Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice

Carolyn Tallon; Benjamin J. Bell; Anjali Sharma; Arindom Pal; Medhinee M. Malvankar; Ajit G. Thomas; Seung-Wan Yoo; Kristen R. Hollinger; Kaleem Coleman; Elizabeth L. Wilkinson; Sujatha Kannan; Norman J. Haughey; Rangaramanujam M. Kannan; Rana Rais; Barbara S. Slusher

doi:10.3390/pharmaceutics14102066

Pharmaceutics (Sep 2022)

Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice

Carolyn Tallon,
Benjamin J. Bell,
Anjali Sharma,
Arindom Pal,
Medhinee M. Malvankar,
Ajit G. Thomas,
Seung-Wan Yoo,
Kristen R. Hollinger,
Kaleem Coleman,
Elizabeth L. Wilkinson,
Sujatha Kannan,
Norman J. Haughey,
Rangaramanujam M. Kannan,
Rana Rais,
Barbara S. Slusher

Affiliations

Carolyn Tallon: Johns Hopkins Drug Discovery, Baltimore, MD 21205, USA
Benjamin J. Bell: Johns Hopkins Drug Discovery, Baltimore, MD 21205, USA
Anjali Sharma: Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Arindom Pal: Johns Hopkins Drug Discovery, Baltimore, MD 21205, USA
Medhinee M. Malvankar: Johns Hopkins Drug Discovery, Baltimore, MD 21205, USA
Ajit G. Thomas: Johns Hopkins Drug Discovery, Baltimore, MD 21205, USA
Seung-Wan Yoo: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Kristen R. Hollinger: Johns Hopkins Drug Discovery, Baltimore, MD 21205, USA
Kaleem Coleman: Johns Hopkins Drug Discovery, Baltimore, MD 21205, USA
Elizabeth L. Wilkinson: Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Sujatha Kannan: Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Norman J. Haughey: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Rangaramanujam M. Kannan: Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Rana Rais: Johns Hopkins Drug Discovery, Baltimore, MD 21205, USA
Barbara S. Slusher: Johns Hopkins Drug Discovery, Baltimore, MD 21205, USA

DOI: https://doi.org/10.3390/pharmaceutics14102066
Journal volume & issue: Vol. 14, no. 10
p. 2066

Abstract

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Alzheimer’s disease (AD) is characterized by the progressive accumulation of amyloid-β and hyperphosphorylated tau (pTau), which can spread throughout the brain via extracellular vesicles (EVs). Membrane ceramide enrichment regulated by the enzyme neutral sphingomyelinase 2 (nSMase2) is a critical component of at least one EV biogenesis pathway. Our group recently identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), the most potent (30 nM) and selective inhibitor of nSMase2 reported to date. However, DPTIP exhibits poor oral pharmacokinetics (PK), modest brain penetration, and rapid clearance, limiting its clinical translation. To enhance its PK properties, we conjugated DPTIP to a hydroxyl-PAMAM dendrimer delivery system, creating dendrimer-DPTIP (D-DPTIP). In an acute brain injury model, orally administered D-DPTIP significantly reduced the intra-striatal IL-1β-induced increase in plasma EVs up to 72 h post-dose, while oral DPTIP had a limited effect. In a mouse tau propagation model, where a mutant hTau (P301L/S320F) containing adeno-associated virus was unilaterally seeded into the hippocampus, oral D-DPTIP (dosed 3× weekly) significantly inhibited brain nSMase2 activity and blocked the spread of pTau to the contralateral hippocampus. These data demonstrate that dendrimer conjugation of DPTIP improves its PK properties, resulting in significant inhibition of EV propagation of pTau in mice. Dendrimer-based delivery of DPTIP has the potential to be an exciting new therapeutic for AD.

Published in Pharmaceutics

ISSN: 1999-4923 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Pharmacy and materia medica
Website: http://www.mdpi.com/journal/pharmaceutics/

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