Dendrimer-enabled targeted delivery attenuates glutamate excitotoxicity and improves motor function in a rabbit model of cerebral palsy

Fan Zhang, Zhi Zhang, Jesse Alt, Siva P. Kambhampati, Anjali Sharma, Sarabdeep Singh, Elizabeth Nance, Ajit G. Thomas, Camilo Rojas, Rana Rais, Barbara S. Slusher, Rangaramanujam M. Kannan, Sujatha Kannan

Research output: Contribution to journalArticlepeer-review

Abstract

Glutamate carboxypeptidase II (GCPII), localized on the surface of astrocytes and activated microglia, regulates extracellular glutamate concentration in the central nervous system (CNS). We have previously shown that GCPII is upregulated in activated microglia in the presence of inflammation. Inhibition of GCPII activity could reduce glutamate excitotoxicity, which may decrease inflammation and promote a ‘normal’ microglial phenotype. 2-(3-Mercaptopropyl) pentanedioic acid (2-MPPA) is the first GCPII inhibitor that underwent clinical trials. Unfortunately, immunological toxicities have hindered 2-MPPA clinical translation. Targeted delivery of 2-MPPA specifically to activated microglia and astrocytes that over-express GCPII has the potential to mitigate glutamate excitotoxicity and attenuate neuroinflammation. In this study, we demonstrate that 2-MPPA when conjugated to generation-4, hydroxyl-terminated polyamidoamine (PAMAM) dendrimers (D-2MPPA) localize specifically in activated microglia and astrocytes only in newborn rabbits with cerebral palsy (CP), not in controls. D-2MPPA treatment led to higher 2-MPPA levels in the injured brain regions compared to 2-MPPA treatment, and the extent of D-2MPPA uptake correlated with the injury severity. D-2MPPA was more efficacious than 2-MPPA in decreasing extracellular glutamate level in ex vivo brain slices of CP kits, and in increasing transforming growth factor beta 1 (TGF-β1) level in primary mixed glial cell cultures. A single systemic intravenous dose of D-2MPPA on postnatal day 1 (PND1) decreased microglial activation and resulted in a change in microglial morphology to a more ramified form along with amelioration of motor deficits by PND5. These results indicate that targeted dendrimer-based delivery specifically to activated microglia and astrocytes can improve the efficacy of 2-MPPA by attenuating glutamate excitotoxicity and microglial activation.

Original languageEnglish (US)
Pages (from-to)27-42
Number of pages16
JournalJournal of Controlled Release
Volume358
DOIs
StatePublished - Jun 2023

Keywords

  • 2-(3-mercaptopropyl) pentanedioic acid
  • Cerebral palsy
  • Glutamate carboxypeptidase II
  • Glutamate excitotoxicity
  • N-Acetylaspartylglutamic acid
  • Polyamidoamine dendrimer

ASJC Scopus subject areas

  • Pharmaceutical Science

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