Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 341

RES cells. The optimal chemical stability at low endosome/lysosome
pH and the fact that the doxorubicin is an amphipathic weak base is
supportive of the MPS cells acting as a doxorubicin depot. In eff ect,
the liposomes deliver the drug to the MPS cells, which serve as a
drug depot for liver tumor treatment.
A high dose of doxorubicin (50 mg/m 2 ) is needed to achieve
therapeutic efficacy. The physicochemical properties and especially
the low doxorubicin solubility are unfavorable to achieve sufficient
passive loading into a 100-nm liposome's intraliposome aqueous
phase. Therefore larger liposomes have to be used.
At that time, we (Gabizon and Barenholz) were not the only group
that selected doxorubicin (or anthracyclines) as the anticancer drug
of choice for the development of liposome-based cancer treatment.
Other scientists in academia worked along similar considerations,
which were based on the same common knowledge (Rahman et al.,
1980, 1985, 1986a, 1986b; Forssen and Tokes, 1979, 1981, 1983;
Olson et al., 1982; Van Hossel et al., 1984; Mayhew et al., 1983, 1985,
1987; Strom et al, 1987, and others).
Most liposomal doxorubicin formulations developed during the
1980s took advantage of doxorubicin's being an amphipathic weak
base that can associate efficiently with negatively charged membrane
lipids. Doxorubicin's mannose amine-derived positive charge allows
for association with negatively charged phospholipids (such as PS,
PA, PG, and DPG), while its amphipathicity supports doxorubicin
partition to the liposome lipid bilayer (Forssen and Tokes, 1979,
1981; Mayhew et al., 1983a, 1983b; Rahman et al., 1985; Storm et
al., 1987). The working hypothesis behind all these studies called for
the use of liposomes that are larger than the nano-scale, as they can
better and faster be taken up by the RES system and be processed
there to release the drug. Not less important is that liposomes of
such size may have high enough drug levels associated with them to
reach therapeutic levels for human treatment.
We selected doxorubicin as our drug of choice on the basis of
medical, scientific, and practical considerations. Doxorubicin, like
many other anthracyclines, is produced by one of the Streptomyces
bacteria, ( Streptomyces peucetius var. caesius). It was discovered in
the 1960s near the Adriatic Sea, which explains the source of the
brand name Adriamycin. It showed significant anticancer activity
(Blum and Carter, 1974; McKelvey et al., 1976; Gundersen et al.,
1986). Doxorubicin acts on the nucleic acids of dividing cells by