Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 375

clearance ( k c ) will the liposome determine drug pharmacokinetics
and biodistribution. When k off > k c , then the ratio k off / k c is a measure
of the rate of drug release in vivo . Controlling this ratio is obligatory to
achieve controlled drug release in blood or in the tissues reached by
the liposomes. Therefore, this ratio also aff ects therapeutic efficacy
of the liposomal drug. For drugs of fast clearance, when k off >> k c the
benefits of use of liposomes for drug delivery will be minimal or none,
as the performance of the liposomal drug will be similar to that of
the free drug. This is exemplified by our first-generation failed OLV-
DOX formulation (see above). An efficient and functional way to test
the release rate is a cytotoxicity test measuring doxorubicin IC 50 in
cell culture. As described by Horowitz et al. (1992) Doxil has about a
2-order of magnitude higher IC 50 (lower cytotoxic activity) than free
doxorubicin, while as described in Section 12.2.3, our failed OLV-DOX
had similar IC 50 to free doxorubicin. These diff erences demonstrate
nicely that the large dilution-induced release that basically “killed”
the performance of OLV-DOX in humans does not occur in Doxil. To
make sure that our interpretation is correct, we studied the eff ect of
nigericin on doxorubicin release and IC 50 . Nigericin is an ionophore
that breaks the pH and ammonium gradient by exchanging the
intraliposome proton with potassium ion. The exposure of Doxil
to nigericin caused complete drug release, which was paralleled
by reducing the IC 50 to the low level of free doxorubicin, proving
that Doxil's excellent drug retention is the reason for its poor IC 50
(Horowitz et al., 1992).
However, the opposite (very low k off ) is as bad. Namely, when k off
is too slow and there is no liposome uptake by the target cells, there
will be no therapeutic efficacy even if the loaded liposomes will reach
the target very efficiently, as the free drug concentration at the target
tissue will be too low, as exemplified by sterically stabilized cisplatin
liposomes (Lasic et al., 1999; Barenholz, 2001; Peleg-Shulman et al.,
2001).

12.4.7 Doxil: Each Part Mat ers

In Doxil, each part matters and contributes to the optimized
performance (Figure 12.7). Doxil is an excellent example to
demonstrate the obligatory role of lipid biophysics in the success of
liposome-based drugs.