The CD44‐Mediated Uptake of Hyaluronic Acid‐Based Carriers in Macrophages. Issue 4 (19th December 2016)

• Record Type: Journal Article
• Authors: Rios de la Rosa, Julio M.; Tirella, Annalisa; Gennari, Arianna; Stratford, Ian J.; Tirelli, Nicola
• Is Part Of: Advanced healthcare materials. Volume 6:Issue 4(2017)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2016-12-19
• Subjects: CD44 -- endocytosis -- hyaluronan -- nanoparticles; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1002/adhm.201601012
• Languages: English
• ISSNs: 2192-2640

Abstract

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. Abstract : This study addresses how the expression of CD44 affects the binding and internalization of hyaluronic acid‐based materials, by using the polarization of human macrophages to vary the expression of this receptor. The results suggest that higher CD44 expression (classical activation) does correlate with enhanced binding, but lower expression levels (non‐polarized and alternative activation) promote better internalization.