Abstracts

Rationale: Because uncontrolled seizures during pregnancy can lead to serious consequences for both mother and child, pregnant women with epilepsy should continue their antiepileptic medication throughout pregnancy. However, prenatal exposure to such drugs is linked to increased risks for birth defects. We hypothesize that nanoparticles designed with peptides targeting the brain will enhance the delivery of antiepileptic drugs (AEDs) to the brain and limit the transfer of AEDs across the placenta. Methods: To test the utility of the peptide TGNYKALHPHNG (TGN) to target the blood-brain barrier, this peptide was covalently conjugated to the surface of poly(ethylene glycol)-poly(e-caprolactone) (PEG-PCL) nanoparticles and compared to a scrambled peptide GTHLAYHKNPGN containing the same amino acids, which was also covalently linked to PEG-PCL nanoparticles. Both peptides were synthesized with a fluorescent tag (FITC) in order to quantify the efficiency of peptide conjugation to the nanoparticles as well as to quantify cellular uptake in hCMEC/D3 cells (an in vitro model of the blood-brain barrier) and in BeWo b30 cells (an in vitro model of human placental trophoblast cells). Results: Following a 2-hour exposure of hCMEC/D3 cells to each nanoparticle type, the uptake of the TGN peptide-conjugated nanoparticles was 3-fold higher than the uptake of the control nanoparticles conjugated with the scrambled peptide sequence (P < 0.05). In contrast, no significant difference was observed between the uptake of the TGN peptide nanoparticles and the scrambled peptide nanoparticles in the BeWo b30 placental trophoblast cells. This suggests that there is no specific uptake mechanism for TGN peptide-conjugated nanoparticles into human placenta. Conclusions: The increased uptake of TGN peptide nanoparticles into the brain?"together with the demonstrated lack of any targeting potential for the TGN peptide in human placental trophoblast cells?"suggests a reduced likelihood of targeted transplacental delivery of AEDs. This could reduce fetal exposure to AEDs when treating a pregnant woman with epilepsy. Funding: The authors are grateful for research support from Citizens United for Research in Epilepsy, the Saudi Cultural Mission, and the Institute for Translational Sciences at the University of Texas Medical Branch, which is supported in part by a Clinical and Translational Science Award (UL1TR000071) from the National Center for Advancing Translational Sciences, National Institutes of Health.