Biomedical Engineering Reference
In-Depth Information
(PC and PG), acyl chains were composed of ~50 mole% unsaturated
fatty acids [C18:1 (30.2%) > C18:2 (16.3%) > C20:4 (3.5%) > C22: 5
(0.9%) > C22:6 (0.7%)] (Barenholz and Amselem, 1993 ). We had to
deal with two types of chemical stability issues: acyl ester hydrolysis
and lipid auto/peroxidation (Lichtenberg and Barenholz, 1988).
Major eff orts were dedicated to solve these stability issues. The best
protection against oxidative damage was obtained by inclusion in the
lipid mixture of 1.5 mole% D- a -tocopherol succinate (TCS). This by
itself was not sufficient, and therefore the fabrication and storage of
the formulation was done in the presence of the highly efficient iron
ion chelator Desferal (deferoxamine mesylate) using the aqueous
medium of 0.15 M NaCl (saline) containing 200 mM Desferal, at pH
range of pH 5.7-6.8 at 4 ° C (Barenholz and Gabizon, 1990, 1991;
Amselem et al., 1990; Barenholz and Amselem, 1993; Barenholz et al.,
1993). Under such conditions, doxorubicin degradation was minimal
(<5%), lipid hydrolysis was low (<5%), cholesterol degradation was
below detection limit, and lipid oxidation was minimal even after
19 months storage at 4 ° C (Barenholz and Amselem, 1993). TCS acts
as a pro-antioxidant slowly hydrolyzing and continuously supplying
a -tocopherol as an active antioxidant, while Desferal is one the
most potent iron chelating agents, which eff ectively neutralizes iron
ions that are highly potent inducers of lipid and doxorubicin auto/
peroxidation (Lichtenberg and Barenholz, 1988, Barenholz and
Amselem, 1993).
Figure 12.2 Optimization of OLV-DOX to the mole percent PG. Eff ect on
doxorubicin (DXR) association with the liposomes (Amselem et al., 1990).
The white square equals input DXR:PL ratio; White circle equals DXR loading
method I; Black circle equals DXR loading method II.
 
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