Biomedical Engineering Reference
In-Depth Information
damage, and hyperpigmentation of skin overlying veins used for
drug injection) (Skeel, 1999; Peng et al., 2005; Takimoto and Calvo,
2005; Kenyon, 2008)].
It is the combination of doxorubicin's clinical use for such a broad
spectrum of tumor types and the very large number of patients
treated with it, combined with its major deficiencies of dose-
limiting and accumulating-dose-limiting toxicities, that made it very
appealing and attractive to us (and others) and was the major driving
force for selecting doxorubicin as the drug of choice for delivery by
liposomes. The scientific supportive reasons that were available in
1980 were that the drug's stability (Beijnen et al., 1985), chemistry,
and physicochemical properties were well established and drug
ADME (
a
bsorption,
d
istribution,
m
etabolism, and
e
xcretion) was
common knowledge (Andrews et al., 1980).
Our practical reasons that supported and encouraged work with
doxorubicin were its distinct spectral properties, which allow easy
quantification of doxorubicin level, its chemical degradation, and
even state of aggregation, as well as changes in its local environment
(pH and level of hydrophobicity). Doxorubicin's reasonably high
molar extinction at 486 nm (12,500 OD/M) allows for its easy
quantification by a spectrophotometer, especially when combined
with HPLC. Another major practical advantage of doxorubicin is its
long wavelength (>550 nm) and high quantum yield fluorescence
emission. The use of fluorescence detection increases the limit of
detection by more than 100-fold. The fluorescence excitation and
emission spectra are distinguished from each other, and both are
sensitive to the environment. Doxorubicin's excitation and emission
fluorescence spectra are both sensitive to the absorbance variables
described above, but at much higher (>300-fold) sensitivity. This
enables one to follow doxorubicin PK and BD for long periods of time
(Barenholz and Amselem, 1993, 1993b; Haran et al., 1993; Barenolz
et al., 1993, 1993a; Amselem et al., 1993a, 1993b; Bandak et al.,
1999; Gabizon et al., 1994, 2003).
12.2.2
Liposomal Doxorubicin (First Generation): From
Design to Formulation, Characterization, and
Stability
We designed, studied, and compared a few liposomal formulations,
all having three lipid components: (1) a phosphatidylcholine (PC)
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