ABSTRACT
The purpose of the present study was to develop the Solutol HS15-based doxorubicin submicron emulsion with good stability and overcoming multi-drug resistance. In this study, we prepared doxorubicin submicron emulsion, and examined the stability after autoclaving, the in vitro cytotoxic activity, the intracellular accumulation and apoptpsis of doxorubicin submicron emulsion in MCF-7/ADR cells. The physicochemical properties of doxorubicin submicron emulsion were not significantly affected after autoclaving. The doxorubicin submicron emulsion significantly increased the intracellular accumulation of doxorubicin submicron emulsion and enhanced cytotoxic activity and apoptotic effects of doxorubicin. These results may be correlated to doxorubicin submicron emulsion inhibitory effects on efflux pumps through the progressive release of intracellular free Solutol HS15 from doxorubicin submicron emulsion. Furthermore, these in vitro results suggest that the Solutol HS15-based submicron emulsion may be a potentially useful drug delivery system to circumvent multi-drug resistance of tumor cells.
ABSTRACT
The isolated rat liver mitochondria were used in vitro to study the effect of doxorubicin on lipid peroxidation. We found that NADH-dependent mitochondrial peroxidation, measured by thiobarbituric acid (TBA) method, was stimulated to fourfold by doxorubicin (50 mumol.L-1). The addition of Fe3+ produced a significant increase of malondialdehyde (MDA) formation induced by doxorubicin. Doxorubicin enhanced the peroxidation of lipids in liver mitochondria through enzymatic mechanism especially in the presence of Fe3+. Probimane, bimolane, dexrazoxane (dioxopiperazine compounds), and edetic acid (EDTA) inhibited the formation of MDA in doxorubicin or doxorubicin+FeCl3 systems in a concentration-dependent manner. The inhibitory rates of MDA formation by probimane at the concentrations of 0.01, 0.05, 0.1, and 0.25 mmol.L-1 were 27.80%, 25.19%, 47.80%, and 59.77% respectively; bimolane were 21.04%, 25.55%, 24.83%, and 54.13%; dexrazoxane were 11.29%, 20.68%, 34.94%, and 58.65%; EDTA were 57.52%, 55.67%, 61.62%, and 63.16% in Dox and FeCl3 system. The inhibitory rates of MDA formation by probimane at concentration 0.01, 0.05, 0.1, and 0.25 mmol.L-1 were 19.27, 39.02, 59.60, and 58.63% respectively; bimolane were 6.10, 17.19, 41.58, and 53.22%; dexrazoxane were 27.24, 33.26, 58.21, and 59.11%; EDTA were 63.76, 67.43, 61.68, and 63.27% respectively in Dox system. These results suggested that protection against cardiotoxicity of doxorubicin afforded by probimane, bimolane, and dexrazoxane may be related to their ability to combine with the complex iron so that the iron was no longer able to take part in free radical reactions.
Subject(s)
Doxorubicin/pharmacology , Edetic Acid/pharmacology , Malondialdehyde/metabolism , Mitochondria, Liver/metabolism , Razoxane/analogs & derivatives , Animals , Antineoplastic Agents/pharmacology , Chlorides , Ferric Compounds/pharmacology , In Vitro Techniques , Male , Rats , Rats, Sprague-Dawley , Razoxane/pharmacologyABSTRACT
Distribution of [14C] AT-1902 in mice was studied by means of whole body autoradiography. After [14C] AT-1902 was injected im to mice, radioactivity was rapidly taken up by various organs. The highest radioactivity was found in kidneys, then the liver, lung, tumor and skin etc. Lowest radioactivity was found in brain. It is suggested that [14C] AT-1902 may be excreted through the gastrointestinal tract and kidneys.
