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 glycolderivatized 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 I I I to < 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.