The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid
tumors, and it can serve as a basis for the development of macromolecular anticancer
therapy. We have previously found that recombinant
human serum albumin dimer, and especially its S-nitrosated form (
SNO-HSA-Dimer), is an enhancer of the EPR effect. In this study, we investigated the influence of
SNO-HSA-Dimer on the anti-
tumor effect of two types of macromolecular anti-
tumor drugs, namely
N-(2-hydroxypropyl)methacrylamide polymer conjugated with
zinc protoporphyrin, which forms
micelles and can be used for fluorescence studies. The other was
PEGylated liposomal doxorubicin (
Doxil), a typical example of a stealth
liposome approved for medical usage. In mice having C26
tumors with highly permeable vasculature,
SNO-HSA-Dimer increases
tumor accumulation of the drugs by
a factor 3-4 and thereby their anti-
tumor effects. Experiments with
Evans blue revealed increased EPR effect in all parts of the
tumor. Furthermore,
SNO-HSA-Dimer improves the anti-metastatic effects of
Doxil and reduces its minor uptake in non-tumorous organs such as liver and kidney.
Tumor accumulation of
Doxil in B16
tumors, which are characterized by a low permeable vasculature, increased even more (6-fold) in the presence of
SNO-HSA-Dimer, and the improved accumulation lead to decreased
tumor volume and increased survival of the animals. The administration of
SNO-HSA-Dimer itself is safe, because it has no effect on blood pressure, heart rate or on several biochemical parameters. The present findings indicate that
SNO-HSA-Dimer is promising for enhancing the EPR effect and consequently the specific,
therapeutic effects of macromolecular anticancer drugs.