Effect of co-treatment with doxorubicin and verapamil loaded into chitosan nanoparticles on diethylnitrosamine-induced hepatocellular carcinoma in mice

Abstract

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.

Mild Hyperthermia Responsive Liposomes for Enhanced In Vitro and In Vivo Anticancer Efficacy of Doxorubicin against Hepatocellular Carcinoma

“…In addition, the histopathological evaluation of the healed group ( Figure 7 C) presented the maximum amount of normal cells which might be attributed with the green signal regarding efficient treatment and healing of HCC through MTL1-E (AL) . The achieved results are well in accordance with the reported literature as well [ 32 , 52 ].…”

“…The optimized formulation (MTL1-E (AL) ) equivalent to 5 mg/Kg of Dox was administered to six mice through intraperitoneal injections as three doses weekly for three weeks (8th, 9th, and 10th week). Regarding an in vivo study, the selection of amounts of cancer inducing agent (83 mg/kg of body weight) and the equivalent amounts of Dox (5 mg/kg of body weight) in the optimized formulation (MTL1-E(AL)) was based on the already reported study [ 32 ]. One mice died during the dosing of the formulation, and the remaining five mice were also dissected at the mid of 11th week and subjected for histopathological study ( n = 5) by the protocols suggested by Pittala et al, 2018 [ 33 ].…”

Calotropis gigantea stem bark extracts inhibit liver cancer induced by diethylnitrosamine

“…TNF-α levels in cardiomyocytes increased in DEN-treated mice after DOX administration at 5 mg/kg for 4 weeks, indicating severe cardiotoxicity and cardiac hypertrophy 139 . After a single injection of 20 mg/kg DOX was given to mice for 72 h, blood TNF-α was likewise elevated, causing muscle weakness 140 .…”

“…It was hypothesized that the therapeutic and harmful effects of DOX were proportionate to increased blood concentration when DOX (7 mg/kg) was combined with ADI Z52020236, which comprises extracts of Astragali Radix , A. senticosus , Ginseng Radix , and Mylabris 145 . DOX and verapamil combined as an adjuvant treatment, on the other hand, improved anticancer activity in HepG2 cells, resulting in a positive outcome and reducing DOX's negative side effects 139 . Our findings demonstrated that combining CGDCM with a low dose of DOX (0.5 mg/kg) improved the anticancer activity of DOX by lowering inflammation-induced liver fibrosis and hepatocarcinogenesis, which was comparable to what was observed in the treatment of DEN-induced HCC by CGDCM.…”

Myocardial Cell Preservation from Potential Cardiotoxic Drugs: The Role of Nanotechnologies

“…Regarding other nanoparticle formulations, chitosan has been investigated in mice tumor models. Mansour et al [ 66 ] found improved lactic dehydrogenase and CK-MB values in hepatocellular carcinoma-bearing mice treated with doxorubicin-containing chitosan nanoparticles and verapamil, compared to values in mice treated with standard unloaded doxorubicin and verapamil.…”