Plasma clearance, biodistribution and therapeutic properties of mitoxantrone encapsulated in conventional and sterically stabilized liposomes after intravenous administration in BDF1 mice

摘要

Mitoxantrone can be efficiently loaded into large unilamellar vesicles using a transmembrane pH gradient. Release studies indicate that these drug-loaded carriers are highly stable and even after dissipation of the residual pH gradient retain more than 85% of encapsulated mitoxantrone following dialysis at 37 degrees C for 5 days. In murine studies we have compared the plasma clearance and biodistribution of both mitoxantrone and liposomal lipid following intravenous administration of free drug or mitoxantrone encapsulated in either conventional or sterically stabilized liposomes. In contrast to the rapid blood clearance observed for free mitoxantrone, both liposomal systems provided extended circulation lifetimes, with over 90% of the drug present 1 h after administration and 15-30% remaining at 24 h. In agreement with previous reports, longer plasma half-lives were observed for sterically stabilized liposomes than for conventional systems. In addition, a strong correlation between drug and carrier biodistribution was seen, with uptake occurring mainly in the liver and spleen and paralleling plasma clearance. This would suggest that tissue disposition reflects that of drug-loaded liposomes rather than the individual components. Liposomal encapsulation also significantly reduced mitoxantrone toxicity, allowing administration of higher, more efficacious drug doses. In a murine L1210 tumour model, for example, no long-term survivors were seen in animal groups treated with free drug, whereas at the maximum therapeutic dose of liposomal mitoxantrone survival rates of 40% were observed.