Pharmacokinetics and antitumor activity of epirubicin encapsulated in long-circulating liposomes incorporating a polyethylene glycol-derivatized phospholipid.

The antitumor activity of epirubicin (EPI) entrapped in long circulating "Stealth" liposomes containing a polyethylene glycol-derivatized phospholipid (S-EPI) was compared to epirubicin encapsulated in a conventional liposome formulation (L-EPI) and free epirubicin (F-EPI) against mouse colon 26 tumor in vivo. Pharmacokinetics of S-EPI and F-EPI were also compared in rats. F-EPI was distributed to tissues within minutes of injection. In contrast, when administered in the S-EPI formulation, the distribution half-life of the drug was over 22 hr. S-EPI also exhibited a reduced clearance compared to F-EPI, from 111 to less than 1.0 ml/hr. S-EPI inhibited tumor growth more effectively than F-EPI or L-EPI by causing tumors to regress and increasing survival of mice. There were 9/10 (S-EPI) compared to 0/10 (F-EPI) 120-day survivors when treatment was started 3 days after tumor implant. When treatment was delayed for 10 days, tumors, which had reached approx. 0.1-0.3 cm3 in volume, regressed in 8/10 animals receiving S-EPI, whereas in all animals treated with F-EPI the tumors progressed. L-EPI was no more effective therapeutically than F-EPI in this model. The maximum tolerated dose of S-EPI was higher than that of F-EPI. The enhanced therapeutic efficacy of S-EPI is probably related to the extended circulation time of the formulation and its accumulation in tumors.