title: Targeting of the epidermal growth factor receptor with mesoporphyrin IX-peptide conjugates.
abstract: The synthesis andin vitroevaluation of four mesoporphyrin IX-peptide conjugates designed to target EGFR, over-expressed in colorectal and other cancers, are reported. Two peptides with known affinity for EGFR, LARLLT (1) and GYHWYGYTPQNVI (2), were conjugated to mesoporphyrin IX (MPIX,3)viaone or both the propionic side chains, directly (4,5) or with a triethylene glycol spacer (7,8). The conjugates were characterized using NMR, MS, CD, SPR, UV-vis and fluorescence spectroscopies. Energy minimization and molecular dynamics suggest different conformations for the conjugates. SPR studies show that conjugate4, bearing two LARLLT with no PEG spacers, has the greatest affinity for binding to EGFR, followed by conjugate7with two PEG and two LARLLT sequences. Molecular modeling and docking studies suggest that both conjugates4and7can bind to monomer and dimer EGFR in open and closed conformations. The cytotoxicity and cellular targeting ability of the conjugates were investigated in human HEp2 cells over-expressing EGFR. All conjugates showed low dark- and photo-toxicities. The cellular uptake was highest for conjugates4and8and lowest for7bearing two LARLLT linkedviaPEG groups, likely due to decreased hydrophobicity. Among the conjugates investigated4is the most efficient EGFR-targeting agent, and therefore the most promising for the detection of cancers that over-express EGFR.
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA.
authors.forename: Krystal R
authors.initials: KR
authors.lastname: Fontenot
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA.
authors.forename: Benson G
authors.initials: BG
authors.lastname: Ongarora
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA.
authors.forename: Logan E
authors.initials: LE
authors.lastname: LeBlanc
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA.
authors.forename: Zehua
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: University of Louisiana at Monroe, School of Pharmacy, Monroe, LA 71201, USA.
authors.forename: Seetharama D
authors.initials: SD
authors.lastname: Jois
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA.
authors.forename: M Graça H
authors.initials: MG
authors.lastname: Vicente
keywords: EGFR; docking; peptide; photosensitizer; porphyrin