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

JOURNAL OF CONTROLLED RELEASE

卷:249

Article

Zhang, Fan^1,6,7  Magruder, J. Trent²  Lin, Yi-An¹  Crawford, Todd C.²  Grimm, Joshua C.²  Sciortino, Christopher M.²  Wilson, Mary Ann^3,4  Blue, Mary E.^3,4  Kannan, Sujatha^3,5  Johnston, Michael V.^3,4  Baumgartner, William A.²  Kannan, Rangaramanujam M.¹ 

[1] Johns Hopkins Sch Med, Ctr Nanomed, Wilmer Eye Inst, Dept Ophthalmol, Baltimore, MD 21287 USA

[2] Johns Hopkins Univ, Sch Med, Dept Surg, Div Cardiac Surg, Baltimore, MD 21287 USA

[3] Kennedy Krieger Inc, Hugo W Moser Res Inst, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA

[5] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21287 USA

[6] Johns Hopkins Univ, Dept Mat Sci & Engn, Baltimore, MD 21218 USA

[7] Fred Hutchinson Canc Res Canc, 1100 Fairview Ave N, Seattle, WA 98109 USA

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

DOI  :  10.1016/j.jconrel.2017.01.032

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free