Glutamate carboxypeptidase II (GCPII) is a brain metallopeptidase which regulates extracellular glutamate concentration. GCPII is upregulated in activated microglia in the presence of neuroinflammation leading to excessive glutamate release and excitotoxicity. Inhibition of GCPII activity has been shown to reduce glutamate excitotoxicity, which may further decrease microglial activation. 2-(Phosphonomethyl)-pentadioic acid (2-PMPA) is a highly potent GCPII inhibitor but it has to be administered at high systemic doses or directly injected in the brain to observe efficacy. Hydroxyl PAMAM dendrimers have been shown to target activated microglia across the impaired blood brain barrier in various neuroinflammatory models. Dendrimer mediated, systemic and targeted delivery of 2-PMPA to activated microglia can be highly beneficial to improve its brain delivery and efficacy and reduce peripheral side effects. 2-PMPA was conjugated to the dendrimer hydroxyl groups <i>via</i> cleavable ester linkages using click chemistry, and the efficacy was evaluated in a rabbit model of cerebral palsy. Fluorescently labeled Cy5-D-2-PMPA showed co-localization with activated microglia and astrocytes in rabbit primary mixed glial cells. D-2-PMPA treatment increased TGF-β1 levels in LPS-activated mixed glial cells and was significantly more efficacious than the free drug. Intravenous administration of Cy5-D-2-PMPA showed uptake in activated astrocytes and microglia in CP rabbit kits. No cellular uptake was seen in age-matched healthy controls. These results suggest D-2-PMPA as a potential dendrimer-based therapeutic to target GCPII in activated glia to attenuate glutamate excitotoxicity and neuroinflammation.

Dendrimer-mediated targeted drug delivery to glial glutamate carboxypeptidase II for the treatment of neurological diseases

256th National Meeting (2018)

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