RESUMEN
The resistance of malignant tumors to multiple drugs is a significant obstacle in cancer treatment and prognosis. Accordingly, we synthesized a celastrol (Cel) prodrug (Cel-CSO) by conjugating chitosan oligosaccharides (CSO) to Cel for reversing Taxol resistance in chemotherapy, followed by self-assembly with Taxol into a novel nanoplatform of Cel-CSO/Taxol nanoparticles (termed NPs). NPs showed a suitable size (about 153 nm), excellent stability and prolonged release of Cel and Taxol in a manner that depended on both pH and time. NPs effectively inhibited the overexpression of multidrug resistance-related protein P-gp, hypoxia inducible factor-1α (HIF-1α), and triggered the MCF-7/Taxol cell apoptosis through inhibiting the PI3K/AKT/NF-κB/HIF-1α pathway. In tumor-bearing mice, NPs exhibited significant curative effects in inducing apoptosis of MCF-7/Taxol tumors which showed a low expression level of P-gp, microtubule-related proteins TUBB3 and Tau. The results indicated that NPs may be a promising strategy to overcome drug resistance caused by P-gp, which improve the antitumor effects in drug-resistant breast cancer.
RESUMEN
Ultrasonic fatigue tests were performed on Ti60 titanium alloy up to a very high cycle fatigue (VHCF) regime at various stress ratios to investigate the characteristics. The S-N curves showed continuous declining trends with fatigue limits of 400, 144 and 130 MPa at 109 cycles corresponding to stress ratios of R = -1, 0.1 and 0.3, respectively. Fatigue cracks found to be initiated from the subsurface of the specimens in the VHCF regime, especially at high stress ratios. Two modified fatigue life prediction models based on fatigue crack initiation mechanisms for Ti60 titanium alloy in the VHCF regime were developed which showed good agreement with the experimental data.