title: The CD44-Mediated Uptake of Hyaluronic Acid-Based Carriers in Macrophages.
abstract: CD44 is a potentially rewarding target in cancer therapy, although its mechanisms of ligand binding and internalization are still poorly understood. In this study, we have established quantitative relationships between CD44 expression in differently polarized macrophages (M0, M1, and M2-polarized THP-1 human macrophages) and the uptake of hyaluronic acid (HA)-based materials, which are potentially usable for CD44 targeting. We have validated a robust method for macrophage polarization, which sequentially uses differentiating and polarizing factors, and allows to show that CD44 expression depends on polarization (M1 > M0 ≥ M2). It is noteworthy that THP-1 M2 expressed CD44v6, suggesting their suitability as a model of tumor-associated macrophages. In the uptake of HA, both as a soluble polymer and in the form of (siRNA-loaded) nanoparticles, CD44 expression correlated positively with binding, but negatively with internalization. Counterintuitively, it appears that a higher presence of CD44 (in M1) allows a more efficient capture of HA materials, but a lower expression (in M2) is conducive to better internalization. Although possibly cell-specific, this unexpected relationship indicates that the common paradigm "higher CD44 expression = better targetability" is too simplistic; mechanistic details of both receptor presentation and association still need to be elucidated for a predictable targeting behavior.
authors.affiliation: NorthWest Centre for Advanced Drug Delivery (NoWCADD), Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Julio M
authors.initials: JM
authors.lastname: Rios de la Rosa
authors.affiliation: NorthWest Centre for Advanced Drug Delivery (NoWCADD), Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tirella
authors.affiliation: NorthWest Centre for Advanced Drug Delivery (NoWCADD), Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Arianna
authors.initials: A
authors.lastname: Gennari
authors.affiliation: NorthWest Centre for Advanced Drug Delivery (NoWCADD), Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
authors.affiliation: NorthWest Centre for Advanced Drug Delivery (NoWCADD), Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tirelli
mesh_terms: D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid
keywords: CD44; endocytosis; hyaluronan; nanoparticles