利用优化的壳聚糖纳米颗粒联合递送二甲双胍和甲氨蝶呤，在体内协同治疗三阴性乳腺癌。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics Pub Date : 2024-11-01 DOI:10.1016/j.ijpharm.2024.124897

Alireza Karimian-Shaddel , Hamed Dadashi , Milad Mashinchian , Aria Mohabbat , Amir Reza Nazemiyeh , Somayeh Vandghanooni , Morteza Eskandani

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引用次数: 0

摘要

三阴性乳腺癌（TNBC）是一种侵袭性亚型癌症，治疗方案有限，开发有效的治疗策略仍是一项严峻的挑战。本研究旨在设计和评估一种使用壳聚糖纳米颗粒（Cs NPs）负载二甲双胍（Met）和甲氨蝶呤（MTX）的联合疗法，作为治疗 TNBC 的一种有前景的方法。空白Cs NPs的平均尺寸为78.8 ± 25.84 nm，Met-Cs NPs的平均尺寸为84.50 ± 22.54 nm，MTX-Cs NPs的平均尺寸为86.70 ± 30.90 nm，表面正电荷分别为26.40 ± 1.40 mV、28.20 ± 1.60 mV和14.30 ± 2.40 mV。Met-Cs NPs 的药物封装效率为 88.56 ± 2.26 %，MTX-Cs NPs 为 97.03 ± 0.52 %。细胞摄取研究表明，Shikonin 标记的 Cs NPs 在 4T1 细胞中的积累随时间而增加。细胞毒性实验显示，与普通药物相比，Met-Cs NPs 和 MTX-Cs NPs 在 48 小时内的 IC50 值（分别为 19.85 μg/mL 和 103.2 ng/mL）明显较低。Met-/MTX-Cs NPs 组合显示出协同细胞毒性效应，当 Met 为 15.233 μg/mL 和 MTX 为 0.166 μg/mL 时，可诱导 50% 的细胞死亡。使用 4T1 异种移植小鼠模型进行的体内研究表明，Met-/MTX-Cs NPs 组合可使初始肿瘤体积缩小 100%，而游离药物组合则缩小 40%。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%。这项研究的结果凸显了Met-/MTX-Cs NPs组合作为一种新颖有效的TNBC治疗方法的潜力。疗效的提高、安全性的改善以及调节关键信号通路的能力使这种基于纳米粒子的联合疗法成为有望进一步临床研究的候选药物。

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Codelivery of metformin and methotrexate with optimized chitosan nanoparticles for synergistic triple-negative breast cancer therapy in vivo

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Codelivery of metformin and methotrexate with optimized chitosan nanoparticles for synergistic triple-negative breast cancer therapy in vivo

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.

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来源期刊

International Journal of Pharmaceutics 医学-药学

CiteScore

10.70

自引率

8.60%

发文量

951

审稿时长

72 days

期刊介绍： The International Journal of Pharmaceutics is the third most cited journal in the "Pharmacy & Pharmacology" category out of 366 journals, being the true home for pharmaceutical scientists concerned with the physical, chemical and biological properties of devices and delivery systems for drugs, vaccines and biologicals, including their design, manufacture and evaluation. This includes evaluation of the properties of drugs, excipients such as surfactants and polymers and novel materials. The journal has special sections on pharmaceutical nanotechnology and personalized medicines, and publishes research papers, reviews, commentaries and letters to the editor as well as special issues.