Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 349

lymphoma with predominant dissemination to the liver (Gabizon
et al., 1982, 1983, 1985) and the BCL1 leukemia, which infiltrates
mainly the spleen and bone marrow (Gabizon et al., 1986a). In both
models, OLV -DOX was much superior to F-DOX at equal drug dose
and, as higher doses of OLV-DOX can be administered due to its
superior LD 50 , the therapeutic efficacy of OLV-DOX is much higher
than that of F-DOX. Levels of the drug after administration OLV-DOX
i.v. administration at the J-6456 lymphoma cells isolated from the
liver of tumor-bearing mice (by Percoll density gradient) were more
than three-fold higher than after injection of an equal dose of F-DOX
for at least the first 64 h post drug administration (i.e., compare 195
ng and 25 ng of drug per 10 7 isolated lymphoma cells for DOX-OLV
and F-DOX, respectively, at 24 h post injection). Table 12.1 is one
of many examples that clearly show that the therapeutic efficacy
of DOX-OLV in mice bearing J-6456 metastatic lymphoma was also
much superior to an equal dose of F-DOX.
One explanation for the fact that we did not get a cure or many
long-term (>100 days) mice survivors is that the result of the
presence of metastatic lymphoma cells in tissues other than liver
and spleen, to which OLV-DOX does not deliver high drug levels.
This is an important lesson to learn about our OLV-DOX
performance.

Table 12.1 Superior anti-tumor activity of OLV-DOX over F-DOX based on
survival time (days) a

Exp No. of Mice Mean ± s.e. Median (range) p a

Untreated 7 19.3 + 0.5 18.5 (18-21) <0.01

F-DOX 8

40.5 + 2.3 40.0 (28-50) <0.01

OLV-DOX
(PG:PC:Chol)

8

71.1 + 12.9 53.0 (41-148)

Note: For more details, see Gabizon et al. (1985).
a BALB/c mice inoculated with 10 6 J-6456 cells and treated i.v. with 8 mg kg -1
doxorubicin in either free or liposome-entrapped form.
b Wilcoxon test: F-DOX analyzed versus Untreated; OLV-DOX analyzed versus F-DOX.

Overall, the above results suggest that our treatment modality
with OLV-DOX may meet the expectation of being superior to F-DOX
in treatment of liver tumors including liver metastasis in humans.