Reduction toxicity by doxorubicin entrapped in liposomes nanocapsules

Doxorubicin induced an irreversible congestive heart failure, renal and hematological toxicity that are often fatal. The molecular mechanisms involved are only partially known and are complex and different from the anticancer mechanism involving oxidative stress. Encapsulation of doxorubicine in liposomes was elaborated in order to prevent the toxicity observed with the free form. The study was conducted in vivo by treatment of Wistar rats with doxorubicin encapsulated in liposomes or naked at different doses (10, 20 and 30mg/kg) and in vitro on H9c2 cells. In addition to the oxidative status, different mitochondrial parameters (CR, Swelling, bioenergy...) were evaluated. The study is complemented by MTT and LDH tests.

In vivo doxorubicin causes oxidative stress more pronounced than liposomal doxorubicin. A activity inhibition cytochrome c oxidase, depletion of tissue glutathione concomitant with increased production of ROS, swelling of mitochondria are observed. The mitochondrial dysfunction at origin of the cardioticity is confirmed by the MTT assay and LDH test. We observed also renal dysfunction and aplasia in blood, spleen and bone marrow more serious with naked doxorubicin than with the encapsulated one.

In conclusion, doxorubicin would be responsible for cytotoxicity by apoptosis involving the mitochondria. Theses disorders may be prevented by its encapsulation in liposomes.

Keywords: Cardiotoxicity, Nephrotoxicity, Haematotoxicity, Doxorubicin, Liposomes, Oxidative stress

References: 1. Plassat V et al. (2007) Int J Pharm 118–127.

2. Leite A et al. (2007) Life Sciences 80: 1327–34.

3. Lahouel M et al. (1987) Drugs Exptl Clin Res 10: 593–599.