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.
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