Dextran oxygen-loaded nanobubbles counteract hypoxia effects on MMP/TIMP balances in human adherent monocytes.

Hypoxia modifies the invasive phenotype of immune cells, thus playing a key role in several pathological conditions of different etiology, including chronic wounds, atherosclerosis and cancer. Intriguingly, such pathologies might be targeted by new effective oxygenating drugs such as O2-Loaded Nanobubbles (OLNs). In the present work, the effects of hypoxia on MMP/TIMP release from human adherent monocytes isolated from peripheral blood were investigated, and the therapeutic potential of dextran-shelled, decafluoropentane-containing OLNs was evaluated. Normoxic monocytes released basal MMP-9, TIMP-1 and TIMP-2 protein levels. Hypoxia strongly impaired MMP/TIMP balances by reducing MMP-9 and increasing TIMP-1, without affecting TIMP-2 secretion. Dextran OLNs, with spherical morphology, diameters of 550 nm and anionic surfaces, did not display cell cytotoxicity and did not affect cell viability of monocytes after uptake. Interestingly, OLNs abrogated all hypoxia effects, restoring normoxic MMP/TIMP levels. Such an event was specifically dependent on time-sustained O2 diffusion from OLN core, as it was mimicked by neither O2-saturated solution (OSS) nor O2-free nanobubbles (OFNs). In conclusion, dextran OLNs proved effective in counteracting hypoxia effects on MMP/TIMP balances in human monocytes, potentially presenting themselves as innovative, low-cost, non-toxic therapeutic devices which can restore physiological invasive phenotype of immune cells in hypoxia-associated diseases.