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

Fan Zhang, J. Trent Magruder, Yi An Lin, Todd C. Crawford, Joshua C. Grimm, Christopher M. Sciortino, Mary Ann Wilson, Mary E. Blue, Sujatha Kannan, Michael V. Johnston, William A. Baumgartner, Rangaramanujam M. Kannan

Research output: Contribution to journalArticle

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, ~ 6.7 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/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.

Original languageEnglish (US)
Pages (from-to)173-182
Number of pages10
JournalJournal of Controlled Release
Volume249
DOIs
StatePublished - Mar 10 2017

Fingerprint

Dendrimers
Intravenous Administration
Hydroxyl Radical
Brain Injuries
Brain
Cerebrospinal Fluid
Serum
Blood Circulation Time
Nervous System Trauma
Microglia
Nervous System
Thoracic Surgery
Canidae
Spleen
Pharmacokinetics
Kidney
Neurons
Drug Therapy
Liver

Keywords

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

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model. / Zhang, Fan; Trent Magruder, J.; Lin, Yi An; Crawford, Todd C.; Grimm, Joshua C.; Sciortino, Christopher M.; Wilson, Mary Ann; Blue, Mary E.; Kannan, Sujatha; Johnston, Michael V.; Baumgartner, William A.; Kannan, Rangaramanujam M.

In: Journal of Controlled Release, Vol. 249, 10.03.2017, p. 173-182.

Research output: Contribution to journalArticle

Zhang F, Trent Magruder J, Lin YA, Crawford TC, Grimm JC, Sciortino CM et al. Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model. Journal of Controlled Release. 2017 Mar 10;249:173-182. Available from, DOI: 10.1016/j.jconrel.2017.01.032

Zhang, Fan; Trent Magruder, J.; Lin, Yi An; Crawford, Todd C.; Grimm, Joshua C.; Sciortino, Christopher M.; Wilson, Mary Ann; Blue, Mary E.; Kannan, Sujatha; Johnston, Michael V.; Baumgartner, William A.; Kannan, Rangaramanujam M. / Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model.

In: Journal of Controlled Release, Vol. 249, 10.03.2017, p. 173-182.

Research output: Contribution to journalArticle

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