Biomedical Engineering Reference
In-Depth Information
This asymmetry means that the
K
p
of DOX in the extraliposomal
medium supports influx in a direction opposite to the ammonium
sulfate gradient (namely, into the liposomes), while the
K
p
of DOX
in the intraliposomal aqueous phase acts to reduce partition into
the membrane, thereby reducing the desorption rate (
k
off
). The
reduction in DOX
K
p
in the intraliposomal aqueous phase is driven
by the ammonium sulfate remaining inside the intraliposomal
aqueous phase after DOX remote loading. Therefore, it seems that
ammonium sulfate plays a multifactorial role in the remote loading
and retention of the loaded drug in the liposomes. For Doxil the
interplay between the above four points, when combined with Doxil
membrane composition and liposome size, determines liposome
performance.
Another issue, so far neglected, which is especially relevant
to drugs such as doxorubicin, is their tendency to self-aggregate
(reviewed in [21]), forming oligomers of various mer number. This
phenomenon results from the stacking of the planar aromatic rings
of the anthracyclines due to interaction between the
π
electrons
of the rings. This self-aggregation is facilitated by increasing ionic
strength. DOX dimers appear already at 1
μ
M and larger aggregates
at higher DOX concentrations. The eff ect of such oligomerization
on therapeutic efficacy is not yet clear. However, based on simple
geometric considerations, it is obvious that nonmonomeric DOX
cannot interact with DNA in the same way as monomeric DOX, and
the exact location between the two DNA strands should diff er [21].
Therefore, the way by which the drug is internalized (monomers
versus aggregated form) by the tumor cell may be an important
factor in drug efficacy.
The breakthrough in using remote (active) loading driven by the
transmembrane ammonium sulfate gradient for the doxorubicin is
one of the main reasons that enabled successful clinical use of Doxil
and its approval by the regulatory agencies worldwide.
12.4.6
The Role of Drug Release Rate (
k
off
)
The results of liposome loading when combined with liposome
structure, lipid composition, and site of injection will determine rate
of drug release in plasma (Barenholz and Cohen, 1995). For example,
for i.v.-administrated liposomal drug formulations, only when
the drug release (determined by
k
off
) is slower than the liposome
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