Ramos Santiago, Tania

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    Understanding the impact of dextran iron oxide nanoparticles in monocytes and macrophages and impaired ubiquitination in ovarian cancer culture modalities upon magnetic fluid hyperthermia
    (2023-05-11) Ramos Santiago, Tania; Torres Lugo, Madeline; College of Engineering; Domenech García, Maribella; Latorre Esteves, Magda M.; Resto Irrizarry, Pedro J.; Other; Ramos Pérez, Ángela
    Magnetic fluid hyperthermia (MFH) has demonstrated thermal potentiation of chemotherapeutic drugs. However, there are challenges to its clinical translation. The overall objective was to investigate the interaction of iron oxide nanoparticles (IONPs) with macrophages and impaired ubiquitination in ovarian cancer culture modalities upon MFH. We hypothesize that understanding the effect of IONPs in macrophages and controlling the protective mechanisms of ovarian cancer will improve MFH effect. The first objective involved the characterization of IONPs, cell viability, iron uptake, and phenotypical characteristics of macrophages upon exposure to IONPs and MFH. The second objective involved using ovarian cancer to assess cell viability and aggresome formation after MFH and impaired ubiquitination. Results indicated that dextran-coated IONPs had a hydrodynamic diameter of 55 ± 12 nm, a slightly negative charge at physiological pH, and an absorption rate of 650 ± 54 W/gFe. Iron uptake between cell types was cell and concentration-dependent, except for M1-macrophages. The highest uptake was for M2-macrophages. The expression of characteristic markers and cytokine secretion confirmed the phenotype for each cell type. The exposure to IONPs and MFH led to changes in phenotypical characteristics demonstrated by the immune response, while remaining viable. For the second objective, A2780 and HeyA8 spheroids were obtained. Ubiquitin C (UBC) expression showed upregulation after 1 hour of recovery for both ovarian cell lines after MFH exposure. Inhibition of ubiquitination led to MFH potentiation of cell death for 2D monolayer, while there was resistance for 3D spheroids at 41ºC, but an increment at 43ºC. Aggresome formation was observed for A2780, while there was a lack of aggresome formation when inhibiting ubiquitination. For HeyA8, individual and combinatorial treatments did not induce aggresome formation. In conclusion, this data showed different nanoparticle uptake patterns and phenotypical characteristics changes of macrophages when exposed to IONPs and MFH, which could potentiate MFH. Moreover, inhibition of ubiquitination helped potentiate cell death in ovarian cancer in combination with MFH.