New diketopiperazines as vectors for peptide protection and brain delivery: Synthesis and biological evaluation

Autor: Virgone Carlotta, A., Dufour, E., Bacot, S., Ahmadi, M., Cornou, M., Moni, Lisa, Garcia, J., Chierici, S., Garin, D., Marti Batlle, D., Perret, P., Ghersi Egea, J. F., Moulin Sallanon, M., Fagret, D., Ghezzi, C.
Přispěvatelé: Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département de Chimie Moléculaire (DCM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This study was partially supported by the France Alzheimer Association, by the French program 'Investissement d'Avenir' run by the 'Agence National pour la Recherche', grant 'Infrastructure d'Avenir en Biologie Santé ANR‐11‐INBS‐0006', and the grant Cesame ANR‐10‐IBHU‐0003. The authors acknowledge support from ICMG FR 2607, LabEx ARCANE (ANR‐11-LABX‐0003‐01)., ANR-11-LABX-0003,ARCANE,Grenoble, une chimie bio-motivée(2011), ANR-10-IBHU-0003,CESAME,Institut Cerveau et Santé Mentale(2010), ANR-11-INBS-0006,FLI,France Life Imaging(2011), Perret, Pascale, Grenoble, une chimie bio-motivée - - ARCANE2011 - ANR-11-LABX-0003 - LABX - VALID, Instituts Hospitalo-Universitaires B - Institut Cerveau et Santé Mentale - - CESAME2010 - ANR-10-IBHU-0003 - IBHU - VALID, Infrastructures - France Life Imaging - - FLI2011 - ANR-11-INBS-0006 - INBS - VALID, Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: Journal of Labelled Compounds and Radiopharmaceuticals
Journal of Labelled Compounds and Radiopharmaceuticals, 2016, 59 (12), pp.517-530. ⟨10.1002/jlcr.3442⟩
Journal of Labelled Compounds and Radiopharmaceuticals, Wiley-Blackwell, 2016, 59 (12), pp.517-530. ⟨10.1002/jlcr.3442⟩
ISSN: 0362-4803
1099-1344
DOI: 10.1002/jlcr.3442⟩
Popis: International audience; New strategies allowing the transfer of molecules, especially peptides, through the blood-brain barriers are a major pharmacological challenge for the treatment of brain diseases. The present study aims at evaluating in vivo the cerebral bioavailability of carrier systems, based on small and functionalizable 2,5-diketopiperazine (DKP) motifs. We studied 2 different cyclo(Lys-Lys) DKP scaffolds alone and a cyclo(Lys-Gly) DKP carrier bearing as peptide model, the tau protein hexapeptide VQIVYK sequence. The different carrier systems were synthesized and radiolabeled using one of the free domains. The stability, biodistribution, and ability to cross blood-brain barrier were investigated in vivo in mice for 99m Tc-DKP scaffolds, 99m Tc-HVQIVYK peptide alone, and 99m Tc-DKP-VQIVYK. 125 I-labelled bovine serum albumin was used as negative control for brain uptake. Both radiolabeled DKPs scaffolds and 99m Tc-DKP-VQIVYK showed a high stability, while peptide 99m Tc-HVQIVYK alone was quickly degraded in vivo. The presence of 99m Tc-DKPs scaffolds and 99m Tc-DKP-VQIVYK was observed in the ventricular and subarachnoid spaces and to a lower extent in the brain parenchyma up to 45 minutes post-injection in mice. This work highlights the potentiality of DKP scaffolds as vectors to transport peptides into the brain by limiting proteolysis and favoring cerebral bioavailability.
Databáze: OpenAIRE
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