Introduction: Immunoliposomes (ILs) are nano-delivery systems functionalized with monoclonal antibodies, with the aim of ameliorating the pharmacokinetics and tolerability of incapsulated drugs and permitting targeted therapy. Binding poly-ethylene-glycol (PEG) chains to their surface, thus obtaining stealth ILs (SILs), delays their elimination, which is mainly due to the clearance operated by the reticuloendothelial system (RES). Recently, to further improve their pharmacokinetic features, the super stealth immunoliposomes (SSIL) have been proposed, by adding mPEG-dendron-phospholipids. However, these nano-sized materials can accumulate in the liver and cause hepatic toxicity. Aims: To evaluate the in vivo liver toxicity of two formulations, one of stealth (SIL) and one of new super-stealth IL (SSIL2), both loaded with doxorubicin, in rats. Methods: A dose of 2.5 mg/kg of doxorubicin-loaded immunoliposomes (SIL and SSIL2) was administered via caudal vein to Sprague-Dawley female rats (n=3 per group) and vehicle-administered rats were used as controls. Rats were sacrificed 48 hours after the treatment. Hepatic toxicity of the formulations was assessed by: 1) standard histological analysis performed on 5-µm sections of liver tissues stained with H&E; 2) mRNA hepatic expression of IL-1b, IL-6 and TNF-a; 3) reactive oxygen species (ROS) in liver tissues. Results were compared by one-way ANOVA followed by Dunnett’s post-hoctest. p<0.05 was considered statistically significant. Results: SIL-treated rats showed histological alterations, i.e. numerous granulomatous lesions, sometimes associated with apoptotic bodies, whereas in SSIL2-treated animals only few isolated granulomas could be observed in the otherwise healthy livers. The hepatic expression of IL-1β and TNFα, and ROS concentration in the liver increased only in in SIL-treated rats (p <0.001 vs controls) and they were comparable to that of controls in SSIL2–treated rats. Conclusions:SSIL2s, besides their pharmacokinetic advantages, permit to overcome the hepatic toxicity caused by SIL, thus representing a smart strategy to improve the tolerability of cancer therapy.
Novel Super Stealth immunoliposomes for cancer targeted delivery of doxorubicin: an innovative strategy to reduce liver toxicity
Daniela Gabbia;Elena Canato;Valentina Carraro;Maria Guido;Gianfranco Pasut;Sara De Martin
2019
Abstract
Introduction: Immunoliposomes (ILs) are nano-delivery systems functionalized with monoclonal antibodies, with the aim of ameliorating the pharmacokinetics and tolerability of incapsulated drugs and permitting targeted therapy. Binding poly-ethylene-glycol (PEG) chains to their surface, thus obtaining stealth ILs (SILs), delays their elimination, which is mainly due to the clearance operated by the reticuloendothelial system (RES). Recently, to further improve their pharmacokinetic features, the super stealth immunoliposomes (SSIL) have been proposed, by adding mPEG-dendron-phospholipids. However, these nano-sized materials can accumulate in the liver and cause hepatic toxicity. Aims: To evaluate the in vivo liver toxicity of two formulations, one of stealth (SIL) and one of new super-stealth IL (SSIL2), both loaded with doxorubicin, in rats. Methods: A dose of 2.5 mg/kg of doxorubicin-loaded immunoliposomes (SIL and SSIL2) was administered via caudal vein to Sprague-Dawley female rats (n=3 per group) and vehicle-administered rats were used as controls. Rats were sacrificed 48 hours after the treatment. Hepatic toxicity of the formulations was assessed by: 1) standard histological analysis performed on 5-µm sections of liver tissues stained with H&E; 2) mRNA hepatic expression of IL-1b, IL-6 and TNF-a; 3) reactive oxygen species (ROS) in liver tissues. Results were compared by one-way ANOVA followed by Dunnett’s post-hoctest. p<0.05 was considered statistically significant. Results: SIL-treated rats showed histological alterations, i.e. numerous granulomatous lesions, sometimes associated with apoptotic bodies, whereas in SSIL2-treated animals only few isolated granulomas could be observed in the otherwise healthy livers. The hepatic expression of IL-1β and TNFα, and ROS concentration in the liver increased only in in SIL-treated rats (p <0.001 vs controls) and they were comparable to that of controls in SSIL2–treated rats. Conclusions:SSIL2s, besides their pharmacokinetic advantages, permit to overcome the hepatic toxicity caused by SIL, thus representing a smart strategy to improve the tolerability of cancer therapy.
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