Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Int J Pharm. 2024 Dec 25;667(Pt A):124897. doi: 10.1016/j.ijpharm.2024.124897. Epub 2024 Nov 1.
The development of effective therapeutic strategies for triple-negative breast cancer (TNBC), an aggressive subtype with limited treatment options, remains a critical challenge. This study aimed to design and evaluate a combination therapy using chitosan nanoparticles (Cs NPs) loaded with metformin (Met) and methotrexate (MTX) as a promising approach for TNBC management. The Cs NPs exhibited an average size of 78.8 ± 25.84 nm for blank Cs NPs, 84.50 ± 22.54 nm for Met-Cs NPs, and 86.70 ± 30.90 nm for MTX-Cs NPs, with positive surface charges of 26.40 ± 1.40 mV, 28.20 ± 1.60 mV, and 14.30 ± 2.40 mV, respectively. The drug encapsulation efficiency was 88.56 ± 2.26 % for Met-Cs NPs and 97.03 ± 0.52 % for MTX-Cs NPs. The cellular uptake studies demonstrated a time-dependent increase in the accumulation of Shikonin-labeled Cs NPs in 4T1 cells. The cytotoxicity assays revealed that Met-Cs NPs and MTX-Cs NPs exhibited significantly lower IC50 values (19.85 μg/mL and 103.2 ng/mL, respectively) compared to the plain drugs at 48 h. The combination of Met-/MTX-Cs NPs showed a synergistic cytotoxic effect, inducing 50 % cell death at 15.233 μg/mL of Met and 0.166 μg/mL of MTX. In vivo studies using a 4T1 xenograft mouse model demonstrated that the combination of Met-/MTX-Cs NPs resulted in a 100 % reduction in initial tumor volume, compared to a 40 % decrease with the free drug combination. The tumor growth inhibition was 70.45 % for the Met-/MTX-Cs NPs group, significantly higher than the 33.86 % observed in the free drug combination group. The findings of this study highlight the potential of the Met-/MTX-Cs NPs combination as a novel and effective therapeutic approach for TNBC management. The enhanced therapeutic efficacy, improved safety profile, and the ability to modulate key signaling pathways make this nanoparticle-based combination therapy a promising candidate for further clinical investigation.
设计并评价了一种载二甲双胍（Met）和甲氨蝶呤（MTX）的壳聚糖纳米粒（Cs NPs）联合治疗作为三阴性乳腺癌（TNBC）管理的有前途的方法。空白 Cs NPs 的平均粒径为 78.8±25.84nm，Met-Cs NPs 为 84.50±22.54nm，MTX-Cs NPs 为 86.70±30.90nm，表面正电荷分别为 26.40±1.40mV、28.20±1.60mV 和 14.30±2.40mV。Met-Cs NPs 的药物包封效率为 88.56±2.26%，MTX-Cs NPs 的药物包封效率为 97.03±0.52%。Shikonin 标记的 Cs NPs 在 4T1 细胞中的细胞摄取研究表明，细胞内摄取随时间的增加而增加。细胞毒性测定表明，Met-Cs NPs 和 MTX-Cs NPs 在 48 h 时的 IC50 值（分别为 19.85μg/mL 和 103.2ng/mL）明显低于相应的游离药物。Met-/MTX-Cs NPs 联合具有协同细胞毒性作用，在 15.233μg/mL Met 和 0.166μg/mL MTX 时诱导 50%的细胞死亡。在 4T1 异种移植小鼠模型中的体内研究表明，与游离药物组合相比，Met-/MTX-Cs NPs 的组合导致初始肿瘤体积减少 100%。Met-/MTX-Cs NPs 组的肿瘤生长抑制率为 70.45%，明显高于游离药物组合组的 33.86%。这项研究的结果强调了 Met-/MTX-Cs NPs 联合作为 TNBC 管理的一种新的有效治疗方法的潜力。增强的治疗效果、改善的安全性和调节关键信号通路的能力使这种基于纳米颗粒的联合治疗成为进一步临床研究的有前途的候选药物。
