Improved brain uptake and pharmacological activity of dalargin using a peptide-vector-mediated strategy.
The blood-brain barrier restricts the passage of substances into the brain. Neuropeptides, such as enkephalins, cannot be delivered into the brain when given systemically because of this barrier. Therefore, there is a need to develop efficient transport systems to deliver these drugs to the brain. Recently, we have demonstrated that conjugation of doxorubicin or penicillin to peptide vectors significantly enhances their brain uptake. In this study, we have conjugated the enkephalin analog dalargin with two different peptide vectors, SynB1 and SynB3, to improve its brain delivery and its pharmacological effect. We show by in situ brain perfusion that vectorization markedly enhances the brain uptake of dalargin. We also show using the hot-plate model that this enhancement in brain uptake results in a significant improvement in the observed antinociceptive effect of dalargin. These results support the usefulness of peptide-mediated strategies for improving the availability and efficacy of central nervous system drugs.
Rousselle
Christophe
C
Synt:em, Parc Scientifique Georges Besse, 30000 Nimes, France.
Clair
Philippe
P
Smirnova
Maria
M
Kolesnikov
Yuri
Y
Pasternak
Gavril W
GW
Gac-Breton
Stephanie
S
Rees
Anthony R
AR
Scherrmann
Jean-Michel
JM
Temsamani
Jamal
J
D000698:Analgesia; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D016503:Drug Delivery Systems; D016308:Enkephalin, Leucine-2-Alanine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry
D010455:Peptides; D016308:Enkephalin, Leucine-2-Alanine; C040996:enkephalin-Leu, Ala(2)-Arg(6)-