Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 368

of dilution-induced drug release (Gabizon et al., 1991; Amselem et
al., 1993a) than small rodents with their very small plasma volume
(and therefore almost no dilution).
The Beagle dog doxorubicin PK study clearly demonstrated that
although both liposomal formulations were much superior to F-DOX.
The PEG-DSPE formulation was better, as it showed much slower
plasma clearance than the HPI formulation.

Figure 12.5 A cartoon showing a comparison between conventional
and sterically stabilized (pegylated) liposomes (SSL, Stealth liposomes).
(Courtesy of the late D. Lasic.) The cartoon shows lack of insertion of
opsonins into the membrane of Stealth liposomes. See also Color Insert.

Using mice peritoneal macrophages (obtained from the ascitic
fluid of mice treated with thioglycolate), in vitro , Doxil showed 40%
of the uptake of liposomes of similar size and lipid composition but
lacking 5 mole% PEG-DSPE (Emanuel et al., 1996a). This reduction
in macrophage uptake is in direct correlation with the increase
in plasma circulation time. The increase in mole% of PEG-DSPE
can further reduce macrophage uptake and probably increase
circulation time (Emanuel et al., 1996a, 1996b). For more details
on the eff ect of PEG-DSPE on nano-liposomes, see Garbuzenko
et al. (2005).

12.4.6 Remote Loading of Doxorubicin into Nano

Sterically Stabilized Liposomes (nSSL) to Form Doxil

12.4.6.1 The need for remote loading
For liposome formulation designed for metastatic tumor treatment,
intravenous (i.v.) administration is the only option, and therefore