Nanoparticle-mediated placental imaging and magnetic hyperthermia for management of ectopic pregnancy

摘要/摘要 宫外孕是妊娠前三个月与产妇有关的死亡的主要原因。 大约98%的异位植入发生在输卵管内，如果输卵管破裂，立即 治疗是避免出血和产妇死亡的关键。宫外孕约占每五例中的一例 美国有50例怀孕(每年12万例)。目前的超声检查程序误诊 高达40%的病例发生异位妊娠，而甲氨蝶呤治疗确诊的EP的失败率为 超过10%。在超声显影之前，妊娠生物标记物人类 绒毛膜促性腺激素(HCG)被用来评估生长，但不能很好地衡量植入部位。这 该项目旨在建立一种利用纳米颗粒靶向定位早期胎盘的成像模式 胎盘的滋养层。对比度增强的成像方式(例如，MRI)基本上可以 改进异位妊娠检测。然而，常规造影剂的使用，包括Gd- 以磁共振造影剂为基础的，当低分子化合物穿过胎盘时不被鼓励，并且可以 在可存活的妊娠中引起胎儿毒性。为了应对这一挑战，生物兼容的聚合物纳米平台将 静脉注射后，专门在胎盘组织而不是在胎儿中积累的物质被利用。这 Nano Platform将装载新开发的磁性纳米颗粒，这些纳米颗粒具有高效的磁共振成像对比度 药物和胎盘堆积/检测/可视化将在胎盘细胞和小动物中进行评估 模特们。此外，损害发育中的胎盘从而终止异位妊娠的能力将 通过滋养细胞靶向纳米颗粒介导的磁热疗法证实。这样做的前提是 建议是，专门设计的纳米颗粒可以检测到早期胎盘植入和随后的磁性 热疗可以提供一种治疗异位妊娠的非侵入性选择。推进提议的方法 对于异位妊娠管理，我们的多学科调查团队在以下方面具有互补的专业知识 纳米医学、磁热疗法和临床胎盘研究建议，在目标1中，评估 开发的纳米粒(非靶向和滋养层细胞)的生物分布图和胎盘摄取 靶向)在人/猕猴胎盘细胞和小鼠体内。在目标2中，MRI成像效率和短时 胎盘靶向纳米颗粒的长期毒性将在怀孕小鼠身上进行评估。在目标3中，安全 而由我们的磁性纳米颗粒介导的磁热疗法的治疗效果将用于 在小鼠和非人灵长类动物身上模拟治疗人类异位妊娠，目的是展示一种 新的、有效的、无创的异位妊娠处理方法。

Summary/Abstract Ectopic pregnancy is the leading cause of maternity-related death during the first trimester of pregnancy. Approximately 98 % of ectopic implantations occur in the fallopian tube and, in the event of tubal rupture, prompt treatment is critical to avoid hemorrhage and maternal death. Ectopic pregnancies account for about one in every 50 pregnancies (120,000 per year) in the United States. Current ultrasonography procedures misdiagnose ectopic pregnancy in up to 40% of cases, while methotrexate treatment for confirmed EP has a failure rate of more than 10%. During the time prior to ultrasonographic visualization, the pregnancy biomarker human chorionic gonadotropin (hCG) is used to evaluate growth but is a poor measure of the implantation site. This project aims to establish an imaging modality for localization of the early placenta utilizing nanoparticles targeting the trophoblast layer of the placenta. Contrast-enhanced imaging modalities (e.g., MRI) can substantially improve ectopic pregnancy detection. However, the use of conventional contrast agents, including gadolinium- based MRI contrast agents, is discouraged as low molecular weight compounds cross the placenta and can incur fetal toxicity in viable pregnancies. To address this challenge, a biocompatible polymeric nanoplatform will be utilized that accumulates specifically in placental tissue, but not the fetus, after intravenous injection. This nanoplatform will be loaded with newly developed magnetic nanoparticles that are highly efficient MRI contrast agents, and placenta accumulation/detection/visualization will be assessed in placenta cells and small animal models. Furthermore, the ability to impair the developing placenta, and thus terminate ectopic pregnancy, will be demonstrated by magnetic hyperthermia mediated by trophoblast-targeted nanoparticles. The premise of this proposal is that specifically designed nanoparticles can detect early placentation, and subsequent magnetic hyperthermia can provide a non-invasive option to treat ectopic pregnancy. To advance the proposed approach for ectopic pregnancy management, our multidisciplinary team of investigators with complementary expertise in nanomedicine, magnetic hyperthermia, and clinical placenta research proposes, in Aim 1, to evaluate the biodistribution profile and placenta uptake of the developed nanoparticles (non-targeted and trophoblast- targeted) in human/macaque placental cells and in mice. In Aim 2, the MRI imaging efficiency and short- and long-term toxicity of the placenta-targeted nanoparticles will be evaluated in pregnant mice. In Aim 3, the safety and therapeutic efficacy of magnetic hyperthermia mediated by our magnetic nanoparticles will be accessed for simulated treatment of human ectopic pregnancy in mice and non-human primates, aiming to demonstrate a novel, effective and non-invasive approach for ectopic pregnancy management.