RESUMO
Hearing loss (HL) affects more than 5% of the global population, with projections indicating an impact of up to 50% on young individuals in the next years. HL treatments remain limited due to the inner ear's hermeticism. HL often involves inflammatory processes, underscoring the need for enhanced delivery of antiinflammatory agents to the inner ear. Our research focuses on the development of a directed therapy based on magnetic nanoparticles (MNPs). We previously synthesized biocompatible folic acid-coated iron oxide-core nanoparticles (MNPs@FA) as potential carriers for the anti-inflammatory Diclofenac (Dfc). This study aims to incorporate Dfc onto MNPs@FA to facilitate targeted drug delivery to the inner ear. Through optimizing the loading procedure, we achieved optimal loading capacity. Dfc release was studied in the simulated target fluid and the administration vehicle. Complete characterization is also shown. In vitro biocompatibility testing ensured the biosafety of the resulting formulation. Subsequent ex vivo targeting assays on murine cochleae validated the nanosystems' ability to penetrate the round window membrane, one of the main HL therapy barriers. These findings serve as validation before continuing to more complex in vivo studies. Together, the data here presented represent an advancement in addressing unmet medical needs in HL therapy.
RESUMO
Despite advances in breast cancer (BC) treatment, its mortality remains high due to intrinsic or acquired resistance to therapy. Several ongoing efforts are being made to develop novel drugs to treat this pathology with the aim to overcome resistance, prolong patient survival and improve their quality of life. We have previously shown that the non-hypercalcemic vitamin D analogues EM1 and UVB1 display antitumor effects in preclinical studies employing conventional cell lines and animal models developed from these cells. In this work, we explored the antitumor effects of EM1 and UVB1 employing BC cells derived from patient-derived xenografts (PDXs), which are a powerful preclinical tool for testing new drugs. We demonstrated that the analogues reduced the viability of HER2-positive and Triple Negative BC-PDXs. Moreover, using an in vitro model of acquired resistance to Trastuzumab-emtansine, UVB1 displayed anti-proliferative actions under 2D and 3D culture conditions. It inhibited both formation and growth of established organoids. In addition, a direct correlation between UVB1 antitumor effects and VDR expression in PDXs was found. In conclusion, all the results reinforce the potential use of these vitamin D analogues as antitumor agents to treat HER2-positive and Triple Negative BC.