the myometrial tissue levels of P4 and HDACi measured after vaginal combination delivery in mice were also the most effective in preventing human myometrial cell contractility. Importantly, preliminary neurobehavioral analysis of pups born after exposure to intrauterine inflammation followed by vaginal P4/HDACi suggests that development occurred similar to pups that had not been exposed to intrauterine inflammation. Herein, we propose studies that use in vitro assays for assessing the potential of kinase inhibitors as a drug class for repurposing in PTB prevention. Candidate drugs will be screened for inhibition of myometrial contractility in human myometrial cell culture, and downstream effects on inflammatory signaling will be assessed. The most effective drugs will then be formulated for vaginal administration and incorporation into studies assessing pharmacokinetics and efficacy in an inflammation-induced mouse model of PTB.