Article detail · 2009
A Nanomedicine Transports a Peptide Caspase 3 Inhibitor across the Blood Brain Barrier and Provides Neuroprotection
- Year
- 2009
- Type
- article
Data source split
- YÖKSİS YÖKSİS article record
- YÖKSİS venue Journal of Neuroscience
- Catalog match (ISSN) Journal of Neuroscience
- OpenAlex OpenAlex enrichment (abstract, citations, topics)
Abstract
OpenAlex · English
Caspases play an important role as mediators of cell death in acute and chronic neurological disorders. Although peptide inhibitors of caspases provide neuroprotection, they have to be administered intracerebroventricularly because they cannot cross the blood-brain barrier (BBB). Herein, we present a nanocarrier system that can transfer chitosan nanospheres loaded with N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (Z-DEVD-FMK), a relatively specific caspase-3 inhibitor, across BBB. Caspase-3 was chosen as a pharmacological target because of its central role in cell death. Polyethylene glycol-coated nanospheres were conjugated to an anti-mouse transferrin receptor monoclonal antibody (TfRMAb) that selectively recognizes the TfR type 1 on the cerebral vasculature. We demonstrate with intravital microscopy that this nanomedicine is rapidly transported across the BBB without being measurably taken up by liver and spleen. Pre- or post-treatment (2 h) with intravenously injected Z-DEVD-FMK-loaded nanospheres dose dependently decreased the infarct volume, neurological deficit, and ischemia-induced caspase-3 activity in mice subjected to 2 h of MCA occlusion and 24 h of reperfusion, suggesting that they released an amount of peptide sufficient to inhibit caspase activity. Similarly, nanospheres inhibited physiological caspase-3 activity during development in the neonatal mouse cerebellum on postnatal day 17 after closure of the BBB. Neither nanospheres functionalized with TfRMAb but not loaded with Z-DEVD-FMK nor nanospheres lacking TfRMAb but loaded with Z-DEVD-FMK had any effect on either paradigm, suggesting that inhibition of caspase activity and subsequent neuroprotection were due to efficient penetration of the peptide into brain. Thus, chitosan nanospheres open new and exciting opportunities for brain delivery of biologically active peptides that are useful for the treatment of CNS disorders.
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Citations
OpenAlex cited_by_count. Not a WoS or Scopus citation count; those sources have no separate column here.
187 citations
OpenAlex cited_by_count (cache / database)
20 publications in the local catalog that cite this work (OpenAlex reference match; not the full global list).
- Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options 2018
- Systemically administered brain targeted nanoparticles transport peptides across the blood brain barrier and provide neuroprotection 2015
- Systemically administered brain targeted nanoparticles transport peptides across the blood brain barrier and provide neuroprotection 2015
- Evaluation of brain-targeted chitosan nanoparticles through blood–brain barrier cerebral microvessel endothelial cells 2017
- Transport of a Caspase Inhibitor Across the Blood–Brain Barrier by Chitosan Nanoparticles 2012
- TRANSPORT OF A CASPASE INHIBITOR ACROSS THE BLOOD BRAIN BARRIER BY CHITOSAN NANOPARTICLES 2012
- Preparation and Characterization of Biocompatible Chitosan Nanoparticles for Targeted Brain Delivery of Peptides 2017
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- Nanopharmaceuticals as Drug-Delivery Systems 2018