Unleashing the translational potential of seriniquinone by PLGA nanoparticles: improved solubility, enhanced antimelanoma activity, and first in vivo administration in Galleria mellonella

ABSTRACT Seriniquinone (SQ) is a promising novel drug candidate for antifungal and melanoma therapy, but its poor water solubility has hindered its formulation and in vivo assessment. Molecular modifications and incorporation into lipid-based nanocarriers have not succeeded, because they yielded racemic mixtures or drug precipitation over time. Here, we describe SQ-loaded poly(D,L-lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) as a strategy to overcome its low aqueous solubility, enable its delivery in aqueous-based vehicles and its administration through multiple routes. NPs were produced by single emulsion-solvent evaporation. Spherical NPs with a mean hydrodynamic diameter of 260-280 nm and SQ encapsulation efficiency of ∼83% were obtained. No SQ precipitation was observed by microscopy, indicating effective drug incorporation. Strong SQ-PLGA interactions were demonstrated by FTIR and thermal analyses, which were associated with slow SQ release in physiological pH of 7.4 (16% after 96 h); release increased by 4.2-fold under lysosomal pH. Antifungal activity of encapsulated SQ was time- and genus-dependent, while antimelanoma activity was preserved in SK-MEL-28 and SK-MEL-147 cells. In monolayers, nanoencapsulation increased SQ association with cells and improved long-term cytotoxicity. In spheroids, nanoencapsulation enhanced SQ potency in SK-MEL-28, as evidenced by a 2-fold reduction in the IC 50 value. An additional ∼25% decrease in viability was observed in SK-MEL-147 spheroids, indicating optimized efficacy. SQ encapsulation enabled its first in vivo administration in Galleria mellonella larvae, with no detectable toxicity up to 80 mg/kg. In summary, encapsulation in PLGA NPs addressed key limitations in SQ development, thereby representing a practical approach to the long-standing challenge of SQ delivery.