Development of Nanovectors to Prevent Placental Passage of a Tocolytic Agent

 描述(由申请人提供)：在美国，早产影响多达12%的怀孕，是新生儿发病率和死亡率的主要贡献者。早产的治疗包括解宫药物，如消炎痛，以停止子宫收缩。虽然消炎痛在减少子宫收缩方面是有效的，但长期使用消炎痛的主要临床限制是它能穿过胎盘，导致胎儿和新生儿的不良影响，如动脉导管过早关闭和羊水过少。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部位，从而提高疗效并减少相关毒副作用和不良反应。纳米矢量是具有各种物理化学和生物特性的纳米粒子或集成系统，如尺寸、电荷和靶向部分，可以根据预期的用途进行定制。这些特性使得纳米载体的合理设计能够优先将药物输送到感兴趣的组织，并防止它分布到不想要的位置。在这项提案中，我们将使用脂质体，即基于脂质的纳米载体，目前用于临床上的肿瘤和传染病治疗。尽管纳米药物在其他临床领域的应用已经取得了重大进展，但纳米载体在产科的应用还没有得到充分的探索。我们之前对怀孕啮齿动物的研究表明，通过改变纳米载体的物理化学性质可以防止通过胎盘通过。因此，纳米载体代表了一个未知的治疗机会，通过减少胎盘药物进入胎儿的途径来解决怀孕期间使用吲哚美辛的主要限制。在这个探索性的提案中，我们的目标是确定携带药物的纳米载体将吲哚美辛直接输送到怀孕子宫并抑制子宫肌层收缩的能力。为此，将设计含有吲哚美辛的脂质体，使其具有物理化学特性，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多肽，以允许与怀孕子宫肌层上表达的催产素受体结合。我们将使用我们建立的子宫肌层收缩的体外人体模型来测量携带吲哚美辛的脂质体抑制子宫收缩的功能能力。我们还将确定携带吲哚美辛脂质体在预防早产同时减少胎儿暴露的效果。我们建立的体内早产小鼠模型将用于测试吲哚美辛脂质体预防早产和胎儿不良反应的能力。在这项由多学科研究团队开展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，这项研究将为新的范式转换方向奠定基础 高危妊娠的治疗。

 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.