Sterically stabilized doxorubicin loaded liposomes (DOX-SL^™): From basics to the clinics

This short paper describes the problems, and their solutions, of formulating liposomal dosage forms for clinical use, as exemplified in tumor therapy by liposomal doxorubicin. We will demonstrate that the development of an efficacious drug delivery system requires fitting the delivery system to the micro-anatomy of the tumor. Many tumors have gaps in their capillaries which permit particles smaller than 120 nm to slowly extravasate into the tumor. Therefore small liposomes having a prolonged circulation time may be suitable drug carriers for tumor therapy. Recently a liposomal doxorubicin formulation (DOX-SL^™) was recommended for approval by the US FDA, with indications of treating Kaposi's sarcoma. These liposomes seem to be efficacious in other types of tumors as well. The unique features of this formulation include: control of the biodistribution and pharmacokinetics of the intact liposomes through liposome lipid composition, especially the role of steric stabilization of the liposomes which enable prolonging their circulation time (human t^1/2 > 50 h); stable loading of a sufficient level of drug through an ammonium sulfate gradient; and small particle size (100 nm) These special features enable the development of liposomal doxorubicin which in humans delivers the active drug to the tumor more efficiently than the use of the free drug. These novel liposomal formulations may provide the means for realizing Paul Erlich's dream of active targeting by a "magic bullet".