Placenta-specific drug delivery by trophoblast-targeted nanoparticles in mice.
Placenta-specific drug delivery by trophoblast-targeted nanoparticles in mice.
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通过靶向滋养层的纳米颗粒在小鼠体内进行胎盘特异性药物输送
作者：
Zhang B;Tan L;Yu Y;Wang B;Chen Z;Han J;Li M;Chen J;Xiao T;Ambati BK;Cai L;Yang Q;Nayak NR;Zhang J;Fan X
理由：治疗妊娠并发症的治疗方法严重缺乏，主要是由于对胎儿造成伤害的风险。在胎盘型疟疾中，恶性疟原虫感染的红细胞（IE）通过粘附于滋养层表面的硫酸软骨素A（CSA）而积聚在胎盘中。基于这一原理，我们开发了一种使用衍生自VAR 2CSA（一种在IE上表达的CSA结合蛋白）的合成胎盘CSA结合肽（plCSA-BP）将有效载荷靶向递送至胎盘的方法。研究方法：使用生物素化的plCSA-BP来检查体外组织切片中plCSA-BP与小鼠和人胎盘组织结合的特异性。将不同的纳米颗粒，包括负载有吲哚菁绿色（plCSA-INPs）或甲氨蝶呤（plCSA-MNP）的plCSA-BP缀合的纳米颗粒，静脉内施用给妊娠小鼠，以测试它们在体内向胎盘递送药物的效率。使用IVIS成像系统在活动物中监测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-MNP对胎儿和胎盘发育以及妊娠结局的影响，并且使用高效液相色谱（HPLC）测量胎儿和胎盘组织中甲氨蝶呤的浓度。结果：plCSA-BP特异性结合滋养层，而不结合胎盘中的其他细胞类型或其他组织中的CSA表达细胞。此外，我们发现静脉内施用的plCSA-INPs在小鼠胎盘中积累，并且胎儿和胎盘的离体分析证实了这些纳米颗粒的胎盘特异性递送。我们还证明了通过plCSA-BP缀合的纳米颗粒将甲氨蝶呤特异性地成功递送至胎盘细胞，导致胎盘和胎儿发育的显著损害。重要的是，plCSA-MNP处理对母体组织没有明显的不良影响。结论：这些结果表明，plCSA-BP引导的纳米颗粒可用于将有效载荷靶向递送至胎盘，并用作新的胎盘特异性药物递送选择。
Rationale: The availability of therapeutics to treat pregnancy complications is severely lacking, mainly due to the risk of harm to the fetus. In placental malaria, Plasmodium falciparum-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. Methods: A biotinylated plCSA-BP was used to examine the specificity of plCSA-BP binding to mouse and human placental tissue in tissue sections in vitro. 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 in vivo. 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). Results: 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 ex vivo 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. Conclusion: 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.
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