TOXICITY OF DOXORUBICIN ENTRAPPED WITHIN LONG-CIRCULATING LIPOSOMES

We studied the effect of doxorubicin entrapped within long-circulating liposomes (Dox-LCL) on the phagocytic capacity and bacterial blood cl earance capacity of rat liver macrophages. Dox-LCL (125 nm in diameter ) were composed of egg phosphatidylcholine (PC), cholesterol (CH) and (ethyleneglycol)distearoylphosphatidylethanolamine (PEG-PE) (55:45:5 m olar ratio; MW PEG 1900), and loaded with doxorubicin by means of a tr ans-membrane pH gradient. The doxorubicin/lipid ratio was 0.36:1 (mol/ mol). At different time-points after one, two or three intravenous inj ections of Dox-LCL, radiolabeled negatively charged test liposomes (eg g PC, CH, and phosphatidylserine in a 4:5:1 molar ratio) were injected . After 2 h, liver macrophages were isolated and the amount of macroph age-associated radioactivity was determined. Twenty-four hours after a single injection of 5 mg/kg Dox-LCL, no significant effect was observ ed. However, 48 h after injection, phagocytic activity was reduced sig nificantly (49%). Recovery of phagocytic capacity of the liver macroph ages took 8 days after two injections of Dox-LCL (2 x 5 mg/kg). Sevent y-two hours after the last of two injections of Dox-LCL, bacterial blo od clearance was significantly reduced as compared to clearance in con trol rats and in rats injected twice with doxorubicin combined with pl acebo liposomes. When comparing these Dox-LCL data with previous data on the effects of Dox-L, Dox-LCL appears less toxic than Dox-L for the liver macrophage population following i.v. administration both with r espect to specific phagocytic activity and cell numbers. Due to the de lay in onset of toxic effects and the faster recovery from Dox-LCL tre atment as compared to Dox-L treatment, it is conceivable that therapeu tic protocols can be designed with Dox-LCL that circumvent long-term i mpairment of the liver macrophage population.