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

纳米颗粒介导的胎盘成像和磁热疗治疗异位妊娠

• 批准号: 10639419
• 负责人: Olena Taratula
• 金额: $ 59.24万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639419
• 关键词: Abnormal placentation; Address; Anatomy; Animal Model; Binding; Biodistribution; Biological Markers; Birth; Blood; Cells; Cessation of life; Clinic; Clinical; Contrast Media; Data; Detection; Diagnosis; Diarrhea; Early Diagnosis; Ectopic Pregnancy; Enzymes; Event; Exposure to; Failure; Fertility; Fetus; First Pregnancy Trimester; Future; Gadolinium; Gestational Age; Growth; Growth and Development function; Hemorrhage; Human; Human Chorionic Gonadotropin; Hyperthermia; Image; Impairment; Infant; Interstitial Pneumonia; Intravenous; Life; Ligands; Liver; Location; Macaca; Magnetic Resonance Imaging; Magnetic nanoparticles; Magnetism; Mammalian Oviducts; Maternal Mortality; Measures; Mediating; Medical; Metabolic Clearance Rate; Methotrexate; Modality; Molecular Weight; Mothers; Mus; Nausea; Operative Surgical Procedures; Organ; Outcome; Peptides; Placenta; Placenta Diseases; Placentation; Pregnancy; Procedures; Quality of life; Recovery; Research; Research Personnel; Rupture; Safety; Serum; Signal Transduction; Site; Spontaneous abortion; Syncytiotrophoblast; Technology; Temperature; Termination of pregnancy; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Transvaginal Ultrasound; Treatment Efficacy; Ultrasonography; United States; Uterine cavity; Uterus; Vascularization; Visualization; Vomiting; Work; adverse pregnancy outcome; biocompatible polymer; chemotherapy; clinically relevant; contrast enhanced; design; effective therapy; fetal; imaging modality; implantation; improved; innovation; intravenous injection; magnetic field; malformation; multidisciplinary; nanomedicine; nanoparticle; nanoparticle delivery; nanopolymer; nanotechnology platform; nature therapy; nephrotoxicity; non-invasive imaging; nonhuman primate; noninvasive diagnosis; novel; offspring; pregnant; prevent; side effect; targeted delivery; trophoblast; uptake

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.

摘要/摘要 宫外孕是怀孕头三个月与孕产有关的死亡的主要原因。 大约98%的异位妊娠发生在输卵管，如果发生输卵管破裂， 治疗对于避免出血和产妇死亡至关重要。宫外孕约占每一个 在美国有50例妊娠（每年12万例）。目前超声检查程序误诊 异位妊娠的病例高达40%，而甲氨蝶呤治疗确诊的EP的失败率为 超过10%。在超声显像之前的时间内，妊娠生物标志物人类 绒毛膜促性腺激素（hCG）用于评价生长，但不能很好地测量着床部位。这 该项目旨在建立一种利用纳米粒子靶向定位早期胎盘的成像模式 胎盘的滋养层。对比度增强成像模式（例如，MRI）可以基本上 改善异位妊娠检测。然而，使用常规造影剂，包括钆- 不鼓励使用基于MRI的造影剂，因为低分子量化合物可以穿过胎盘， 在存活妊娠中引起胎儿毒性。为了应对这一挑战，生物相容性聚合物纳米平台将 在静脉注射后，可利用特异性地在胎盘组织中而不是胎儿中积累的药物。这 纳米平台将装载新开发的磁性纳米颗粒， 将在胎盘细胞和小动物中评估药物和胎盘蓄积/检测/可视化 模型此外，损害发育中的胎盘，从而终止异位妊娠的能力， 通过滋养层靶向纳米颗粒介导的磁热疗来证明。此前提 一项研究表明，专门设计的纳米颗粒可以检测早期胎盘形成， 热疗可以提供治疗异位妊娠的非侵入性选择。推进拟议的方法 对于异位妊娠管理，我们的多学科研究团队具有互补的专业知识， 纳米医学、磁热疗和临床胎盘研究在目标1中提出， 所开发的纳米颗粒（非靶向和滋养层- 靶向）在人/猕猴胎盘细胞和小鼠中。在目标2中，MRI成像效率和短-和 胎盘靶向纳米颗粒的长期毒性将在怀孕小鼠中进行评价。目标3：安全 我们的磁性纳米粒子介导的磁热疗的治疗效果将被评估， 在小鼠和非人灵长类动物中模拟治疗人异位妊娠，旨在证明 一种新的、有效的、非侵入性的异位妊娠治疗方法。