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Fluorescence Imaging Studies for the Disposition of Daunorubicin Liposomes (DaunoXome) within Tumor Tissue¹

NeXstar Pharmaceuticals, Inc., San Dimas, California 91773 [E. A. F., R. M-B., J. P. A-M., M. J. A. L., P. G. S.], and Beckman Laser Institute and Medical Clinic, University of California, Irvine, California 92715 [T. B. K., S. S., B. J. T.]

Unilamellar liposomes that retain their contents in the systemic circulation can alter the pharmacokinetics of anticancer agents in favorable ways. It has long been recognized that certain liposome compositions will extravasate at sites of growing tumors and may increase the local drug concentration substantially above that achievable with a free drug. We report here that liposomes can alter the in vivo disposition of an entrapped drug not only on a macroscopic but also on a microscopic scale. We show through in vitro studies that intact liposomes composed of distearoylphos-phatidylcholine and cholesterol and containing daunorubicin (Dauno-Xome) are taken up into P1798 tumor cells. These liposomes produce an enhanced cytotoxicity relative to the free drug for incubation times longer than about 8 h. For in vivo studies, we developed and used a noninvasive fluorescence imaging technique to follow the accumulation of liposomal daunorubicin within murine tumors. With this method, we show that the maximum concentration of the available liposomal drug in tumors exceeds that of the free drug, and additionally, liposomal daunorubicin persists at high levels for several days. Total liposome-delivered drug fluorescence from whole tumor extracts peaks at about 8 h. In comparison, the fluorescence intensity of daunorubicin released from vesicles seen with the in vivo imaging experiment peaks at 28–32 h. This apparent delay is due to a sustained release of the drug from liposomes in the tumor. Fluorescence microscopy of thin sections of tumors from animals injected i.v. with liposomal daunorubicin demonstrate persistent high levels of daunorubicin fluorescence within cells and throughout the tumor masses. Free daunorubicin, in contrast, transiently achieves modest levels of fluorescence and rapidly drops to background within a few h. These results indicate distinct mechanisms for the localization of free and liposomal daunorubicin, suggesting that liposomal daunorubicin can provide sustained intracellular levels of the drug within the tumor.

¹ This work was made possible, in part, through access to the Laser Microbeam and Medical Program (LAMMP) and the Cancer Center Optical Biology Resource at the University of California, Irvine (supported by NIH Grants RR-01192, CA-62203, and R29GM50958), by Department of Energy Grant DE-FG03-91ER61227 to the Beckman Laser Institute and Medical Clinic, and by Office of Naval Research Grant N00014-91-C-0134).

² To whom requests for reprints should be addressed, at NeXstar Pharmaceuticals, Inc., 650 Cliffside Drive, San Dimas, CA 91773.

Received 8/ 1/95. Accepted 3/ 4/96.

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