Nanomedicine approaches for prevention of inflammation-induced preterm birth

早产 (PTB)，即妊娠 37 周前出生，是 2017 年美国婴儿死亡的第二大原因。每年有超过 260 亿美元用于早产婴儿的治疗和护理，这还不考虑发育和认知障碍的终生影响。在这里，我们重点关注 PTB 最常见的原因——炎症。母体炎症会引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神经行为结果，包括脑瘫、自闭症、精神分裂症和认知迟缓等。唯一批准用于预防 PTB 的药物是合成孕激素己酸羟孕酮 (OHPC)，每周为有单胎自发性 PTB 病史的单胎妊娠妇女进行全身注射，最近一项失败的验证性研究导致人们呼吁 FDA 将这种药物从市场上撤回。对于已经早产的女性，可以使用标签外宫缩药物（抗宫缩药物）来减缓子宫收缩，但这通常只会延迟分娩几天。迫切需要新的、有效的治疗方法来预防肺结核。此外，阴道给药途径尚未得到充分探索，但前景广阔。阴道吸收的药物优先输送至子宫。我们已经证明，通过增加粘膜药物渗透并消除引起局部毒性的高渗赋形剂，可以实现增加向目标生殖组织的药物递送。在子宫内炎症的情况下，我们观察到，将阴道黄体酮 (P4) 与有利于 P4 受体和基因表达的非分娩状态的药物（例如组蛋白脱乙酰酶抑制剂 (HDACi)）相结合，可显着增加母猪产下活仔的数量。相比之下，全身给药相同的药物组合或注射批准的产品 OHPC 则没有治疗效果。基因表达变化的分析表明，静止子宫肌层活性是关键，并且我们已经证实，在小鼠阴道联合给药后测量的子宫肌层组织中 P4 和 HDACi 的水平对于预防人类子宫肌细胞收缩性也是最有效的。重要的是，对暴露于宫内炎症和阴道 P4/HDACi 后出生的幼崽进行的初步神经行为分析表明，发育情况与未暴露于宫内炎症的幼崽相似。在此，我们提出利用纳米医学基于激动人心的初步数据进行研究，以解决有关给药途径、药代动力学的基本问题，并验证现有的药物类别，这些药物类别可以重新配制和重新调整用途，以改善对女性生殖道的靶向作用。如果这些临床前研究按预期取得进展，我们将找到预防炎症诱发的 PTB 的新颖、有效的方法，这些方法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.