Antitumor activity of lipophilic prodrugs of mitomycin C entrapped in liposome or O/W emulsion.

Abstract

Nine lipophilic la-N-substituted prodrugs of mitomycin C were formulated in lipid dispersion dosage forms and their fundamental antitumor activities were evaluated. The prodrugs were efficiently incorporated into liposome or O/W emulsion according to their increased lipophilicities , while mitomycin C was hardly entrapped into them. Almost complete incorporation was observed in nonyloxycarbonyl and cholesteryloxycarbonyl mitomycin C which showed partition coefficients over 8000 in chloroform/water system. The release rate from these dosage forms determined by a dynamic dialysis method decreased with an increase in the partition coefficients of the derivatives. All prodrugs entrapped in liposome or O/W emulsion showed significant antitumor activities against L1210 leukemia in i.p.-i.p. system except for cholesteryloxycarbonyl mitomycin C. In spite of considerable antitumor activities showen in the forms of liposome and emulsion, saline suspension of nonyloxycarbonyl mitomycin C failed to exhibit any activity because of its poor aqueous solubility. These results suggested the utility of the combining delivery system of lipophilic prodrug with physical device such as liposome and O/W emulsion.