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The Journal of Neuroscience, November 4, 2009, 29(44):13761-13769; doi:10.1523/JNEUROSCI.4246-09.2009

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Neurobiology of Disease
A Nanomedicine Transports a Peptide Caspase-3 Inhibitor across the Blood–Brain Barrier and Provides Neuroprotection

Hulya Karatas,¹ Yesim Aktas,² Yasemin Gursoy-Ozdemir,¹ Ebru Bodur,³ Muge Yemisci,¹ Secil Caban,² Atay Vural,¹ Onur Pinarbasli,² Yilmaz Capan,² Eduardo Fernandez-Megia,⁴ Ramon Novoa-Carballal,⁴ Ricardo Riguera,⁴ Karine Andrieux,⁵ Patrick Couvreur,⁵ and Turgay Dalkara¹

¹Department of Neurology, Faculty of Medicine and Institute of Neurological Sciences and Psychiatry, ²Department of Pharmaceutical Technology, Faculty of Pharmacy, and ³Department of Biochemistry, Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey, ⁴Departamento de Química Orgánica, Facultad de Química, and Unidad de Resonancia Magnética Nuclear de Biomoléculas Asociada al Consejo Superior de Investigaciones Científicas, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain, and ⁵Physico-Chimie, Pharmacotechnie, Biopharmacie, Faculté de Pharmacie, Université Paris Sud, UMR Centre National de la Recherche Scientifique 8612, 92296 Chatenay Malabry, France

Correspondence should be addressed to Dr. Turgay Dalkara, Department of Neurology, Faculty of Medicine and Institute of Neurological Sciences and Psychiatry, Hacettepe University, 06100 Ankara, Turkey. Email: tdalkara{at}hacettepe.edu.tr

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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Received Aug. 27, 2009; accepted Sept. 10, 2009.

Correspondence should be addressed to Dr. Turgay Dalkara, Department of Neurology, Faculty of Medicine and Institute of Neurological Sciences and Psychiatry, Hacettepe University, 06100 Ankara, Turkey. Email: tdalkara{at}hacettepe.edu.tr

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Re: Z-DEVD-fmk inhibits calpain I (author's reply)

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