title: Tumor-homing peptides as tools for targeted delivery of payloads to the placenta.
abstract: The availability of therapeutics to treat pregnancy complications is severely lacking mainly because of the risk of causing harm to the fetus. As enhancement of placental growth and function can alleviate maternal symptoms and improve fetal growth in animal models, we have developed a method for targeted delivery of payloads to the placenta. We show that the tumor-homing peptide sequences CGKRK and iRGD bind selectively to the placental surface of humans and mice and do not interfere with normal development. Peptide-coated nanoparticles intravenously injected into pregnant mice accumulated within the mouse placenta, whereas control nanoparticles exhibited reduced binding and/or fetal transfer. We used targeted liposomes to efficiently deliver cargoes of carboxyfluorescein and insulin-like growth factor 2 to the mouse placenta; the latter significantly increased mean placental weight when administered to healthy animals and significantly improved fetal weight distribution in a well-characterized model of fetal growth restriction. These data provide proof of principle for targeted delivery of drugs to the placenta and provide a novel platform for the development of placenta-specific therapeutics.
authors.affiliation: Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.; Academic Health Science Centre, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
authors.forename: Anna
authors.identifier: 0000-0001-6558-1959
authors.initials: A
authors.lastname: King
authors.affiliation: Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.; Academic Health Science Centre, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
authors.forename: Cornelia
authors.identifier: 0000-0002-2029-8540
authors.initials: C
authors.lastname: Ndifon
authors.affiliation: Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.; Academic Health Science Centre, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
authors.forename: Sylvia
authors.identifier: 0000-0002-9185-3564
authors.initials: S
authors.lastname: Lui
authors.affiliation: Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.; Academic Health Science Centre, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Widdows
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.; Center for Nanomedicine and Department of Molecular Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9610, USA.
authors.forename: Venkata R
authors.initials: VR
authors.lastname: Kotamraju
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.; Center for Nanomedicine and Department of Molecular Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9610, USA.
authors.forename: Lilach
authors.initials: L
authors.lastname: Agemy
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.; Center for Nanomedicine and Department of Molecular Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9610, USA.
authors.forename: Tambet
authors.identifier: 0000-0002-9458-6385
authors.initials: T
authors.lastname: Teesalu
authors.affiliation: Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.; Academic Health Science Centre, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
authors.forename: Jocelyn D
authors.identifier: 0000-0002-4215-5727
authors.initials: JD
authors.lastname: Glazier
authors.affiliation: School of Pharmacy, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cellesi
authors.affiliation: School of Pharmacy, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.; Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tirelli
authors.affiliation: Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.; Academic Health Science Centre, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
authors.forename: John D
authors.identifier: 0000-0001-8777-9261
authors.initials: JD
authors.lastname: Aplin
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.; Center for Nanomedicine and Department of Molecular Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9610, USA.
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
authors.affiliation: Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.; Academic Health Science Centre, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.; School of Pharmacy, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Lynda K
authors.identifier: 0000-0001-7709-5202
authors.initials: LK
authors.lastname: Harris
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D037282:Calreticulin / Q000235:genetics; D055252:Cell-Derived Microparticles; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000737:chemistry; D008081:Liposomes; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics
chemical_list: D037282:Calreticulin; D004337:Drug Carriers; D008081:Liposomes; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D007335:Insulin-Like Growth Factor II
keywords: IGF-II; Placenta; Pregnancy; drug delivery; fetal growth restriction; homing peptide; liposome; targeted delivery; trophoblast