Liposomal formulation and antitumor activity of 14-O-palmitoyl-hydroxyrubicin.

The 14-O-palmitoyl ester of 3'-deamino-3'-hydroxydoxorubicin was synthesized to study the liposomal formulation and biological activity properties conferred by the attachment of a lipophilic group to position 14 of the anthracycline molecule. The entrapment efficiency of 14-O-palmitoyl-hydroxyrubicin in multilamellar vesicles composed of dimyristoylphosphatidyl choline and dimyristoylphosphatidyl glycerol was greater than 99%. In addition, the stability of liposomes containing 14-O-palmitoyl-hydroxyrubicin was greater than 99% at 14 days as assessed by the amount of drug leaking out of the liposomes and the absence of crystals of free drug in the liposome pellet. Esterification at position 14 did not significantly decrease the potency of the parent compound 3'-hydroxydoxorubicin. Liposome-entrapped 14-O-palmitoyl-hydroxyrubicin was significantly more active than doxorubicin against two murine tumor models. Against ip L-1210 leukemia, liposome-entrapped 14-O-palmitoyl-hydroxyrubicin injected i.p. into mice at doses of 60 and 80 mg/kg resulted in a %T/C value (median survival of treated/control animals x 100) of greater than 600, with 3-4 of 6 animals being cured, whereas in the same experiments, doxorubicin injected at the optimal dose (10 mg/kg) resulted in a %T/C value of 340, with 1 of 6 animals being cured. In animals bearing liver metastases of M-5076 reticulosarcoma, liposome-entrapped 14-O-palmitoyl-hydroxyrubicin showed significant antitumor activity when given on a three-i.v.-injection schedule of 20 mg/kg on days 4, 8, and 12 (%T/C, 175), whereas doxorubicin injected at optimal doses of 6-8 mg/kg on the same days was devoid of antitumor activity (%T/C, 129-133). These results indicate that esterification at position 14 enhances the affinity of this type of compounds for lipid bilayers without negatively affecting their biological activity.