Nanomedicine approaches for prevention of inflammation-induced preterm birth

早产(PTB)，即怀孕37周前出生，是2017年美国婴儿死亡的第二大原因。每年，超过260亿美元用于治疗和照顾早产婴儿，这还不包括发育和认知障碍对终身的影响。在这里，我们关注的是肺结核最常见的原因--炎症。母体炎症触发促炎细胞因子反应，也可能导致胎儿炎症反应综合征和围产期脑损伤。脑损伤会导致一系列不良的神经行为结果，包括脑瘫、自闭症、精神分裂症和认知延迟等。唯一被批准的预防肺结核的药物是合成孕酮己酸羟孕酮(OHPC)，每周系统地注射给有单胎自发性肺结核病史的单身妊娠妇女，最近一项失败的验证性研究导致呼吁FDA将该药物从市场上召回。对于已经早产的女性，可以使用标签外的宫缩药物(抗宫缩药物)来减缓子宫收缩，但这通常只会推迟几天分娩。迫切需要预防肺结核的新的有效治疗方法。此外，阴道给药途径尚未得到充分探索，但前景看好；经阴道吸收的药物优先输送到子宫。我们已经证明，通过增加粘膜药物的渗透率和消除引起局部毒性的高渗辅料，可以增加对目标生殖组织的药物输送。在宫内炎症的背景下，我们观察到，将阴道孕酮(P4)与有利于P4受体和基因表达的非分娩状态的药物(如组蛋白去乙酰酶抑制剂(HDACi))相结合，可显著增加继续分娩活体幼崽的母马数量。相比之下，系统地给相同的药物组合剂量或注射批准的产品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，在小鼠经阴道联合分娩后测量的子宫肌层组织中P4和HDACi的水平在防止人类子宫肌层细胞收缩方面也是最有效的。重要的是，对暴露在宫内炎症和阴道P4/HDACi之后出生的幼崽进行的初步神经行为分析表明，发育过程类似于没有暴露于宫内炎症的幼崽。在此，我们建议进行研究，利用纳米药物的令人兴奋的初步数据来解决有关给药途径、药代动力学以及验证现有药物类别的基本问题，这些药物类别可能会重新配制和改变用途，以改善针对女性生殖道的靶向。如果这些临床前研究如预期那样取得进展，我们将找到新的、有效的方法来预防炎症诱导的肺结核，同时也支持胎儿和新生儿的免疫规划和发育。

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 build from exciting preliminary data using nanomedicine to address fundamental questions regarding route of administration, pharmacokinetics, as well as validating existing drug classes that may be reformulated and repurposed for improved targeting to the female reproductive tract. If these preclinical studies progress as expected, we will have identified novel, effective methods for prevention of inflammation-induced PTB that also support fetal and neonatal immunological programming and development.