Abstract
Drug-induced hepatotoxicity is one of the major barriers limiting application of current pharmaceuticals as well as clinical translation of novel and perspective drugs. In this context, numerous hepatoprotective molecules have been proposed to prevent or mitigate drug-induced hepatotoxicity. To date, silibinin (SBN) is a one the most studied hepatoprotective plant-derived agents for prevention/alleviation of drug-induced liver injury. Hepatoprotective mechanisms of SBN include scavenging of free radicals, upregulation of detoxifying enzymes via Nrf2 activation and inhibition of inflammatory activation of resident macrophages. However, low solubility of this phytochemical in water prevents its intravenous administration and constrains its bioavailability and efficacy. Here, we developed SBN-loaded poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles for intravenous administration aiming at mitigation of drug-induced hepatotoxicity. Obtained nanoparticles demonstrated a slow drug release profile in vitro and caused upregulation of antioxidant and phase II enzymes in AML12 hepatocytes including superoxide dismutase 2, glutathione-S-transferase P1, and glutathione-reductase. Intravenous administration of PLGA nanoparticles to mice led to their fast liver accumulation. In vivo analysis of hepatoprotective effects of PLGA/SBN nanoparticles was carried out on melanoma tumor-bearing syngeneic mouse model treated with the antineoplastic drug dacarbazine (DTIC), which often causes severe hepatotoxicity including development of veno-occlusive disease. It was found that PLGA/SBN caused effective induction of detoxifying liver enzymes. Moreover, pre-treatment with PLGA/SBN nanoparticles reduced elevated transaminase and bilirubin levels in blood, caspase 3 activation, and morphological histology changes in liver tissue upon DTIC treatment. Treatment with PLGA/SBN nanoparticles did not interfere with therapeutic efficacy of DTIC.
Highlights
Drug-induced liver injury remains a serious problem during pharmaceutical treatment of different diseases including cancer
In spite of high therapeutic efficacy, numerous studies report hepatotoxic adverse effects related with DTIC treatment including elevated liver enzymes and hepatic vascular toxicity (Erichsen and Jönsson, 1984; McClay et al, 1987; Ceci et al, 1988; Vincenzi et al, 2016)
In a syngeneic model of melanoma tumor-bearing mice we showed that pre-treatment with an intravenous poly(lactic-co-glycolic) acid (PLGA)/SBN formulation significantly reduced DTIC-induced liver toxicity without therapeutic efficacy interference of chemotherapy
Summary
Drug-induced liver injury remains a serious problem during pharmaceutical treatment of different diseases including cancer. DTIC is a very effective alkylating cytotoxic agent generally prescribed for the treatment of malignant melanoma, soft tissues sarcoma, classical Hodgkin’s and non-Hodgkin’s lymphoma (Marchesi et al, 2007). In spite of high therapeutic efficacy, numerous studies report hepatotoxic adverse effects related with DTIC treatment including elevated liver enzymes and hepatic vascular toxicity (Erichsen and Jönsson, 1984; McClay et al, 1987; Ceci et al, 1988; Vincenzi et al, 2016). Hepatotoxic effects of DTIC are related with inhibition of DNA, RNA and protein synthesis due to its alkylating activity (Vincenzi et al, 2016). The main contribution to liver injury is associated with generation of the reactive oxygen species after DTIC treatment (Pourahmad et al, 2009)
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