Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 370

dependent, which determines the level of ionization of the molecule.
(Barenholz and Cohen, 1995; Barenholz, 2001, 2003)).
Although the use of octanol/water partition coefficient to
determine suitability of molecules to reside in a lipid bilayer is
controversial, it is well established that it is indicative of agent
transmembrane diff usion rate (Stein, 1986), and therefore it is
relevant to loading efficiency, loading stability, and the drug release
profile.
12.4.6.3 Remote loading optimization
Recently, we developed a much more detailed and precise
computation means to predict remote loading performance, which
is based on more variables than only the partition coefficient (logP
and/or logD), including the details on apolar and polar surface areas
of the desired molecule (and the ratio between the two surface
areas), its p K a , and logD at diff erent pHs. This enables us to better
predict, analyze, and optimize the loading process. In order to have
an efficient remote loading, p K a and logD have to be in a certain range,
which means that at least a certain fraction of the loaded molecule
has to be uncharged, and in this range of logD, we found the apolar
and polar surface areas to be highly informative indicators (Zucker
et al., 2009).
That paper describes how applying data-mining algorithms to a
data bank based on our laboratory's 15 years of liposome research
experience on remote loading of nine diff erent drugs enabled us
to build a model that relates drug physicochemical properties
and loading conditions to loading efficiency. This model enables
choosing candidate molecules for remote loading and optimizing
loading conditions according to logical considerations. The model
should also help in designing prodrugs suitable for remote loading.
This approach is now further improved by including data from over
50 diff erent molecules that were remote loaded in many diff erent
laboratories in the world by ion or pH transmembrane gradients
(Cern, Goldblum, and Barenholz, in preparation) and are expected to
improve and accelerate the development of liposomal formulations
for clinical applications.
Only remote (active) drug loading enables transforming pegy-
lated nano-liposomes (nSSL) into an approved efficacious drug. This
drug loading approach is based on the strategy of fabricating nano-
liposomes that exhibit a transmembrane intraliposome high/extra