| Summary: | Melanoma is the most aggressive form of skin cancer. Hypoxia is a feature of the tumor microenvironment that reduces efficacy of immuno- and chemotherapies, resulting in poor clinical outcomes. <i>Lactococcus lactis</i> is a facultative anaerobic gram-positive lactic acid bacterium (LAB) that is Generally Recognized as Safe (GRAS). Recently, the use of LAB as a delivery vehicle has emerged as an alternative strategy to deliver therapeutic molecules; therefore, we investigated whether <i>L. lactis</i> can target and localize within melanoma hypoxic niches. To simulate hypoxic conditions <i>in vitro</i>, melanoma cells A2058, A375 and MeWo were cultured in a chamber with a gas mixture of 5% CO<sub>2</sub>, 94% N<sub>2</sub> and 1% O<sub>2</sub>. Among the cell lines tested, MeWo cells displayed greater survival rates when compared to A2058 and A375 cells. Co-cultures of <i>L. lactis</i> expressing GFP or mCherry and MeWo cells revealed that <i>L. lactis</i> efficiently express the transgenes under hypoxic conditions. Moreover, multispectral optoacoustic tomography (MSOT), and near infrared (NIR) imaging of tumor-bearing BALB/c mice revealed that the intravenous injection of either <i>L. lactis</i> expressing β-galactosidase (β-gal) or infrared fluorescent protein (IRFP713) results in the establishment of the recombinant bacteria within tumor hypoxic niches. Overall, our data suggest that <i>L. lactis</i> represents an alternative strategy to target and deliver therapeutic molecules into the tumor hypoxic microenvironment.
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