Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 381

with conventional doxorubicin. Of the >10 liposomal drugs approved
(Zhang et al., 2001), Doxil has the most extensive clinical use.
Based on Doxil success, various novel drug formulations including
modified Doxil, and other drugs or drug combinations with a similar
approach to that of Doxil are now at diff erent stages of development.
These novel nano-drug formulations should have reduced (or no)
side eff ect of acute infusion reactions or foot-hand syndrome. One
approach to achieve the latter objective is to slightly reduce the half-
life of the liposomal doxorubicin by replacing the sulfate counterion
of the ammonium used for the remote loading with glucuronate.
The use of glucuronate, which has a permeability coefficient similar
to sulfate but does not induce intra-liposome drug precipitation,
results in somewhat shorter circulation time of the doxorubicin,
but without loss of therapeutic efficacy in tumor-bearing mice
(Wasserman et al., 2007; Barenholz, 2007; Gabizon and Barenholz,
2005). This relatively small but distinct eff ect on the PK is expected
to lower accumulation of doxorubicin in the skin, lowering hand and
foot syndrome. Other ways to extend and improve nano-liposome-
based anticancer therapy are to have better control of drug release
(rev. in Barenholz, 2007) using external means, such as hyperthermia
(Needham et al., 2000, 2001) or focused ultrasound (Schroeder et
al., 2007, 2009a, 2009b); or to use a combination by remote loading
of two drugs that act synergistically in one liposome (Zucker et al.,
2010), or a combination of two diff erent treatment modalities such
as Doxil and interleukin 2 (IL-2) in liposome-based immunotherapy
(Cabanes et al., 1999). The latter stems from the fact that doxorubicin
when administered as Doxil is not toxic to the immune system and
therefore IL-2 when delivered in liposomes is highly efficacious.
The idea behind this chemo-immuno treatment combination is
that the Doxil will take care of most of the tumor burden, while the
immunotherapy elicited by the IL-2 will activate the intact immune
system enabling it to kill the residual tumor cells (Cabanes et al.,
1999). The use of liposomal IL-2 results in lower toxicity of the IL-2
and prolongation of IL-2 circulation time without loss of its potency
(Kedar et al., 1994a, 1994b). A very promising approach is the one
used recently by Jain and coworkers (Diop-Frimpong et al., 2011).
Accordingly, losartan, which inhibits collagen I synthesis, was used
to modify the interstitial tumor environment, leading to increase in
Doxil (and other nano-particulates) accumulation in tumors, thereby
increasing Doxil therapeutic efficacy.