Doxil® - The first FDA-approved nano-drug: From an idea to a product

Doxorubicin in liposomes (abbreviated and registered as Doxil) is an anticancer nano-drug. Doxil is based on three unrelated principles: (i) using sterically stabilized liposomes, steric stabilization being achieved by the presence of pegylated distearoyl phosphat-idylethanolamine (2000Da PEG-DSPE), which results in long blood circulation time of the liposomes; (ii) high and stable remote loading of doxorubicin driven by a transmembrane ammonium sulfate gradient, which also allows for drug release at the tumor; and (iii) having the liposome lipid bilayer in the "liquid ordered" phase based on the high-T_m(53°C) hydrogenated soy phosphatidylcholine, and on cholesterol. In order to take advantage of the enhanced permeability and retention (EPR) efect and to achieve passive targeting of the liposomes into the tumor, the liposomes are nano-scale. This chapter describes the downs and ups of pre-Doxil and Doxil formulations, and how the lessons learned from the failure of pre-Doxil liposomal doxorubicin formulations were turned into the Doxil success. It demonstrates that such a development requires a multidisciplinary approach and is highly dependent on understanding and optimal use of physicochemical and nano-technology principles. Doxil, which is considered today the gold standard in liposome-based drug delivery systems, has opened the road to the development of other anticancer and anti-inflammatory nano-drugs that make used of the EPR efect and remote drug loading.