title: Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model.
abstract: Hypothermic circulatory arrest (HCA) provides neuroprotection during cardiac surgery but entails an ischemic period that can lead to excitotoxicity, neuroinflammation, and subsequent neurologic injury. Hydroxyl polyamidoamine (PAMAM) dendrimers target activated microglia and damaged neurons in the injured brain, and deliver therapeutics in small and large animal models. We investigated the effect of dendrimer size on brain uptake and explored the pharmacokinetics in a clinically-relevant canine model of HCA-induced brain injury. Generation 6 (G6, ~6.7nm) dendrimers showed extended blood circulation times and increased accumulation in the injured brain compared to generation 4 dendrimers (G4, ~4.3nm), which were undetectable in the brain by 48h after final administration. High levels of G6 dendrimers were found in cerebrospinal fluid (CSF) of injured animals with a CSF/serum ratio of ~20% at peak, a ratio higher than that of many neurologic pharmacotherapies already in clinical use. Brain penetration (measured by drug CSF/serum level) of G6 dendrimers correlated with the severity of neuroinflammation observed. G6 dendrimers also showed decreased renal clearance rate, slightly increased liver and spleen uptake compared to G4 dendrimers. These results, in a large animal model, may offer insights into the potential clinical translation of dendrimers.
authors.affiliation: Center for Nanomedicine/Wilmer Eye Institute, Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, MD 21287, United States; Department of Materials Science and Engineering, The Johns Hopkins University, Baltimore, MD, 21218, United States.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: J
authors.initials: J
authors.lastname: Trent Magruder
authors.affiliation: Center for Nanomedicine/Wilmer Eye Institute, Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Lin
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Crawford
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Grimm
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sciortino
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger Inc., Baltimore, MD 21205, United States; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger Inc., Baltimore, MD 21205, United States; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Blue
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger Inc., Baltimore, MD 21205, United States; Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Kannan
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger Inc., Baltimore, MD 21205, United States; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Johnston
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States. Electronic address: wbaumgar@jhmi.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Baumgartner
authors.affiliation: Center for Nanomedicine/Wilmer Eye Institute, Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, MD 21287, United States. Electronic address: krangar1@jhmi.edu.
authors.forename: Rangaramanujam M
authors.initials: RM
authors.lastname: Kannan
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004285:Dogs; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male
chemical_list: D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst
keywords: Biodistribution; Brain penetration; CSF/serum ratio; Canine model; Dendrimer; Hypothermic circulatory arrest