Heng Zhang,Yizheng Zhou,Hanmo Yang,Xinyi Tao,Yinping Chen,Fuqiang Dong,Yi Sun
The growing resistance of Aspergillus to azoles poses a significant challenge in treating invasive fungal infections. This study aimed to investigate the synergistic effect of berbamine hydrochloride (BBM) combined with azoles in treating Aspergillus fumigatus and explore the role of efflux pump inhibition in this synergy. The efficacy of combining BBM with itraconazole (ITC), voriconazole (VOR), and posaconazole (POS) was tested against 69 A. fumigatus strains that had been identified using the M38-A3 broth microdilution method. quantitative reverse transcription PCR (RT-qPCR) was used to measure gene expression related to synergy, while flow cytometry was employed to assess mitochondrial reactive oxygen species (ROS) levels, and Rhodamine 6G exocytosis assays were performed to quantify efflux pump activity. BBM alone showed no significant antifungal activity. BBM combined with POS exhibited synergy against 66 strains (95.7%), while two clinical isolates (Af05/Af08) and one defective strain (Δcdr1B) showed no synergy. Synergy with ITC was observed in three strains (4.3%), but not with VOR. In the non-synergistic Af05 and Af08 strains, the expression of the cdr1B gene was significantly lower compared to wild-type (WT) strains. ROS levels increased significantly in WT with POS and BBM combination therapy, but not in the defective strains. Glucose uptake was also reduced in the POS-BBM combination. BBM enhances azole sensitivity in A. fumigatus primarily by inhibiting the cdr1B-mediated efflux pump, supported by reduced Rhodamine 6G exocytosis and synergy loss in cdr1B-deficient strains. ROS accumulation and metabolic disruption may further contribute to this synergy. Targeting efflux pumps with BBM provides a novel strategy to combat azole resistance.
The development of innovative therapeutic strategies that combine multiple treatment modalities is essential for effective cancer therapy. In this study, we engineered berberine (BER)-loaded mesoporous polydopamine (MPDA) nanoparticles (BER-MPDA) to enhance anti-tumor efficacy through synergistic chemotherapy and photothermal therapy (PTT). The mesoporous structure of MPDA allowed for a high loading capacity of BER, a natural isoquinoline alkaloid with known anticancer properties. Upon near-infrared laser irradiation, BER-MPDA exhibited marked photothermal conversion efficiency, leading to effective tumor cell ablation. Both in vitro and in vivo experiments indicated that the combined treatment of BER-MPDA with near-infrared laser irradiation resulted in superior tumor inhibition compared to monotherapy. The synergistic effect was attributed to the enhanced cellular uptake and the simultaneous induction of chemo- and photothermal cytotoxicity. Our findings suggest that BER-MPDA represents a promising platform for multimodal cancer therapy, offering a potent approach to overcoming the limitations of conventional chemotherapy and PTT.
The application prospects of magnetic nanocomposites in cancer treatment and diagnosis are extensive, as they enable targeted drug delivery to tumors. Herein, a novel therapeutic strategy was proposed for oral squamous cell carcinoma (OSCC), in which polyethylene glycol-folic acid (FA-PEG) was modified on nanocomposites by combining Fe 3 O 4 and layered double hydroxide (LDH) to obtain a drug carrier for the targeted delivery of the anticancer drug berberine (Ber). We have confirmed that FA-PEG/Fe 3 O 4 @LDH exhibited a high drug loading capacity for Ber and excellent biocompatibility. Moreover, it demonstrated remarkable pH-responsive drug release (Ber release of 3.87% and 53.77% within 48 h at pH 7.4 and 5.0, respectively). The cellular experiments demonstrated that FA-PEG/Fe 3 O 4 @LDH@Ber exhibited significant inhibition of cellular activity, while the targeted release of Ber effectively depleted the overexpressed GSH and promoted ROS generation, thereby facilitating oxidative stress and inducing mitochondrial dysfunction in CAL27 cells, thus promoting apoptosis of CAL27 cells. Therefore, FA-PEG/Fe 3 O 4 @LDH can be used as a potential pH-controlled release drug delivery system which has great significance for the targeted therapy of OSCC.
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