(147c) Dendrimer Nanotherapies for the Treatment of Brain Injury Following Hypothermic Circulatory Arrest in a Large Animal Model

Hypothermic circulatory arrest (HCA) can lead to neurological complications including stroke, seizures, neurocognitive dysfunction, and delayed neuropsychomotor development in many patients. Neuroinflammation and excitotoxicity have been identified as key factors leading to the brain injury after HCA. The treatment has remained a challenge, with no suitable therapeutic options. Valproic acid (VPA) has been explored in this model, and offers some neuroprotection against excitotoxicity with a large dose, but leads to systemic side effects. Similarly N-Acetylcysteine (NAC) is known to be effective in reducing neuroinflammation, but large doses are required due to poor blood-brain barrier (BBB) penetration and insufficient brain localization. To overcome these challenges, we are exploring systemic, combination therapies targeted to activated microglia and injured neurons, using dendrimers. We use a well-established, clinically relevant canine model.¹ Using fluorescently labeled, hydroxyl-terminated polyamidoamine (PAMAM) dendrimers, we showed that systemically administered dendrimers can cross the impaired blood-brain-barrier, and target activated microglia and injured neurons, with minimal uptake in the healthy cells in the brain.^1,2  Based on above mentioned findings, we developed glutathione-sensitive dendrimer-NAC (D-NAC) and dendrimer-VPA (D-VPA) conjugates in multi-gram quantities for fast intracellular release. In preliminary efficacy studies, combination therapy with D-NAC and D-VPA produced improvement in 24-hour neurological deficit score comparable to combination therapy with VPA and NAC at 10-30 fold higher doses, while significantly reducing the adverse side effects. This study highlights the potential of dendrimer-drug therapies of two clinically approved drugs in HCA-indued large animal model.¹These are the first dendrimer nanotherapy studies in a large animal brain injury model.

References

1. Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest.Mishra MK, Beaty CA, Lesniak WG, Kambhampati SP, Zhang F, Wilson MA, Blue ME, Troncoso JC, Kannan S, Johnston MV, Baumgartner WA, Kannan RM. ACS Nano. 2014 Mar 25;8(3):2134-47.
2. Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model. Kannan S, Dai H, Navath RS, Balakrishnan B, Jyoti A, Janisse J, Romero R, Kannan RM. Sci Transl Med. 2012 Apr 18;4(130):130ra46.