双硫仑负载纳米颗粒抑制脂肪细胞的长期增殖

IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY
International Journal of Nanomedicine Pub Date : 2024-12-10 eCollection Date: 2024-01-01 DOI:10.2147/IJN.S467909
Helen Yarimet Lorenzo-Anota, José María Gómez-Cantú, Eduardo Vázquez-Garza, Judith Bernal-Ramirez, Héctor Chapoy-Villanueva, Karla Mayolo-Deloisa, Jorge Benavides, Marco Rito-Palomares, Omar Lozano
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引用次数: 0

摘要

简介双硫仑(DSF)可减少肥胖小鼠的胰岛素抵抗和体重增加。然而,由于其在生理条件下的高度不稳定性,其对脂肪组织的影响尚未得到研究,从而限制了其临床应用。因此,开发一种可持续释放到脂肪组织的 DSF 载体很有意义。我们优化了负载 DSF 的聚-ε-己内酯(PCL)纳米颗粒(NPs)的合成,并在体外分析了它们对脂肪组织细胞的影响:采用纳米沉淀法合成 NPs,改变其溶剂丙酮或丙酮/二氯甲烷(60:40)(v/v),以及 PCL:DSF(w/w)的比例 1:2、1:1、2:1 和 1:0;发现丙酮/二氯甲烷混合溶剂和 2:1 PCL:DSF 的条件最佳。然后,分析了 NPs 对脂肪细胞(前脂肪细胞、白样脂肪细胞和巨噬细胞)的毒性,评估了 NPs 的结合和内化、细胞活力和细胞死亡机制:NPs 呈球形,粒度分布为 203.2 ± 29.33 nm,ζ电位为 -20.7 ± 4.58 mV,PDI 为 0.296 ± 0.084,物理载药量为 18.6 ± 5.80%。在生理条件下,从 0.5 小时(10.94 ± 2.38%)到 96 小时(91.20 ± 6.03%),观察到持续释放。NPs 内化到巨噬细胞、类白色脂肪细胞和前脂肪细胞中,不会改变类白色脂肪细胞和巨噬细胞的细胞活力。前脂肪细胞会降低细胞活力,诱导线粒体损伤、线粒体活性氧生成增加和线粒体膜电位丧失,导致效应 Caspases 3/7 被裂解,从而导致细胞凋亡。最后,还观察到了长期增殖抑制作用,这表明 PCL-DSF NPs 与游离 DSF 相比具有生物等效性:我们的数据证明了 PCL NPs 与脂肪细胞在体外的生物相互作用。与游离药物相比,纳米封装的 DSF 对前脂肪细胞的选择性细胞毒性作用更弱。这些结果表明,在脂肪组织中长期递送 DSF 的药理学替代品大有可为。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Disulfiram-Loaded Nanoparticles Inhibit Long-Term Proliferation on Preadipocytes.

Introduction: Disulfiram (DSF) reduces insulin resistance and weight gain in obese mice. However, the effect on adipose tissue is unexplored due to their high instability under physiological conditions, limiting clinical applications. Thus, it is meaningful to develop a DSF carrier for sustained release to adipose tissue. We optimized the synthesis of poly-ε-caprolactone (PCL) nanoparticles (NPs) loaded with DSF and analyzed their effect on adipose tissue cells in vitro.

Methods: The NPs were synthesized by nanoprecipitation method, varying its solvent, either acetone or acetone/dichloromethane (60:40) (v/v), and ratio PCL:DSF (w/w) 1:2, 1:1, 2:1 and, 1:0; finding the best condition was obtained with acetone/dichloromethane solvent mixture and 2:1 PCL:DSF. Then, NPs toxicity was analyzed on adipose cells (preadipocytes, white-like adipocytes, and macrophages) assessing association and internalization, cell viability, and cell death mechanism.

Results: NPs were spherical with a particle size distribution of 203.2 ± 29.33 nm, a ζ-potential of -20.7 ± 4.58 mV, a PDI of 0.296 ± 0.084, and a physical drug loading of 18.6 ± 5.80%. Sustained release was observed from 0.5 h (10.94 ± 2.38%) up to 96 h (91.20 ± 6.03%) under physiological conditions. NPs internalize into macrophages, white-like adipocytes and preadipocytes without modifying cell viability on white-like adipocytes and macrophages. Preadipocytes reduce cell viability, inducing mitochondrial damage, increased mitochondrial reactive oxygen species production and loss of mitochondrial membrane potential, leading to effector caspases 3/7 cleaved, resulting in apoptosis. Finally, long-term proliferation inhibition was observed, highlighting the bioequivalent effect of PCL-DSF NPs compared to free DSF.

Conclusion: Our data demonstrated the biological interaction of PCL NPs with adipose cells in vitro. The selective cytotoxicity of DSF towards preadipocytes resulted in milder effects when it was delivered nanoencapsulated compared to the free drug. These results suggest promising pharmacological alternatives for DSF long-term delivery on adipose tissue.

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来源期刊
International Journal of Nanomedicine
International Journal of Nanomedicine NANOSCIENCE & NANOTECHNOLOGY-PHARMACOLOGY & PHARMACY
CiteScore
14.40
自引率
3.80%
发文量
511
审稿时长
1.4 months
期刊介绍: The International Journal of Nanomedicine is a globally recognized journal that focuses on the applications of nanotechnology in the biomedical field. It is a peer-reviewed and open-access publication that covers diverse aspects of this rapidly evolving research area. With its strong emphasis on the clinical potential of nanoparticles in disease diagnostics, prevention, and treatment, the journal aims to showcase cutting-edge research and development in the field. Starting from now, the International Journal of Nanomedicine will not accept meta-analyses for publication.
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