Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 353

stomatitis being the most significant dose-limiting factors. These
data should be another warning signal (that we ignored) that the
drug is released fast from the liposomes into the blood circulation.
A similar finding has been obtained in a another clinical study
(Treat et al., 1989), with DOX encapsulated in liposomes composed
of cardiolipin, PC, stearylamine, and cholesterol, although the MTD
and recommended dose for Phase II studies reported (90 and 75
mg/m 2 , respectively) are lower than in our study. Drug causing
myelosuppression may reach the bone marrow in several ways. The
ability of liposomes to localize in the bone marrow, a tissue rich in
sinusoidal capillaries, has been demonstrated in animals (Gregoriadis
and Senior, 1986) and in humans (Perez-Soler et al., 1985). Today our
interpretation of these results is that all these formulations that share
that doxorubicin is a liposome membrane component, also share
a fast dilution-induced drug leakage (release) from the liposomes
in the blood circulation, which may explain the myelosuppressive
eff ect of the liposomal formulations. Another possible explanation is
that drug that was released from the liver and spleen macrophages
reached the circulation after the liposomes were endocytosed and
processed. Although human pharmacokinetic studies with liposomal
doxorubicin have been previously reported (Gabizon et al., 1989;
Rahman et al., 1989), they did not enable discrimination between
the various explanations, as the measurements done at that time
did not provide separation between plasma free drug and liposome-
associated drug in the plasma. These two forms of doxorubicin can
now be resolved by the methodology of using the cation exchanger
Dowex-50, described by Druckmann et al. (1989).
The bottom line of our first in man clinical trial indicated that
while the administration of DOX-OLV to humans is feasible and even
up-shifts MTD the major side eff ects were similar to those of the
free drug. This was disappointing and not in agreement with our
expectations, which were based on our mice results. There the DOX-
OLV was superior in all aspects [PK, BD, tolerability, and efficacy
(see above)]. In order to benefit from the disappointing human trial
results, we decided to put major eff orts into the understanding of
the diff erences observed between the failed human study (Gabizon
et al., 1989b) and the successful mice studies (rev. in Gabizon and
Barenholz, 1988). For this, we decided to study pharmacokinetics
and liposome localization by imaging studies in patients.