Nanomedicine approaches for prevention of inflammation-induced preterm birth

项目总结 早产(PTB)，或在怀孕37周前出生，是导致婴儿死亡的第二大原因 2017年的美国。每年，超过260亿美元用于治疗和护理早产婴儿，而不是 考虑到发展和认知障碍的终生影响。在这里，我们关注的是最 肺结核的常见原因是炎症。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 不良神经行为后果的范围，包括脑瘫、自闭症、精神分裂症和认知 在其他方面，延迟。唯一被批准用于预防肺结核的药物是合成孕激素 己酸羟孕酮(OHPC)作为单胎女性每周注射的系统剂量 有独生子女自发性肺结核病史的怀孕，以及最近失败的验证性研究导致了 呼吁FDA将该药物从市场上撤回。对于已经早产的妇女，标签外 宫缩药物(抗宫缩药物)可以用来减缓子宫收缩，但这通常只会延迟。 生了几天。迫切需要预防肺结核的新的有效治疗方法。更进一步，阴道 给药途径探索不足，但前景看好；经阴道吸收的药物优先 被输送到子宫。我们已经证明，通过增加粘膜药物的渗透率和消除 导致局部毒性的高渗辅料，增加靶向生殖组织的药物输送可 已实现。在宫内炎症的背景下，我们观察到联合阴道孕酮 (P4)使用有利于P4受体和基因表达的非工作状态的药物，如组蛋白 脱乙酰酶抑制剂(HDACi)显著增加了接生活体幼崽的母坝数量。在……里面 相比之下，全身给药或注射批准的产品OHPC没有 治疗效果。对基因表达变化的分析表明，停止子宫肌层活动是关键， 我们已经证实，阴道结合后子宫肌层组织中P4和HDACi的水平 在老鼠体内分娩在预防人类子宫肌层细胞收缩方面也是最有效的。重要的是 宫内炎症暴露后出生的幼鼠的初步神经行为分析 阴道P4/HDACi表明，幼崽的发育与未接触过的幼崽相似 宫内炎症。在此，我们建议进行研究，使用体外分析来评估 激酶抑制剂作为一类药物在预防肺结核中的再利用。将对候选药物进行筛选 人子宫肌层细胞培养中肌层收缩能力的抑制及其下游对炎症的影响 将对信号进行评估。然后，最有效的药物将被配方用于阴道给药和 纳入炎症诱导小鼠模型的药代动力学和疗效评估研究 结核杆菌的。

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.