Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 335

Chapter 12
Doxil® — The First FDA-Approved Nano-
Drug: From an Idea to a Product
Yechezkel (Chezy) Barenholz
Laboratory of Membrane and Liposome Research,
Institute of Medical Research Israel Canada (IMRIC),
The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
[e-mail], [e-mail]
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) eff ect 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