Effects of peptide molecular mass and PEG chain length on the vasoreactivity of VIP and PACAP(1-38) in pegylated phospholipid micelles.
Bioactive properties of certain amphipathic peptides are amplified when self-associated with sterically stabilized micelles (SSM) composed of polyethylene glycol (PEG)-conjugated phospholipids. The purpose of this study was to determine the effects of amphipathic peptide molecular mass and PEG chain length on vasoreactivity evoked by vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide, and pituitary adenylate cyclase-activating peptide(1-38) (PACAP(1-38)), a 38-amino acid neuropeptide, associated with PEGylated phospholipid micelles in vivo. Both peptides were incubated for 2 h with SSM composed of PEG with molecular mass of 2000 or 5000 grafted onto distearoyl-phosphatidylethanolamine (DSPE-PEG2000 or DSPE-PEG5000) before use. We found that regardless of peptide molecular mass, PEG chain length had no significant effects on peptide-SSM interactions. Using intravital microscopy, VIP associated with DSPE-PEG5000 SSM or DSPE-PEG2000 SSM incubated at 25 degrees C evoked similar vasodilation in the intact hamster cheek pouch microcirculation. Likewise, PACAP(1-38)-induced vasodilation was PEG chain length-independent. However, SSM-associated PACAP(1-38) evoked significantly smaller vasodilation than that evoked by SSM-associated VIP (P < 0.05) at 25 degrees C. When the incubation temperature was increased to 37 degrees C, SSM-associated PACAP(1-38)-induced vasodilation was now similar to that of SSM-associated VIP. This response was associated with a corresponding increase in alpha-helix content of both peptides in the presence of phospholipids. Collectively, these data indicate that for a larger amphipathic peptide, such as PACAP(1-38), greater kinetic energy or longer incubation period is required to optimize peptide-SSM interactions and amplify peptide bioactivity in vivo.
Ashok
Beena
B
Department of Biopharmaceutical Sciences (M/C 865), University of Illinois at Chicago, 833 S. Wood Street, Room 335, Chicago, IL 60612-7231, USA.
Rubinstein
Israel
I
Tsueshita
Takaya
T
Onyüksel
Hayat
H
D000818:Animals; D001160:Arterioles / Q000187:drug effects; D006224:Cricetinae; D004337:Drug Carriers / Q000737:chemistry; D008647:Mesocricetus; D008823:Micelles; D008970:Molecular Weight; D009479:Neuropeptides / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010743:Phospholipids / Q000737:chemistry*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011092:Polyethylene Glycols / Q000737:chemistry*; D014660:Vasoactive Intestinal Peptide / Q000737:chemistry / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D004337:Drug Carriers; D008823:Micelles; D009479:Neuropeptides; D010446:Peptide Fragments; D010455:Peptides; D010743:Phospholipids; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C108046:pituitary adenylate cyclase-activating-peptide (1-38), pig; D014660:Vasoactive Intestinal Peptide; D011092:Polyethylene Glycols