Abstract
Multimodal polymeric nanoparticles have many exciting diagnostic and therapeutic applications, yet their uptake and passage by the placenta, and applications in the treatment of pregnancy complications have not been thoroughly investigated. In this work, the maternal-fetal-placental biodistribution of anionic and cationic multimodal poly(glycidyl methacrylate) (PGMA) nanoparticles in pregnant rats at mid (ED10) and late (ED20) gestation was examined. Fluorescently-labelled and superparamagnetic PGMA nanoparticles functionalized with/without poly(ethyleneimine) (PEI) were administered to pregnant rats at a clinically-relevant dose and biodistribution and tissue uptake assessed. Quantitative measurement of fluorescence intensity or magnetic resonance relaxometry in tissue homogenates lacked the sensitivity to quantify tissue uptake. Confocal microscopy, however, identified uptake by maternal organs and the decidua (ectoplacental cone) and trophoblast giant cells of conceptuses at ED10. At ED20, preferential accumulation of cationic vs. anionic nanoparticles was observed in the placenta, with PGMA-PEI nanoparticles localised mainly within the chorionic plate. These findings highlight the significant impact of surface charge and gestational age in the biodistribution of nanoparticles in pregnancy, and demonstrate the importance of using highly sensitive measurement techniques to evaluate nanomaterial biodistribution and maternal-fetal exposure.
Highlights
Nanoscale drug delivery agents have been developed and exploited to enhance the delivery of pharmacologics in the treatment of a number of diseases
In humans the placental barrier is comprised of two cellular layers: the syncytiotrophoblast membrane, which is in contact with the maternal circulation, and the endothelial layer of the fetal capillaries that is perfused by the fetal circulation[4]
The human placental structure is essentially complete by the first month of pregnancy, villous blood perfusion and maternal-fetal exchange is not established until the end of the first trimester[5]
Summary
Nanoscale drug delivery agents have been developed and exploited to enhance the delivery of pharmacologics in the treatment of a number of diseases. The rat placenta, on the other hand, does not achieve its definitive chorioallantoic structure until half way through pregnancy, and has a different zonal structure to the human placenta: a junctional zone and a labyrinth zone[6] The latter is composed of three layers of trophoblast cells across which the majority of maternal-fetal transfer takes place[7]. Most molecules larger than ~600 Da do not readily cross the human placenta, unless they are ligands for transporters or receptors Despite their relatively large size, studies have shown that some nanoparticles appear to be able to traverse the placenta and accumulate in the fetus, albeit at low levels[11,12,13,14,15]. Yang et al reported that the uptake of gold nanoparticles in fetal tissue was markedly reduced following the establishment of the chorioallantoic placenta and haemotrophic nutrition in mid pregnancy[18]
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