Development of Nanovectors to Prevent Placental Passage of a Tocolytic Agent

 描述（由申请人提供）：早产影响美国高达12%的妊娠，是新生儿发病率和死亡率的主要原因。早产的治疗包括宫缩抑制药物，如吲哚美辛，以停止子宫收缩。尽管吲哚美辛能有效地减少子宫收缩，但长期使用吲哚美辛的主要临床局限性是它能够穿过胎盘，导致对胎儿和新生儿的不良影响，如动脉导管过早闭合和羊水过少。纳米医学是一个新兴的临床领域，其主要目标之一是将药物优先导向疾病位点，从而提高疗效并减少相关毒性和不良反应。纳米载体是具有多种物理化学和生物学性质（例如大小、电荷和靶向部分）的纳米级颗粒或集成系统，其可以基于预期用途定制。这些性质允许合理设计纳米载体，以优先将药物递送到感兴趣的组织，并防止其分布到不需要的位置。在这项提案中，我们将使用脂质体，基于脂质的纳米载体，目前用于肿瘤和感染性疾病治疗的临床环境。虽然在其他临床领域使用纳米医学已经取得了重大进展，但纳米载体在产科中的应用尚未得到充分探索。我们以前在怀孕啮齿动物中的研究表明，可以通过修改纳米载体的理化性质来防止经胎盘通过。因此，纳米载体代表了一种未知的治疗机会，通过减少药物通过胎盘到达胎儿来解决妊娠中使用吲哚美辛的主要限制。在这个探索性的建议中，我们的目的是确定携带药物的纳米载体直接将吲哚美辛递送到妊娠子宫并抑制子宫肌层子宫收缩的能力。为此，将设计具有物理化学性质的负载吲哚美辛的脂质体，以保留在母体循环中并提高子宫中的浓度。此外，我们将在脂质体表面使用催产素受体拮抗剂肽，以允许结合妊娠子宫肌层上表达的催产素受体。我们将使用我们建立的子宫肌层收缩性的离体人类模型来测量携带吲哚美辛的脂质体抑制子宫收缩性的功能能力。我们还将确定携带吲哚美辛的脂质体在预防早产同时减少胎儿暴露方面的功效。我们建立的体内早产妊娠小鼠模型将用于测试携带吲哚美辛的脂质体预防早产和胎儿不良反应的能力。在这个由多学科研究人员组成的团队进行的新颖的探索性提案中，我们将把纳米医学的好处扩展到产科领域。除了当前项目的直接目标之外，这项研究还将为新的范式转变方向铺平道路。 治疗高危妊娠。

 DESCRIPTION (provided by applicant): Preterm birth affects up to 12% of pregnancies in the United States and is a major contributor to neonatal morbidity and mortality. The treatment of preterm labor includes tocolytic drugs, such as indomethacin, to stop uterine contractions. Although indomethacin is effective in reducing uterine contractions, the primary clinical limitatio with prolonged use of indomethacin is its ability to cross the placenta leading to adverse fetal and neonatal effects such as premature closure of the ductus arteriosus and oligohydramnios. Nanomedicine is an emerging clinical field with one of the main goals of vectoring the drugs preferentially to the disease loci and, thus, increasing the efficacy and reducing associated toxicities and adverse reactions. Nanovectors are nanoscale particles or integrated systems with a variety of physico-chemical and biological properties, such as size, charge and targeting moieties, that can be customized based on the intended use. These properties allow the rational design of the nanovectors to preferentially deliver a drug to the tissue of interest and prevent it distribution to unwanted locations. In this proposal, we will use liposomes, lipid-based nanovectors, currently used in the clinical setting for tumor and infectious disease therapy. Although significant progress has been made with the use of nanomedicine in other clinical areas, the applications of nanovectors in obstetrics are underexplored. Our previous studies in pregnant rodents have shown that transplacental passage can be prevented through modifications of the physico-chemical properties of the nanovectors. Thus, nanovectors represent an uncharted therapeutic opportunity to address the primary limitation of using indomethacin in pregnancy by reducing placental passage of the drug to the fetus. In this exploratory proposal, we aim to determine the ability of a drug-carrying nanovector to direct the delivery of indomethacin to the pregnant uterus and inhibit myometrial uterine contractility. For this purpose, liposomes, loaded with indomethacin will be designed with physicochemical properties to retain in the maternal circulation and enhance the concentration in the uterus. Additionally, we will use oxytocin receptor antagonist peptide on the liposome's surface to allow binding to the oxytocin receptor expressed on the pregnant myometrium. We will use our established ex vivo human model of myometrial contractility to measure the functional ability of the indomethacin carrying liposomes to inhibit uterine contractility. We will also determine the efficacy of the indomethacin carrying liposomes in preventing preterm birth while reducing fetal exposure. Our established in vivo preterm pregnant mouse model will be used to test the ability of the indomethacin carrying liposomes to prevent preterm birth and fetal adverse effects. In this novel, exploratory proposal, carried out by a multi-disciplinary team of investigators, we will extend the benefits of nanomedicine to the field of obstetrics. Beyond the immediate goals of the current project, this study will pave the ground for the new paradigm-shifting direction in the treatment of high risk pregnancies.