title: Dendrimer-epidermal growth factor conjugate displays superagonist activity.
abstract: Binding of ligands on to epidermal growth factor receptor (EGFR) can stimulate cell growth; therefore, any application employing EGF as a targeting ligand for a "drug carrier" must evaluate the effect of the conjugate on cell growth. We report the synthesis and in vitro biological activity of EGF molecules coupled to a fluorescein-labeled polyamidoamine dendrimer. The conjugate bound and internalized into several EGFR-expressing cell lines in a receptor-specific fashion. The conjugate effectively induced EGFR phosphorylation and acted as a superagonist by stimulating cell growth to a greater degree than free EGF. Concomitant administration of the chemotherapeutic drug methotrexate completely inhibited cell growth to a degree similar to its effect in the absence of the conjugate. Thus, dendrimer-EGF conjugates serve as EGFR superagonists, but this activity can be overcome by chemotherapeutic drugs. The agonist activity of these materials must be taken into consideration when using EGF conjugates for imaging applications.
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, Department of Internal Medicine, Division of Allergy, University of Michigan, 9220 MSRB III, Box 0648, Ann Arbor, Michigan 48109, USA.
authors.forename: Thommey P
authors.initials: TP
authors.lastname: Thomas
authors.forename: Rameshwer
authors.initials: R
authors.lastname: Shukla
authors.forename: Alina
authors.initials: A
authors.lastname: Kotlyar
authors.forename: Bradley
authors.initials: B
authors.lastname: Liang
authors.forename: Jing Yong
authors.initials: JY
authors.lastname: Ye
authors.forename: Theodore B
authors.initials: TB
authors.lastname: Norris
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000031:analogs & derivatives* / Q000378:metabolism; D066246:ErbB Receptors / Q000819:agonists* / Q000378:metabolism; D006801:Humans; D051379:Mice; D011485:Protein Binding / Q000502:physiology
chemical_list: D050091:Dendrimers; D004815:Epidermal Growth Factor; D066246:ErbB Receptors