Megalin-targeting liposomes for placental drug delivery.
Megalin-targeting liposomes for placental drug delivery.
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DOI：
10.1016/j.jconrel.2020.05.033
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发表时间：
2020-08-10
期刊：
影响因子：
--
通讯作者：
da Rocha SRP
中科院分区：
文献类型：
--
作者：
Alfaifi AA;Heyder RS;Bielski ER;Almuqbil RM;Kavdia M;Gerk PM;da Rocha SRP
每年，怀孕期间的并发症影响到2600多万妇女。其中一些疾病的发病率和死亡率很高，例如全球孕产妇死亡的主要原因先兆子痫。改善药物在母体给药时向胎盘输送的能力可能为治疗妊娠疾病提供新的机会。本研究的目的是开发用于胎盘给药的巨噬蛋白靶向脂质体纳米载体。meggalin是一种参与网格蛋白介导的内吞过程的跨膜蛋白，在母胎界面的上皮细胞合体滋养细胞（SynT）中表达。因此，靶向meggalin为脂质体搭车进入SynT提供了机会，从而增加胎盘组织中任何相关治疗货物的浓度。聚乙二醇化（2kda）脂质用庆大霉素（GM）修饰，正如我们在早期研究中所显示的那样，庆大霉素是巨噬细胞肽受体的底物，用于制备胎盘靶向脂质体。在妊娠期（GD） 18.5的Balb/c小鼠体内胎盘模型中，研究了靶向脂质体增强荧光探针积累的能力。含有10 mol%转基因修饰脂质的靶向脂质体增加了共轭荧光探针在胎盘中的积累，总积累量为初始剂量的2.8%，与自由探针相比，积累量增加了94倍（p<0.0001），与非靶向对照脂质体相比，积累量增加了2-4倍（p<0.0001），通过组织提取试验和离体成像测量。此外，胎盘SynT横切面的共聚焦图像显示靶向脂质体比非靶向脂质体增加了3倍。在人胎盘屏障（极化BeWo单层）的体外模型中，用流式细胞术检测了包裹在靶向脂质体内的荧光探针的摄取速率和程度。靶向脂质体含有5 mol%转基因修饰脂质，与非靶向对照相比，探针的摄取增加了1.5倍。增加到10 mol%的修饰脂质导致摄取进一步增强，与对照组相比，这是2倍大。在竞争分析中，与没有自由抑制剂的摄取相比，抑制meggalin受体导致转基因修饰脂质体中封装的荧光探针的摄取显著减少（p < 0.0001），这表明meggalin受体参与了脂质体的内化。综上所述，这些结果表明，巨噬蛋白靶向脂质体可能提供了一个机会，以增强治疗药物的输送到胎盘，以治疗妊娠疾病。
Every year, complications during pregnancy affect more than 26 million women. Some of those diseases are associated with significant morbidity and mortality, as is the case of preeclampsia, the main cause of maternal deaths globally. The ability to improve the delivery of drugs to the placenta upon administration to the mother may offer new opportunities in the treatment of diseases of pregnancy. The objective of this study was to develop megalin-targeting liposome nanocarriers for placental drug delivery. Megalin is a transmembrane protein involved in clathrin-mediated endocytic processes, and is expressed in the syncytiotrophoblast (SynT), an epithelial layer at maternal-fetal interface. Targeting megalin thus offers an opportunity for the liposomes to hitchhike into the SynT, thus enriching the concentration of any associated therapeutic cargo in the placental tissue. PEGylated (2 KDa) lipids were modified with gentamicin (GM), a substrate to megalin receptors as we have shown in earlier studies, and used to prepare placental-targeting liposomes. The ability of the targeting liposomes to enhance accumulation of a fluorescence probe was assessed in an in vivo placental model - timed-pregnant Balb/c mice at gestational day (GD) 18.5. The targeting liposomes containing 10 mol% GM-modified lipids increased the accumulation of the conjugated fluorescence probe in the placenta with a total accumulation of 2.8% of the initial dose, which corresponds to a 94 fold increase in accumulation compared to the free probe (p<0.0001), and 2–4 fold accumulation compared to the non-targeting control liposomes (p<0.0001), as measured by both tissue extraction assay and ex vivo imaging. Furthermore, confocal images of placental SynT cross-sections show a 3-fold increase of the targeting liposomes compared with the non-targeting liposomes. The rate and extent of uptake of a fluorescent probe encapsulated within targeting liposomes was also probed in an in vitro model of the human placental barrier (polarized BeWo monolayers) using flow cytometry. Targeting liposomes containing 5 mol% GM-modified lipids enhanced the uptake of the probe by 1.5 fold compared to the non-targeting control. An increase to 10 mol% of the modified lipid resulted in further enhancement in uptake, which was 2 fold greater compared to control. In a competition assay, inhibition of the megalin receptors resulted in a significant reduction in uptake of the fluorescence probe encapsulated in GM-modified liposomes compared to the uptake without free inhibitor (p < 0.0001), implicating the involvement of megalin receptor in the internalization of the liposomes. Taken together, these results demonstrate that megalin-targeted liposomes may offer an opportunity to enhance the delivery of therapeutics to the placenta for the treatment of diseases of pregnancy.
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