PMID- 32461116 OWN - NLM STAT- MEDLINE DCOM- 20210617 LR - 20240402 IS - 1873-4995 (Electronic) IS - 0168-3659 (Print) IS - 0168-3659 (Linking) VI - 324 DP - 2020 Aug 10 TI - Megalin-targeting liposomes for placental drug delivery. PG - 366-378 LID - S0168-3659(20)30310-2 [pii] LID - 10.1016/j.jconrel.2020.05.033 [doi] AB - 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 < .0001), and 2-4 fold accumulation compared to the non-targeting control liposomes (p < .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 < .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. CI - Copyright (c) 2020 Elsevier B.V. All rights reserved. FAU - Alfaifi, Ali A AU - Alfaifi AA AD - Department of Biomedical Engineering, Wayne State University, Detroit, MI, United States of America; Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America; Center for Pharmaceutical Engineering and Sciences - School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America. FAU - Heyder, Rodrigo S AU - Heyder RS AD - Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America; Center for Pharmaceutical Engineering and Sciences - School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America. FAU - Bielski, Elizabeth R AU - Bielski ER AD - Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America; Center for Pharmaceutical Engineering and Sciences - School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America. FAU - Almuqbil, Rashed M AU - Almuqbil RM AD - Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America; Center for Pharmaceutical Engineering and Sciences - School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America. FAU - Kavdia, Mahendra AU - Kavdia M AD - Department of Biomedical Engineering, Wayne State University, Detroit, MI, United States of America. FAU - Gerk, Phillip M AU - Gerk PM AD - Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America. FAU - da Rocha, Sandro R P AU - da Rocha SRP AD - Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America; Center for Pharmaceutical Engineering and Sciences - School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America. Electronic address: srdarocha@vcu.edu. LA - eng GR - P30 CA016059/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200524 PL - Netherlands TA - J Control Release JT - Journal of controlled release : official journal of the Controlled Release Society JID - 8607908 RN - 0 (Gentamicins) RN - 0 (Liposomes) RN - 0 (Low Density Lipoprotein Receptor-Related Protein-2) SB - IM MH - Animals MH - Drug Delivery Systems MH - Female MH - Gentamicins MH - *Liposomes MH - *Low Density Lipoprotein Receptor-Related Protein-2 MH - Placenta MH - Pregnancy PMC - PMC8247794 MID - NIHMS1599432 EDAT- 2020/05/29 06:00 MHDA- 2021/06/22 06:00 PMCR- 2021/08/10 CRDT- 2020/05/29 06:00 PHST- 2020/02/02 00:00 [received] PHST- 2020/05/09 00:00 [revised] PHST- 2020/05/20 00:00 [accepted] PHST- 2020/05/29 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/05/29 06:00 [entrez] PHST- 2021/08/10 00:00 [pmc-release] AID - S0168-3659(20)30310-2 [pii] AID - 10.1016/j.jconrel.2020.05.033 [doi] PST - ppublish SO - J Control Release. 2020 Aug 10;324:366-378. doi: 10.1016/j.jconrel.2020.05.033. Epub 2020 May 24.