4.8 Article

Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model

Journal

JOURNAL OF CONTROLLED RELEASE
Volume 249, Issue -, Pages 173-182

Publisher

ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2017.01.032

Keywords

Dendrimer; Hypothermic circulatory arrest; Canine model; Brain penetration; CSF/serum ratio; Biodistribution

Funding

  1. National Institutes of Health [R01 HL091541-21, R01 EB018306, R01 HD076901]

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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, -6.7 nm) dendrimers showed extended blood circulation times and increased accumulation in the injured brain compared to generation 4 dendrimers (G4, -4.3 nm), which were undetectable in the brain by 48 h 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/serumlevel) of G6 dendrimers correlatedwith 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. (C) 2017 Elsevier B. V. All rights reserved.

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