ABSTRACT
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 phosphatidylethanolamine (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-Tm (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 nanoscale. 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
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 yb@cc.huji.ac.il, chezyb@gmail.com
Handbook of Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications Edited by Dan Peer Copyright © 2012 Pan Stanford Publishing Pte. Ltd. ISBN 978-981-4316-46-0 (Hardback), 978-981-4364-27-0 (eBook) www.panstanford.com
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 eff ect and remote drug loading.
