Biomedical Engineering Reference
In-Depth Information
a viable product that could overcome all (or at least most) of the
deficiencies demonstrated by our OLV-DOX. These included the facts
that in this failed formulation, doxorubicin is liposome-membrane-
associated and that liposome membrane is composed of two fluid
unsaturated phospholipids (having the solid ordered to liquid
disordered phase transition much below 37 ° C): the zwitterionic
“fluid” liposome-forming lipid EPC, and the negatively charged
“fluid” liposome-forming lipid EPG, and cholesterol. These failed
liposomes were oligolamellar, and of size distribution in the range
of 200-500 nm. The combination of this size distribution range and
lipid composition resulted in fast uptake of the liposomes by the RES;
namely, there was no RES avoidance. Not less important are the facts
that in the RES the liposomes were not taken up by tumors (Gabizon
et al., 1991a, 1991b). These liposomes reached the liver with a
very low level of drug (Gabizon et al., 1991a, 1991b Amselem et al.,
1993a) due to the fact that most encapsulated drug was membrane-
associated (electrostatically) and in humans undergoes fast dilution-
induced drug release upon intravenous injection. In addition, such
large liposomes could not make use of extravasation typical of nano-
particulates (having long circulation time) via the porous blood
vessels of the tumor tissue. This unique nano-anatomy can be used
as the Achilles' Heel of the cancer tissue for selective accumulation
of macromolecules and nanoparticles in the tumor tissue. The latter
unique extravasation was described first by Matsumura and Maeda
(1986) and referred to as the enhanced permeability and retention
(EPR) eff ect.
The microanatomy of tumor blood vessels and its relevance
to tumor therapy was studied extensively by Jain and coworkers
(Hashizume et al., 2000), while Bassermann (1986) described the
changes in vascular pattern of tumors and surrounding tissues
during diff erent phases of metastatic growth. Jain and coworkers also
point out the high pressure in tumors (but not in healthy tissues),
which reduces drug diff usion from blood vessels into the tumors,
thereby reducing the therapeutic efficacy and increasing toxicity of
chemotherapy.
After our failed “first in man” clinical trial, we were back at square
one, but we were much more educated and more knowledgeable on
both the scientific and technological levels of the issues and the need
to solve the major problems described above. We were also confident
 
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