{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T23:55:09Z","timestamp":1788825309867,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T00:00:00Z","timestamp":1635120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P023401\/1"],"award-info":[{"award-number":["MR\/P023401\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["2014-2020.4.01.15-0012"],"award-info":[{"award-number":["2014-2020.4.01.15-0012"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002301","name":"Estonian Research Council","doi-asserted-by":"publisher","award":["PRG230"],"award-info":[{"award-number":["PRG230"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Placental dysfunction is the underlying cause of pregnancy complications such as fetal growth restriction (FGR) and pre-eclampsia. No therapies are available to treat a poorly functioning placenta, primarily due to the risks of adverse side effects in both the mother and the fetus resulting from systemic drug delivery. The use of targeted liposomes to selectively deliver payloads to the placenta has the potential to overcome these issues. In this study, we assessed the safety and efficacy of epidermal growth factor (EGF)-loaded, peptide-decorated liposomes to improve different aspects of placental function, using tissue from healthy control pregnancies at term, and pregnancies complicated by FGR. Phage screening identified a peptide sequence, CGPSARAPC (GPS), which selectively homed to mouse placentas in vivo, and bound to the outer syncytiotrophoblast layer of human placental explants ex vivo. GPS-decorated liposomes were prepared containing PBS or EGF (50\u2013100 ng\/mL), and placental explants were cultured with liposomes for up to 48 h. Undecorated and GPS-decorated liposomes containing PBS did not affect the basal rate of amino acid transport, human chorionic gonadotropin (hCG) release or cell turnover in placental explants from healthy controls. GPS-decorated liposomes containing EGF significantly increased amino acid transporter activity in healthy control explants, but not in placental explants from women with FGR. hCG secretion and cell turnover were unaffected by EGF delivery; however, differential activation of downstream protein kinases was observed when EGF was delivered via GPS-decorated vs. undecorated liposomes. These data indicate that targeted liposomes represent a safe and useful tool for the development of new therapies for placental dysfunction, recapitulating the effects of free EGF.<\/jats:p>","DOI":"10.3390\/pharmaceutics13111778","type":"journal-article","created":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T21:42:05Z","timestamp":1635198125000},"page":"1778","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Targeted Delivery of Epidermal Growth Factor to the Human Placenta to Treat Fetal Growth Restriction"],"prefix":"10.3390","volume":"13","author":[{"given":"Lewis J.","family":"Renshall","sequence":"first","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK"},{"name":"Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary\u2019s Hospital, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Beards","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK"},{"name":"Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary\u2019s Hospital, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelos","family":"Evangelinos","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK"},{"name":"Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary\u2019s Hospital, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L.","family":"Greenwood","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK"},{"name":"Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary\u2019s Hospital, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Brownbill","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK"},{"name":"Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary\u2019s Hospital, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Stevens","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK"},{"name":"Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary\u2019s Hospital, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2713-0492","authenticated-orcid":false,"given":"Colin P.","family":"Sibley","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK"},{"name":"Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary\u2019s Hospital, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Aplin","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK"},{"name":"Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary\u2019s Hospital, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward D.","family":"Johnstone","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK"},{"name":"Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary\u2019s Hospital, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tambet","family":"Teesalu","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"},{"name":"Center for Nanomedicine, University of California Santa Barbara, Santa Barbara, CA 93106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7709-5202","authenticated-orcid":false,"given":"Lynda K.","family":"Harris","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK"},{"name":"Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary\u2019s Hospital, Manchester M13 9WL, UK"},{"name":"Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1002\/uog.9008","article-title":"Neurodevelopment following fetal growth restriction and its relationship with antepartum parameters of placental dysfunction","volume":"37","author":"Baschat","year":"2011","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/S0140-6736(10)62233-7","article-title":"Major risk factors for stillbirth in high-income countries: A systematic review and meta-analysis","volume":"377","author":"Flenady","year":"2011","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ajog.2010.08.009","article-title":"The \u201cGreat Obstetrical Syndromes\u201d are associated with disorders of deep placentation","volume":"204","author":"Brosens","year":"2011","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1111\/j.1471-0528.2008.02027.x","article-title":"Systematic analysis of research underfunding in maternal and perinatal health","volume":"116","author":"Fisk","year":"2009","journal-title":"BJOG"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1111\/1471-0528.14151","article-title":"The pregnant women as a drug orphan: A global survey of registered clinical trials of pharmacological interventions in pregnancy","volume":"124","author":"Scaffidi","year":"2017","journal-title":"BJOG"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"GBD 2013 Mortality and Causes of Death Collaborators (2015). Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990\u20132013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet, 385, 117\u2013171.","DOI":"10.1016\/S0140-6736(14)61682-2"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e1600349","DOI":"10.1126\/sciadv.1600349","article-title":"Tumor-homing peptides as tools for targeted delivery of payloads to the placenta","volume":"2","author":"King","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Higgins, L.E., De Castro, N.R., Addo, N., Wareing, M., Greenwood, S., Jones, R.L., Sibley, C.P., Johnstone, E., and Heazell, A. (2015). Placental Features of Late-Onset Adverse Pregnancy Outcome. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129117"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.placenta.2014.07.013","article-title":"Fetoplacental vascular alterations associated with fetal growth restriction","volume":"35","author":"Junaid","year":"2014","journal-title":"Placenta"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ptacek, I., Smith, A., Garrod, A., Bullough, S., Bradley, N., Batra, G., Sibley, C.P., Jones, R.L., Brownbill, P., and Heazell, A.E.P. (2016). Quantitative assessment of placental morphology may identify specific causes of stillbirth. BMC Clin. Pathol., 16.","DOI":"10.1186\/s12907-016-0023-y"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5686","DOI":"10.1210\/jc.2002-020214","article-title":"Activity and protein expression of the Na+\/H+ exchanger is reduced in syncytiotrophoblast microvillous plasma membranes isolated from preterm intrauterine growth restriction pregnancies","volume":"87","author":"Johansson","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1203\/00006450-199710000-00016","article-title":"Association between the Activity of the System A Amino Acid Transporter in the Microvillous Plasma Membrane of the Human Placenta and Severity of Fetal Compromise in Intrauterine Growth Restriction","volume":"42","author":"Glazier","year":"1997","journal-title":"Pediatr. Res."},{"key":"ref_13","first-page":"124","article-title":"Telomerase and Proliferative Activity in Placenta From Women With and Without Fetal Growth Restriction","volume":"93","author":"Izutsu","year":"1999","journal-title":"Obstet. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s10495-010-0551-3","article-title":"Intra-uterine growth restriction is associated with increased apoptosis and altered expression of proteins in the p53 pathway in villous trophoblast","volume":"16","author":"Heazell","year":"2010","journal-title":"Apoptosis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1067\/mob.2002.122250","article-title":"Trophoblast apoptosis from pregnancies complicated by fetal growth restriction is associated with enhanced p53 expression","volume":"186","author":"Levy","year":"2002","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1534\/genetics.109.104372","article-title":"Placental and Embryonic Growth Restriction in Mice With Reduced Function Epidermal Growth Factor Receptor Alleles","volume":"183","author":"Dackor","year":"2009","journal-title":"Genetics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1172\/JCI117067","article-title":"Alterations of human placental epidermal growth factor receptor in intrauterine growth retardation","volume":"93","author":"Fondacci","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1007\/s10495-007-0092-6","article-title":"Epidermal growth factor rescues trophoblast apoptosis induced by reactive oxygen species","volume":"12","author":"Moll","year":"2007","journal-title":"Apoptosis"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1095\/biolreprod.105.044206","article-title":"Epidermal growth factor stimulation of trophoblast differentiation requires MAPK11\/14 (p38 MAP kinase) activation","volume":"73","author":"Johnstone","year":"2005","journal-title":"Biol. Reprod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1053\/plac.2001.0783","article-title":"Growth Factor Rescue of Cytokine Mediated Trophoblast Apoptosis","volume":"23","author":"Smith","year":"2002","journal-title":"Placenta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16157","DOI":"10.1073\/pnas.0908201106","article-title":"C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration","volume":"106","author":"Teesalu","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/B978-0-12-396962-0.00002-1","article-title":"Mapping of Vascular ZIP Codes by Phage Display","volume":"503","author":"Teesalu","year":"2012","journal-title":"Methods Enzymol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1093\/molehr\/gau039","article-title":"A role for the mitochondrial-associated protein p32 in regulation of trophoblast proliferation","volume":"20","author":"Matos","year":"2014","journal-title":"Mol. Hum. Reprod."},{"key":"ref_24","first-page":"253","article-title":"In vitro methods for studying human placental amino acid transport placental villous fragments","volume":"122","author":"Greenwood","year":"2006","journal-title":"Methods Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"R1116","DOI":"10.1152\/ajpregu.2001.280.4.R1116","article-title":"The functional regeneration of syncytiotrophoblast in cultured explants of term placenta","volume":"280","author":"Sibley","year":"2001","journal-title":"Am. J. Physiol. Integr. Comp. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"941","DOI":"10.2217\/nnm-2015-0012","article-title":"Nanoparticle transport across the placental barrier: Pushing the field forward!","volume":"11","author":"Muoth","year":"2016","journal-title":"Nanomedicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41565-018-0085-3","article-title":"Nanoparticle-induced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes","volume":"13","author":"Hawkins","year":"2018","journal-title":"Nat. Nanotechnol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.placenta.2004.12.004","article-title":"The extent and variability of effects of culture conditions on the secretion of human chorionic gonadotrophin and interleukin-6 by human, term placental explants in culture","volume":"27","author":"Turner","year":"2006","journal-title":"Placenta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3715","DOI":"10.7150\/thno.19678","article-title":"Selective Targeting of a Novel Vasodilator to the Uterine Vasculature to Treat Impaired Uteroplacental Perfusion in Pregnancy","volume":"7","author":"Cureton","year":"2017","journal-title":"Theranostics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4502","DOI":"10.1210\/en.2011-1930","article-title":"Caffeine Inhibits EGF-Stimulated Trophoblast Cell Motility through the Inhibition of mTORC2 and Akt","volume":"153","author":"Grant","year":"2012","journal-title":"Endocrinology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1210\/en.2007-1253","article-title":"Epidermal Growth Factor Abrogates Hypoxia-Induced Apoptosis in Cultured Human Trophoblasts through Phosphorylation of BAD Serine 112","volume":"149","author":"Humphrey","year":"2008","journal-title":"Endocrinology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1071\/RD9951465","article-title":"Role of epidermal growth factor (EGF) and its receptor in the development of the human placenta","volume":"7","author":"Maruo","year":"1995","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1677\/joe.0.1430291","article-title":"Involvement of epidermal growth factor (EGF)\/EGF receptor autocrine and paracrine mechanism in human trophoblast cells: Functional differentiation in vitro","volume":"143","author":"Amemiya","year":"1994","journal-title":"J. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0165-0378(98)00021-7","article-title":"Functional regulation of human trophoblast differentiation","volume":"39","author":"Morrish","year":"1998","journal-title":"J. Reprod. Immunol."},{"key":"ref_35","first-page":"3271","article-title":"Liposomal Thyroxine: A Noninvasive Model for Transplacental Fetal Therapy","volume":"82","author":"Bajoria","year":"1997","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1016\/j.placenta.2013.10.005","article-title":"Effect of lipid composition of cationic SUV liposomes on materno-fetal transfer of warfarin across the perfused human term placenta","volume":"34","author":"Bajoria","year":"2013","journal-title":"Placenta"},{"key":"ref_37","first-page":"79","article-title":"Placental transfer of valproic acid after liposome encapsulation during in vitro human placenta perfusion","volume":"277","author":"Barzago","year":"1996","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"34710","DOI":"10.1038\/srep34710","article-title":"Uterus-targeted liposomes for preterm labor management: Studies in pregnant mice","volume":"6","author":"Refuerzo","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"283.e1","DOI":"10.1016\/j.ajog.2016.08.027","article-title":"Drug delivery to the human and mouse uterus using immunoliposomes targeted to the oxytocin receptor","volume":"216","author":"Paul","year":"2017","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.jconrel.2020.05.033","article-title":"Megalin-targeting liposomes for placental drug delivery","volume":"324","author":"Alfaifi","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.ijpharm.2017.07.076","article-title":"Assessment of dually labelled PEGylated liposomes transplacental passage and placental penetration using a combination of two ex-vivo human models: The dually perfused placenta and the suspended villous explants","volume":"532","author":"Valero","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"118479","DOI":"10.1016\/j.ijpharm.2019.118479","article-title":"Qualitative and quantitative analysis of the uptake of lipoplexes by villous placenta explants","volume":"567","author":"Alhareth","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1677\/JOE-10-0174","article-title":"Maternal growth factor regulation of human placental development and fetal growth","volume":"207","author":"Forbes","year":"2010","journal-title":"J. Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1042\/bj20031253","article-title":"Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis","volume":"377","author":"Rejman","year":"2004","journal-title":"Biochem. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/j.1749-6632.2003.tb03208.x","article-title":"Characterization and expression of novel 60-kDa and 110-kDa EGFR isoforms in human placenta","volume":"995","author":"Reiter","year":"2003","journal-title":"Ann. N. Y. Acad. 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