INTRATUMOR DISTRIBUTION OF DOXORUBICIN FOLLOWING IV ADMINISTRATION OFDRUG ENCAPSULATED IN EGG PHOSPHATIDYLCHOLINE CHOLESTEROL LIPOSOMES/

Purpose: A pharmacological evaluation of an egg phosphatidylcholine/ch olesterol (55:45 mole ratio, EPC/Chol) liposome doxorubicin formulatio n was carried out. The objective was to define liposomal lipid and dru g distribution within sites of tumor growth following intravenous (i.v .) administration to female BDF1 mice bearing either Lewis lung carcin oma, B16/BL6 melanoma, or L1210 ascitic tumors. Methods: Mice were inj ected i.v. with EPC/Chol liposomal doxorubicin, and plasma and tumor l evels of lipid and drug were determined 1, 4 and 24 h later with radio labeled lipid and fluorimetry or fluorescence microscopy, respectively , In addition, single-cell suspensions of the Lewis lung and B16/BL6 t umors were prepared and the presence of macrophages was determined wit h an FITC-labeled rat antimouse CD11b (MAC-I) antibody. Results: For m ice bearing the Lewis lung solid tumors, there was a time-dependent ac cumulation of liposomal lipid, with a plateau of approximately 500 mu g lipid/g tumor at 48 h. In contrast, the apparent plateau (Gig doxoru bicin/g tumor) for doxorubicin was achieved at 1 h and remained consta nt over a 72-h time course. In comparison with free drug administered at the maximum tolerated dose (MTD, 20 mg/kg) doxorubicin levels in tu mors were two- to threefold greater when the drug was administered in liposomal form. The increase in drug delivery was comparable for both solid tumors. With animals bearing the L1210 ascitic tumor, drug expos ure was as much as ten times greater (in comparison with free drug) wh en doxorubicin was administered in liposomes, An evaluation of single- cell suspensions prepared from the two solid tumors suggested that mor e than 98% of the tumor-associated drug and liposomal lipid was not tu mor cell-associated, Histological studies with the Lewis lung carcinom a, however, revealed that a proportion of the drug did colocalize with tumor-associated macrophages, Analysis of cells obtained from mice be aring ascitic tumors showed that more than 80% of the cell-associated drug could be removed by procedures designed to remove adherent cells. Conclusion: The results summarized here suggest drug concentrations w ithin a solid tumor, such as the Lewis lung carcinoma, are constant ov er time when the drug is given in a ''leaky'' EPC/Chol formulation. Th e results also suggest that liposomal lipid within sites of tumor grow th is primarily localized within the interstitial spaces or tumor-asso ciated macrophages.