Schmidt Jenna K, Wilson Rebecca L, Davenport Baylea N, Hacker Timothy A, Fitz Casey, Simmons Heather A, Schotzko Michele L, Golos Thaddeus G, Jones Helen N
bioRxiv. 2024 Apr 14:2024.04.10.588902. doi: 10.1101/2024.04.10.588902.
Nanoparticles offer promise as a mechanism to non-invasively deliver targeted placental therapeutics. Our previous studies utilizing intraplacental administration demonstrate efficient nanoparticle uptake into placental trophoblast cells and overexpression of human ( ). Nanoparticle-mediated placental overexpression of in small animal models of placental insufficiency and fetal growth restriction improved nutrient transport and restored fetal growth. The objective of this pilot study was to extend these studies to the pregnant nonhuman primate and develop a method for local delivery of nanoparticles to the placenta via maternal blood flow from the uterine artery. Nanoparticles containing plasmid driven by the placenta-specific promoter were delivered to a mid-gestation pregnant rhesus macaque via a catheterization approach that is clinically used for uterine artery embolization. Maternal-fetal interface, fetal and maternal tissues were collected four days post-treatment to evaluate the efficacy of treatment in the placenta. The uterine artery catheterization procedure and nanoparticle treatment was well tolerated by the dam and fetus through the four-day study period following catheterization. Nanoparticles were taken up by the placenta from maternal blood as plasmid-specific expression was detected in multiple regions of the placenta via in situ hybridization and qPCR. The uterine artery catheterization approach enabled successful delivery of nanoparticles to maternal circulation in close proximity to the placenta with no concerns to maternal or fetal health in this short-term feasibility study. In the future, this delivery approach can be used for preclinical evaluation of the long-term safety and efficacy of nanoparticle-mediated placental therapies in a rhesus macaque model.
Novel method to deliver therapeutics to maternal-fetal interfaceDelivery of nanoparticles to the placenta via maternal catheterization.
纳米颗粒有望成为一种非侵入性递送靶向胎盘治疗药物的机制。我们之前利用胎盘内给药的研究表明，纳米颗粒能有效被胎盘滋养层细胞摄取，并使人[具体基因]过表达。在胎盘功能不全和胎儿生长受限的小动物模型中，纳米颗粒介导的胎盘[具体基因]过表达改善了营养物质运输并恢复了胎儿生长。这项初步研究的目的是将这些研究扩展到怀孕的非人类灵长类动物，并开发一种通过子宫动脉的母体血流将纳米颗粒局部递送至胎盘的方法。含有由胎盘特异性[具体启动子]驱动的[具体基因]质粒的纳米颗粒，通过临床上用于子宫动脉栓塞的导管插入法，递送至妊娠中期的恒河猴。治疗后四天收集母胎界面、胎儿和母体组织，以评估[具体基因]治疗在胎盘中的疗效。在导管插入后的四天研究期内，母猴和胎儿对子宫动脉导管插入程序和纳米颗粒治疗耐受性良好。纳米颗粒从母体血液中被胎盘摄取，因为通过原位杂交和定量聚合酶链反应在胎盘的多个区域检测到了质粒特异性[具体基因]表达。在这项短期可行性研究中，子宫动脉导管插入法能够成功地将纳米颗粒递送至胎盘附近的母体循环，而无需担心对母体或胎儿健康的影响。未来，这种递送方法可用于在恒河猴模型中对纳米颗粒介导的胎盘治疗的长期安全性和有效性进行临床前评估。
将治疗药物递送至母胎界面的新方法通过母体导管插入将纳米颗粒递送至胎盘。
