Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 359

doxorubicin with liposomes is related to the drug-liposomes
association constant [which determines the liposome/medium
(liposome/plasma) partition coefficient ( K p )]. The question
is how high K p has to be in order to prevent a major drug
leakage in plasma. This may be a key issue that may explain
the diff erence between our success in rodents and failure in
humans (Amselem et al., 1993; Barenholz and Cohen, 1995;
Barenholz, 2001, 2003). Plasma volume in mice is ~1.0 mL
compared with 3,500 mL in humans. Therefore, upon slow
infusion, the liposomes undergo a very large dilution of 3500-
fold for each milliliter that reaches the plasma, compared with
only a fivefold dilution with the bolus injection of the same
liposomes to mice. The fast free drug clearance keeps this
huge dilution eff ect active throughout the time of infusion.
The observation of a sudden burst of drug leakage shortly
after injection (Figure 4 in Gabizon et al., 1991) is compatible
with the dilution eff ect.
(ii) The presence of a high mole fraction of PG in the liposome
bilayer may accelerate uptake by the RES (Gabizon and
Papahadjopoulos, 1988); it may also induce complement
activation (Szebeni et al., 2007, and rev. in Szebeni and
Barenholz, 2012, this topic).
(iii) The liposome size is too large to allow for extravasation in
extrahepatic tissues (Hwang, 1987) and to take advantage
of the enhanced permeability and retention (EPR) eff ect that
was first described by Matsumura and Maeda (1986) and
recently reviewed by Maeda et al. (2009). This eff ect may
allow for selective accumulation of nanoparticles in tumors
due to unique micro-anatomy of blood vessels there (but
not in normal healthy tissue) being porous and permeable
to 100-nm particles. In addition, the tumor tissue is poor in
lymphatic drainage, which enables prolonged retention of the
nanoparticles there, followed by local (tumor) drug release
and/or for the liposomes to be taken up by the tumor cells.
Based on this analysis, the fact that the same dose-limiting bone
marrow toxicity was observed with DOX-OLV and with F-DOX is
not surprising and can be assigned to a large extent to the fast drug
leakage from circulating liposomes.
In view of the OLV-DOX fast plasma drug release and changes in
tissue distribution and bioavailability, it is uncertain whether the