Purpose: The purpose is to evaluate the CD44-mediated
cellular targeting of HA-But, a hyaluronic acid esterified
with butyric acid (But) residues, to hepatocellular carcinoma
cell lines in vitro and to hepatic tumor metastases in
vivo.
Experimental Design: In vitro, the CD44-dependent cytotoxicity
in two human hepatocellular carcinoma cell lines
(HepB3 and HepG2) with high and low CD44 expression
was investigated; in vivo, the effect on liver metastases originating
from intrasplenic implants of Lewis lung carcinoma
(LL3) or B16-F10 melanoma in mice was compared with the
pharmacokinetics of organ and tissue distribution using different
routes of administration.
Results: HepB3 and HepG2 cell lines showed different
expression of CD44 (78 and 18%, respectively), which resulted
in a CD44-dependent HA-But inhibitory effect as
demonstrated also by the uptake analysis performed using
radiolabeled HA-But (99mTc-HA-But). Pharmacokinetic
studies showed different rates of 99mTc-HA-But distribution
according to the route of administration (i.v., i.p., or s.c.):
very fast (a few minutes) after i.v. treatment, with substantial
accumulation in the liver and spleen; relatively slow
after i.p. or s.c. treatment, with marked persistence of the
drug at the site of injection. The effect of s.c. and i.p.
treatment with HA-But on liver metastases originating from
intrasplenic implants of LL3 carcinoma or B16-F10 melanoma
(both CD44-positive: 68 and 87%, respectively), resulted
in 87 and 100% metastases-free animals, respectively
(regardless of the route of administration), and a significant
prolongation of the life expectancy compared with control
groups.
Conclusions: HA-But tends to concentrate in the liver
and spleen and appears to be a promising new drug for the
treatment of intrahepatic tumor lesions.
