THE ROLE OF TUMOR-ASSOCIATED MACROPHAGES IN THE DELIVERY OF LIPOSOMALDOXORUBICIN TO SOLID MURINE FIBROSARCOMA TUMORS

Murine fibrosarcoma tumors arising from subcutaneous inoculation of FS a-N cells exhibit 4-fold higher tumor-associated macrophage (TAM) leve ls than those from the FSa-R line. These solid tumors were used to ass ess the role of TAMs in the accumulation of liposomal anticancer drugs . Two liposomal formulations of doxorubicin were investigated: a conve ntional formulation composed of distearoylphosphatidylcholine (DSPC) a nd cholesterol and a sterically stabilized liposomal formulation compo sed of DSPC/cholesterol/poly (ethylene glycol)-modified distearoylphos phatidyethanolamine (PEG-PE). Circulating concentrations of PEG-PE con taining liposomes 24 h after i.v. administration were 3-fold greater t han those observed after administration of conventional liposomes. No differences were observed in drug retention or tumor (FSa-R or FSa-N) drug and liposomal lipid delivery when comparisons were made between d ifferent liposomal formulations. However, tumor doxorubicin concentrat ions were increased as much as 4-fold for liposomal formulations relat ive to free drug. Further, there was a 1.5- to 2-fold increase in doxo rubicin delivery to TAM-enriched FSa-N tumors compared with FSa-R tumo rs. Fluorescence microscopy studies revealed a poor correlation betwee n CD11b (Mac-1) positive cells (TAMs) and the appearance of doxorubici n fluorescence, These results suggest that uptake of liposomal drugs b y TAMs does not account for the enhanced accumulation of liposomal dru gs in solid tumors. Rather, the increased tumor drug delivery may be r elated to alternative TAM-mediated processes that increase tumor vascu lar permeability. Therapeutic studies demonstrated that increased tumo r drug uptake observed for the liposomal doxorubicin formulations led to marginal improvements in antitumor activity, and it is suggested th at much of the drug delivered in liposomal form is not biologically av ailable.