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

• Published in: Journal of controlled release Vol. 249; pp. 173 - 182
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10-03-2017
• Subjects: Animals; Biodistribution; Brain - metabolism; Brain Injuries - drug therapy; Brain Injuries - metabolism; Brain penetration; Canine model; CSF/serum ratio; Dendrimer; Dendrimers - administration & dosage; Dendrimers - chemistry; Dendrimers - pharmacokinetics; Disease Models, Animal; Dogs; Drug Carriers - administration & dosage; Drug Carriers - chemistry; Drug Carriers - pharmacokinetics; Drug Delivery Systems; Hypothermic circulatory arrest; Kidney - metabolism; Liver - metabolism; Male; Hypothermic circulatory arrest; Dendrimer; Canine model; Brain penetration; Biodistribution; CSF/serum ratio
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2017.01.032

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.
[Display omitted]