This study aimed to investigate the potential role of co-treatment with doxorubicin (DOX) and verapamil (VRP) nanoparticles in experimentally induced hepatocellular carcinoma in mice and to investigate the possible mechanisms behind the potential favorable effect of the co-treatment. DOX and VRP were loaded into chitosan nanoparticles (CHNPs), and cytotoxicity of loaded and unloaded drugs against HepG2 cells was evaluated. Male albino mice were divided into eight groups (n = 15): (1) normal control, (2) diethylnitrosamine, (3) CHNPs, (4) free DOX, (5) CHNPs DOX, (6) free VRP, (7) CHNPs VRP, and (8) CHNPs DOX + CHNPs VRP. Either VRP or DOX loaded into CHNPs showed stronger growth inhibition of HepG2 cells than their free forms. DOX or VRP nanoparticles displayed pronounced anticancer activity in vivo through the decline of vascular endothelial growth factor and B cell lymphoma-2 contents in liver tissues, upregulation of antioxidant enzymes, and downregulation of multidrug resistance 1. Moreover, reduced cardiotoxicity was evident from decreased level of tumor necrosis factor-α and malondialdehyde in heart tissues coupled with decreased serum activity of creatine kinase-myocardial band and lactate dehydrogenase. Co-treatment with CHNPs DOX and CHNPs VRP showed superior results versus other treatments. Liver sections from the co-treatment group revealed the absence of necrosis, enhanced apoptosis, and nearly normal hepatic lobule architecture. Co-treatment with CHNPs DOX and CHNPs VRP revealed enhanced anticancer activity and decreased cardiotoxicity versus the corresponding free forms.

这项研究旨在调查与阿霉素（DOX）和维拉帕米（VRP）纳米粒子共同治疗在实验性诱导的小鼠肝细胞癌中的潜在作用，并探讨共同治疗潜在有利作用背后的可能机制。将DOX和VRP装入壳聚糖纳米颗粒（CHNP）中，并评估了已加载和未加载的药物对HepG2细胞的细胞毒性。将雄性白化病小鼠分为八组（n= 15）：（1）正常对照，（2）二乙基亚硝胺，（3）CHNP，（4）游离DOX，（5）CHNPs DOX，（6）游离VRP，（7）CHNPs VRP，和（8）CHNPs DOX + CHNPs VRP。加载到CHNPs中的VRP或DOX对HepG2细胞的生长抑制作用均强于其游离形式。DOX或VRP纳米颗粒通过降低肝脏组织中血管内皮生长因子和B细胞淋巴瘤2的含量，抗氧化酶的上调以及对多药耐药性1的下调，表现出明显的体内抗癌活性。此外，降低水平可明显降低心脏毒性组织中肿瘤坏死因子-α和丙二醛的水平降低，加上血清肌酸激酶-心肌带和乳酸脱氢酶的活性降低。与其他疗法相比，CHNPs DOX和CHNPs VRP共同治疗显示出更好的效果。联合治疗组的肝脏切片显示不存在坏死，细胞凋亡增强和几乎正常的肝小叶结构。与相应的游离形式相比，与CHNPs DOX和CHNPs VRP共同治疗显示增强的抗癌活性和降低的心脏毒性。