PLASMA-CLEARANCE, BIODISTRIBUTION AND THERAPEUTIC PROPERTIES OF MITOXANTRONE ENCAPSULATED IN CONVENTIONAL AND STERICALLY STABILIZED LIPOSOMES AFTER INTRAVENOUS ADMINISTRATION IN BDF1 MICE

Mitoxantrone can be efficiently loaded into large unilamellar vesicles using a transmembrane pH gradient. Release studies indicate that thes e drug-loaded carriers are highly stable and even after dissipation of the residual pH gradient retain more than 85% of encapsulated mitoxan trone following dialysis at 37 degrees C for 5 days. in murine studies we have compared the plasma clearance and biodistribution of both mit oxantrone and liposomal lipid following intravenous administration of free drug or mitoxantrone encapsulated in either conventional or steri cally stabilized liposomes. In contrast to the rapid blood clearance o bserved for free mitoxantrone, both liposomal systems provided extende d circulation lifetimes, with over 90% of the drug present 1 h after a dministration and 15-30% remaining at 24 h. In agreement with previous reports, longer plasma half-lives were observed for sterically stabil ized liposomes than for conventional systems. In addition, a strong co rrelation between drug and carrier biodistribution was seen, with upta ke occurring mainly in the liver and spleen and paralleling plasma cle arance. This would suggest that tissue disposition reflects that of dr ug-loaded liposomes rather than the individual components. Liposomal e ncapsulation also significantly reduced mitoxantrone toxicity, allowin g administration of higher, more efficacious drug doses. In a murine L 1210 tumour model, for example, no long-term survivors were seen in an imal groups treated with free drug, whereas at the maximum therapeutic dose of liposomal mitoxantrone survival rates of 40% were observed.