Liposomal anticancer drugs as agents to be used in combination with other anticancer agents: Studies on a liposomal formulation with two encapsulateddrugs

When considering the use of combination therapies with liposomal anticancer agents several approaches can be defined. One approach could rely on admin istration of one liposomal formulation with more than one entrapped cytotox ic drug. This study focuses on an assessment of a liposomal formulation con taining vincristine and mitoxantrone. Distearoyl phosphatidylcholine (DSPC) /Cholesterol (Chol) (55:45 molar ratio) liposomes were loaded with vincrist ine using transmembrane pH gradients. These systems were subsequently incub ated with mitoxantrone to effect uptake of the second drug. Retention of bo th drugs was determined in vitro and in vivo. In vitro drug release indicat ed >95% retention of mitoxantrone and approximately 75% retention of vincri stine when liposomes were prepared with an initial interior pH of 2.0. In v ivo results however, demonstrated that greater than 80% of the encapsulated vincristine was released within 1 hour following i.v. administration. The instability of a liposomal formulation containing two anticancer drugs foll owing i.v. administration may be a consequence of a combination of factors including drug-loading induced collapse of the transmembrane pH gradient, l oss due to osmotic effects and an associated insertion of serum proteins in to the bilayer, as well as the presence of a large biological ''sink'' whic h can alter the transbilayer drug gradient in favor of drug release.