title: The CD44/integrins interplay and the significance of receptor binding and re-presentation in the uptake of RGD-functionalized hyaluronic acid.
abstract: We have studied the interplay between two endocytic receptors for a carrier structure bearing two complementary ligands. Hyaluronic acid (HA; three different molecular weights) was functionalized with an RGD-containing peptide; this ancillary ligand allows the macromolecule to bind to α(v) integrins in addition to the classical HA internalization receptor (CD44). The uptake of HA-RGD and of native HA was assessed in a phagocytic cell model (J774.2 murine macrophages), studying the kinetics of internalization and its mechanistic details. Indications of a synergic binding to integrins and CD44 emerged for HA-RGD; possibly, a first binding to integrins allows for a pre-concentration of the macromolecule on the cell surface, which is then followed by its binding to CD44. The endocytic mechanism and kinetics appeared then dominated by CD44, which has a much slower turnover than integrins. In this study we have demonstrated that the knowledge of the rate-determining steps of the internalization of a carrier is necessary for assessing its performance. In this case, the presence of multiple ligands on a carrier was beneficial in some respect (e.g. in improved binding/targeting), but may not be sufficient to overcome penetration barriers that arise from slow receptor re-presentation.
authors: School of Biomedicine, University of Manchester, Manchester M13 9PL, United Kingdom.
authors: Sihem
authors: S
authors: Ouasti
authors: Paul J
authors: PJ
authors: Kingham
authors: Giorgio
authors: G
authors: Terenghi
authors: Nicola
authors: N
authors: Tirelli
mesh_terms: D000818:Animals; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D004705:Endocytosis; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D016023:Integrins / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D011485:Protein Binding
chemical_list: D004337:Drug Carriers; D018960:Hyaluronan Receptors; D016023:Integrins; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D006820:Hyaluronic Acid