title: Drug delivery to the human and mouse uterus using immunoliposomes targeted to the oxytocin receptor.
abstract: The ability to provide safe and effective pharmacotherapy during obstetric complications, such as preterm labor or postpartum hemorrhage, is hampered by the systemic toxicity of therapeutic agents leading to adverse side effects in the mother and fetus. Development of novel strategies to target tocolytic and uterotonic agents specifically to uterine myocytes would improve therapeutic efficacy while minimizing the risk of side effects. Ligand-targeted liposomes have emerged as a reliable and versatile platform for targeted drug delivery to specific cell types, tissues or organs.
  
  
  
  Our objective was to develop a targeted drug delivery system for the uterus utilizing an immunoliposome platform targeting the oxytocin receptor.
  
  
  
  We conjugated liposomes to an antibody that recognizes an extracellular domain of the oxytocin receptor. We then examined the ability of oxytocin receptor-targeted liposomes to deliver contraction-blocking (nifedipine, salbutamol and rolipram) or contraction-enhancing (dofetilide) agents to strips of spontaneously contracting myometrial tissue in vitro (human and mouse). We evaluated the ability of oxytocin receptor-targeted liposomes to localize to uterine tissue in vivo, and assessed if targeted liposomes loaded with indomethacin were capable of preventing lipopolysaccharide-induced preterm birth in mice.
  
  
  
  Oxytocin receptor-targeted liposomes loaded with nifedipine, salbutamol or rolipram consistently abolished human myometrial contractions in vitro, while oxytocin receptor-targeted liposomes loaded with dofetilide increased contraction duration. Nontargeted control liposomes loaded with these agents had no effect. Similar results were observed in mouse uterine strips. Following in vivo administration to pregnant mice, oxytocin receptor-targeted liposomes localized specifically to the uterine horns and mammary tissue. Targeting increased localization to the uterus 7-fold. Localization was not detected in the maternal brain or fetus. Targeted and nontargeted liposomes also localized to the liver. Oxytocin receptor-targeted liposomes loaded with indomethacin were effective in reducing rates of preterm birth in mice, whereas nontargeted liposomes loaded with indomethacin had no effect.
  
  
  
  Our results demonstrate that oxytocin receptor-targeted liposomes can be used to either inhibit or enhance human uterine contractions in vitro. In vivo, the liposomes localized to the uterine tissue of pregnant mice and were effective in delivering agents for the prevention of inflammation-induced preterm labor. The potential clinical advantage of targeted liposomal drug delivery to the myometrium is reduced dose and reduced toxicity to both mother and fetus.
authors: Mothers and Babies Research Center, School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, New Lambton, Australia.
authors: Jonathan W
authors: JW
authors: Paul
authors: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, New Lambton, Australia.
authors: Susan
authors: S
authors: Hua
authors: Mothers and Babies Research Center, School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, New Lambton, Australia.
authors: Marina
authors: M
authors: Ilicic
authors: Mothers and Babies Research Center, School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, New Lambton, Australia.
authors: Jorge M
authors: JM
authors: Tolosa
authors: Mothers and Babies Research Center, School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, New Lambton, Australia.
authors: Trent
authors: T
authors: Butler
authors: Hunter Medical Research Institute, New Lambton, Australia; Robinson Research Institute and School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors: Sarah
authors: S
authors: Robertson
authors: Mothers and Babies Research Center, School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, New Lambton, Australia; John Hunter Hospital, New Lambton, Australia. Electronic address: Roger.Smith@newcastle.edu.au.
authors: Roger
authors: R
authors: Smith
mesh_terms: D000420:Albuterol / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D016503:Drug Delivery Systems; D005260:Female; D007213:Indomethacin / Q000008:administration & dosage; D008081:Liposomes / Q000276:immunology; D051379:Mice; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000008:administration & dosage / Q000493:pharmacokinetics; D010627:Phenethylamines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011247:Pregnancy; D047928:Premature Birth / Q000517:prevention & control*; D018045:Receptors, Oxytocin / Q000187:drug effects*; D020889:Rolipram / Q000008:administration & dosage / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014590:Uterine Contraction / Q000187:drug effects* / Q000276:immunology; D014599:Uterus / Q000187:drug effects* / Q000276:immunology
chemical_list: D008081:Liposomes; D010627:Phenethylamines; D018045:Receptors, Oxytocin; D013449:Sulfonamides; D009543:Nifedipine; D020889:Rolipram; D000420:Albuterol; C063533:dofetilide; D007213:Indomethacin
keywords: birth; contraction; drug delivery; human; immunoliposomes; labor; liposomes; mouse; myometrium; oxytocin receptor; preterm; targeted; tocolysis; uterotonic