title: Surface functionality affects the biodistribution and microglia-targeting of intra-amniotically delivered dendrimers.
abstract: Cerebral Palsy (CP) is a chronic childhood disorder with limited therapeutic options. Maternal intrauterine inflammation/infection is a major risk factor in the pathogenesis of CP. In pre-clinical models, dendrimer-based therapies are viable in postnatal period, attenuating inflammation and improving motor function in vivo. However, treatment to the mother, in the prenatal period, may provide the possibility of preventing/resolving inflammation at early stages. Towards this goal, we used a maternal intrauterine inflammation-induced rabbit model of CP to study fetal-maternal transport and neuroinflammation targeting of intra-amniotically administrated dendrimers with neutral/anionic surface functionality. Our study suggested both hydroxyl-terminated 'neutral' (D-OH) and carboxyl-terminated 'anionic' (D-COOH) Polyamidoamine (PAMAM) dendrimers were absorbed by fetuses and demonstrated bi-directional transport between fetuses and mother. D-OH was more effective in crossing the fetal blood-brain barrier, and targeting activated microglia. The cell-specific targeting was associated with the extent of microglia activation. This study demonstrated intra-amniotically administered hydroxyl PAMAM dendrimers could be an effective drug delivery vehicle for targeting fetal inflammation and preventing subsequent neurologic injury associated with chorioamnionitis.
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Materials Science, Johns Hopkins University, Baltimore, MD 21218, United States.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nance
authors.affiliation: Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Venkatasai
authors.initials: V
authors.lastname: Jasty
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Siva P
authors.initials: SP
authors.lastname: Kambhampati
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Mishra
authors.affiliation: Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Irina
authors.initials: I
authors.lastname: Burd
authors.affiliation: Perinatology Research Branch, Detroit, MI 48201, United States.
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; Perinatology Research Branch, Detroit, MI 48201, United States. Electronic address: skannan3@jhmi.edu.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Kannan
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Materials Science, Johns Hopkins University, Baltimore, MD 21218, United States; Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Perinatology Research Branch, Detroit, MI 48201, United States. Electronic address: krangar1@jhmi.edu.
authors.forename: Rangaramanujam M
authors.initials: RM
authors.lastname: Kannan
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002547:Cerebral Palsy / Q000378:metabolism / Q000628:therapy*; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000628:therapy; D017628:Microglia / Q000378:metabolism*; D011247:Pregnancy; D011817:Rabbits; D014018:Tissue Distribution
chemical_list: D050091:Dendrimers; C104700:PAMAM Starburst
keywords: Blood-placental barrier; Dendrimer; Intra-amniotic delivery; Microglia; Neuroinflammation; Surface functionality