RESUMEN
Magnetic nanocomposites (MNC) are promising theranostic platforms with tunable physicochemical properties allowing for remote drug delivery and multimodal imaging. Here, we developed doxorubicin-loaded Fe3O4-Au MNC (DOX-MNC) using electron beam physical vapor deposition (EB-PVD) in combination with magneto-mechanochemical synthesis to assess their antitumor effect on Walker-256 carcinosarcoma under the influence of a constant magnetic (CMF) and electromagnetic field (EMF) by comparing tumor growth kinetics, magnetic resonance imaging (MRI) scans and electron spin resonance (ESR) spectra. Transmission (TEM) and scanning electron microscopy (SEM) confirmed the formation of spherical magnetite nanoparticles with a discontinuous gold coating that did not significantly affect the ferromagnetic properties of MNC, as measured by vibrating-sample magnetometry (VSM). Tumor-bearing animals were divided into the control (no treatment), conventional doxorubicin (DOX), DOX-MNC and DOX-MNC + CMF + EMF groups. DOX-MNC + CMF + EMF resulted in 14% and 16% inhibition of tumor growth kinetics as compared with DOX and DOX-MNC, respectively. MRI visualization showed more substantial tumor necrotic changes after the combined treatment. Quantitative analysis of T2-weighted (T2W) images revealed the lowest value of skewness and a significant increase in tumor intensity in response to DOX-MNC + CMF + EMF as compared with the control (1.4 times), DOX (1.6 times) and DOX-MNC (1.8 times) groups. In addition, the lowest level of nitric oxide determined by ESR was found in DOX-MNC + CMF + EMF tumors, which was close to that of the muscle tissue in the contralateral limb. We propose that the reason for the relationship between the observed changes in MRI and ESR is the hyperfine interaction of nuclear and electron spins in mitochondria, as a source of free radical production. Therefore, these results point to the use of EB-PVD and magneto-mechanochemically synthesized Fe3O4-Au MNC loaded with DOX as a potential candidate for cancer magnetic nanotheranostic applications.
RESUMEN
Intermittent hypoxia-hyperoxia training (IHHT) is a non-pharmacological therapeutic modality for management of some chronic- and age-related pathologies, such as Alzheimer's disease (AD). Our previous studies demonstrated significant improvement of cognitive function after IHHT in the patients with mild cognitive impairment (MCI). The present study further investigated the effects of IHHT on pro-inflammatory factors in healthy elderly individuals and patients with early signs of AD. Twenty-nine subjects (13 healthy subjects without signs of cognitive impairment syndrome and 16 patients diagnosed with MCI; age 52 to 76 years) were divided into four groups: Healthy+Sham (n = 7), Healthy+IHHT (n = 6), MCI+Sham (n = 6), and MCI+IHHT (n = 10). IHHT was carried out 5 days per week for 3 weeks (total 15 sessions), and each daily session included 4 cycles of 5-min hypoxia (12% FIO2) and 3-min hyperoxia (33% FIO2). Decline in cognitive function indices was observed initially in both MCI+Sham and MCI+IHHT groups. The sham training did not alter any of the parameters, whereas IHHT resulted in improvement in latency of cognitive evoked potentials, along with elevation in APP110, GDF15 expression, and MMP9 activity in both healthy subjects and those with MCI. Increased MMP2 activity, HMGB1, and P-selectin expression and decreased NETs formation and Aß expression were also observed in the MCI+IHHT group. There was a negative correlation between MoCA score and the plasma GDF15 expression (R = −0.5799, p < 0.05) before the initiation of IHHT. The enhanced expression of GDF15 was also associated with longer latency of the event-related potentials P330 and N200 (R = 0.6263, p < 0.05 and R = 0.5715, p < 0.05, respectively). In conclusion, IHHT upregulated circulating levels of some inflammatory markers, which may represent potential triggers for cellular adaptive reprogramming, leading to therapeutic effects against cognitive dysfunction and neuropathological changes during progression of AD. Further investigation is needed to clarify if there is a causative relationship between the improved cognitive function and the elevated inflammatory markers following IHHT.