Laboratory for Reproductive Health, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, Guangdong, China, 518055.
College of Veterinary Medicine, Hunan Agricultural University, Changsha, Hunan, China, 410128.
Theranostics. 2018 Apr 9;8(10):2765-2781. doi: 10.7150/thno.22904. eCollection 2018.
The availability of therapeutics to treat pregnancy complications is severely lacking, mainly due to the risk of harm to the fetus. In placental malaria, infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) on the surfaces of trophoblasts. Based on this principle, we have developed a method for targeted delivery of payloads to the placenta using a synthetic placental CSA-binding peptide (plCSA-BP) derived from VAR2CSA, a CSA-binding protein expressed on IEs. A biotinylated plCSA-BP was used to examine the specificity of plCSA-BP binding to mouse and human placental tissue in tissue sections . Different nanoparticles, including plCSA-BP-conjugated nanoparticles loaded with indocyanine green (plCSA-INPs) or methotrexate (plCSA-MNPs), were administered intravenously to pregnant mice to test their efficiency at drug delivery to the placenta . The tissue distribution and localization of the plCSA-INPs were monitored in live animals using an IVIS imaging system. The effect of plCSA-MNPs on fetal and placental development and pregnancy outcome were examined using a small-animal high-frequency ultrasound (HFUS) imaging system, and the concentrations of methotrexate in fetal and placental tissues were measured using high-performance liquid chromatography (HPLC). plCSA-BP binds specifically to trophoblasts and not to other cell types in the placenta or to CSA-expressing cells in other tissues. Moreover, we found that intravenously administered plCSA-INPs accumulate in the mouse placenta, and analysis of the fetuses and placentas confirmed placenta-specific delivery of these nanoparticles. We also demonstrate successful delivery of methotrexate specifically to placental cells by plCSA-BP-conjugated nanoparticles, resulting in dramatic impairment of placental and fetal development. Importantly, plCSA-MNPs treatment had no apparent adverse effects on maternal tissues. These results demonstrate that plCSA-BP-guided nanoparticles could be used for the targeted delivery of payloads to the placenta and serve as a novel placenta-specific drug delivery option.
治疗妊娠并发症的疗法严重缺乏，主要是因为存在对胎儿造成伤害的风险。在胎盘疟疾中，感染的红细胞（IEs）通过黏附在滋养层细胞表面的硫酸软骨素 A（CSA）而在胎盘内积聚。基于这一原理，我们开发了一种使用源自 VAR2CSA 的胎盘 CSA 结合肽（plCSA-BP）将有效载荷靶向递送至胎盘的方法，VAR2CSA 是在 IEs 上表达的 CSA 结合蛋白。 生物素化的 plCSA-BP 用于检查 plCSA-BP 在组织切片中与小鼠和人胎盘组织的特异性结合。 将不同的纳米颗粒，包括负载吲哚菁绿（plCSA-INPs）或甲氨蝶呤（plCSA-MNPs）的 plCSA-BP 偶联纳米颗粒，静脉内给予怀孕小鼠，以测试其向胎盘递药的效率。 使用 IVIS 成像系统在活体动物中监测 plCSA-INPs 的组织分布和定位。 使用小动物高频超声（HFUS）成像系统检查 plCSA-MNPs 对胎儿和胎盘发育以及妊娠结局的影响，并使用高效液相色谱法（HPLC）测量胎儿和胎盘组织中甲氨蝶呤的浓度。 plCSA-BP 特异性结合滋养层细胞，而不与胎盘中的其他细胞类型或其他组织中表达 CSA 的细胞结合。 此外，我们发现静脉内给予的 plCSA-INPs 在小鼠胎盘内积聚，并且对胎儿和胎盘的分析证实了这些纳米颗粒的胎盘特异性递药。 我们还证明了 plCSA-BP 偶联纳米颗粒可将甲氨蝶呤特异性递送至胎盘细胞，导致胎盘和胎儿发育严重受损。 重要的是，plCSA-MNPs 治疗对母体组织没有明显的不良影响。 这些结果表明，plCSA-BP 指导的纳米颗粒可用于有效载荷的胎盘靶向递药，并且是一种新型的胎盘特异性药物递药选择。
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