FLUORESCENCE IMAGING STUDIES FOR THE DISPOSITION OF DAUNORUBICIN LIPOSOMES (DAUNOXOME) WITHIN TUMOR-TISSUE

Unilamellar liposomes that retain their contents in the systemic circu lation can alter the pharmacokinetics of anticancer agents in favorabl e ways, It has long been recognized that certain liposome compositions will extravasate at sites of growing tumors and may increase the loca l drug concentration substantially above that achievable with a free d rug, We report here that liposomes can alter the in vivo disposition o f an entrapped drug not only on a macroscopic but also on a microscopi c scale, We show through ill vitro studies that intact liposomes compo sed of distearoylphosphatidylcholine and cholesterol and containing da unorubicin (Dauno-Xome) are taken up into P1798 tumor cells, These lip osomes produce an enhanced cytotoxicity relative to the free drug for incubation times longer than about 8 h, For in vivo studies, we develo ped and used a noninvasive fluorescence imaging technique to follow th e accumulation of liposomal daunorubicin within murine tumors, With th is method, we show that the maximum concentration of the available lip osomal drug in tumors exceeds that of the free drug, and additionally, liposomal daunorubicin persists at high levels for several days, Tota l liposome-delivered drug fluorescence from whole tumor extracts peaks at about 8 h, In comparison, the fluorescence intensity of daunorubic in released from vesicles seen with the in vivo imaging experiment pea ks at 28-32 h, This apparent delay is due to a sustained release of th e drug from liposomes in the tumor, Fluorescence microscopy of thin se ctions of tumors from animals injected i.v. with liposomal daunorubici n demonstrate persistent high levels of daunorubicin fluorescence with in cells and throughout the tumor masses, Free daunorubicin, in contra st, transiently achieves modest levels of fluorescence and rapidly dro ps to background within a few h, These results indicate distinct mecha nisms for the localization of free and liposomal daunorubicin, suggest ing that liposomal daunorubicin can provide sustained intracellular le vels of the drug within the tumor.