Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 348

F-DOX. This was paralleled by a large reduction in the viability of
tumor cells isolated from the liver of tumor-bearing mice (by Percoll
density gradient) after injection of OLV-DOX, which was achieved
only after administration of OLV-DOX and not of F-DOX.
12.2.5 Toxicity
We studied the toxicity of a few liposomal doxorubicin formulations
of diff erent lipid compositions in small rodents as a part of the
selection process of the optimal formulation. Here we will summarize
our comparison of the leading formulation of EPC/EPG/Cholesterol/
TCS 7:3:4:0.2 OLV-DOX with free drug (F-DOX). The comparison
included a few studies that included single-dose and multi-dose
experiments (Gabizon et al., 1986b). We demonstrated that OLV-
DOX is much less toxic than F-DOX; LD 50 value of OLV-DOX is twofold
higher than the LD 50 value of F-DOX. The lower toxicity of OLV-DOX
was also demonstrated by higher, close to normal, body weight
and organ weights and almost no histopathological damage to the
kidney and myocardium. The low level of cardiotoxicity observed
was fully reversible. It is also very important that despite the fact
that i.v. administration of OLV-DOX resulted in high accumulation
of doxorubicin in the liver, hepatotoxicity was minimal and limited
to some megalonucleosis, with slight changes in liver function
observed at the end of a six-month-long experiment in rodents.
The much lower toxicity of OLV-DOX than of F-DOX is related first
to the fact the encapsulation in the OLV aff ected dramatically the
drug biodistribution, with much less drug reaching the heart and
the kidneys (Gabizon et al., 1982, 1983). However, this is not the
only eff ect of the encapsulation. Not less important is the eff ect on
subcellular distribution, which results in the diminishing interaction
of the intracellular doxorubicin with the mitochondria. The latter
may explain part of the chronic free drug toxicity (related to the high
affinity of the drug to the mitochondrial lipid DPG. The bottom line
of the toxicity studies is that our OLV-DOX is significantly less toxic
than F-DOX.
12.2.6 Therapeuticefficacy
For the therapeutic efficacy, we studied two in vivo models of tumor-
bearing mice with major involvement of RES organs, the J-6456