Amelioration of the therapeutic efficacy of 5-Flurouracil loaded chitosan nanoparticles in experimentally induced Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The most important risk factor for the development of HCC is cirrhosis regardless of etiology. 5-Fluorouracil (5-FU) is widely used in the treatment of cancer. Drug resistance remains a significant limitation to the clinical use of 5-FU. The present study aimed to evaluate the therapeutic efficacy of 5-FU loaded chitosan nanoparticles in experimentally induced HCC. To achieve our purpose, one hundred and five male Swiss Albino mice were divided randomly into two major groups:  Group A: comprised 25 mice served as normal control, Group B: comprised 80 mice received a daily oral dose of 0.06% DAB (165 mg/kg body.wt.) for 30 days after which the water was replaced with 0.05% aqueous solution of Phenobarbital (PB). Five chosen mice randomly from groups A and B at the time intervals 15, 30, 45 and 60 days were sacrificed to follow up with the development of HCC by biochemical and histopathological examination. Animals of group B were divided into 3 groups Group I: included 20 mice served as an untreated group, group II: included 20 mice injected intraperitoneally with 5-FU only (40mg/kg body.wt) every 2 days for 16 days, group III:  included 20 mice injected intraperitoneally with 5-FU Cs NPs. Each group was further divided into two subgroups 10 mice each, one subgroup treated with ultrasonic waves; meanwhile the other subgroup without ultrasonic waves exposure. At the end of the experiment, animals were sacrified, serum ALT, hepatic ALT, and hepatic MDA were estimated; HCC was histopathologically monitored in all studied groups. There was 276.5%, 145.7%and 438.5% increase in serum ALT, hepatic ALT and hepatic MDA levels respectively comparing to the corresponding control. Liver tumors that ultimately became neoplastic were produced after 45 days. US exposure triggered a significant decline in serum and hepatic ALT activity (P = 0.001) and in hepatic MDA (P = 0.009) within 5-FU loaded Cs NPs group. Moreover, tumor growth delay and more enhanced correction in hepatic architecture was obtained by a combination of US and 5-FU loaded Cs NPs therapy. Based on these results, we can conclude that the use of 5-FU loaded chitosan nanoparticles in combination with low-intensity ultrasound ameliorates the efficacy of 5-FU as anticancer therapy for HCC.