Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 371

liposome medium low) ion gradient, which acts as the driving force
for the remote loading of amphipathic weak acid or base drugs into
these liposomes. Historically, in my laboratory the remote loading
approach began from the need to achieve a highly efficient and stable
liposomal drug encapsulation that would be stable during storage
and after administration during the long circulation time in the
blood (up to 100-h half-life; Gabizon et al., 2003). This approach was
recently discussed by us in detail for nine diff erent drugs (Zucker et
al., 2009). It was applied for remote loading of the amphipathic weak
base anticancer drug doxorubicin and was the basis for the first
FDA-approved pegylated nano-liposomal anticancer drug Doxil ® .
Since the approval of Doxil (1995), it was successfully employed for
other drugs and agents in our and other laboratories ((Barenholz
and Haran, 1993, 1994; Haran et al., 1993, Lasic et al., 1992, 1995;
Clerc and Barenholz, 1995, 1998; Bolotin et al., 1994; Barenholz,
2001, 2007, 2010; Grant et al., 2004, Wasserman et al., 2007; Avnir
et al., 2008; Zucker et al., 2009).
Overall, from our own experience with nine diff erent drugs
(reviewed in Zucker et al., 2009), we concluded that a transmembrane
ammonium sulfate gradient is most suitable for stable encapsulation
of amphipathic weak bases, while a transmembrane calcium acetate
gradient is most suitable for loading amphipathic weak acids.
The basis of these nanochemical loading engines is that liposomes
are fabricated to exhibit the desired pH and/or ion gradient by using
salts composed of either weak bases (e.g., ammonium) or weak acids
(e.g., acetate). The degree of ionization of these compounds is pH
dependent. Their ionized species (i.e., ammonium and acetate) have
a very low permeability coefficient and octanol-to-buff er partition
coefficient and therefore they do not, or only very slowly, permeate
the liposome lipid bilayer, while their un-ionized species have
high permeability as well as octanol-to-buff er partition coefficient
(exemplified by ammonia gas and acetic acid) and therefore can diff use
relatively fast across the lipid bilayer and reach the intraliposome
aqueous phase (rev. in Barenholz, 2001, 2007, and Zucker et al.,
2009). The magnitude of the intraliposome high/external medium
low transmembrane gradient of such ions is the driving force for
remote loading, as they can be exchanged with amphipathic drugs
(weak acids with acetate and weak bases with ammonium). The
counterion of the gradient-forming ion (e.g., sulfate or calcium in the
case of ammonium or acetate gradient, respectively) can be selected