Low water solubility and development of resistance are important drawbacks in the use of
cisplatin as a
cytostatic agent. A novel
bile acid-
cisplatin complex,
Bamet-R2 [cis-diamminechlorocholylglycinateplatinum (II)], with liver vectoriality, has been synthesized. Our aim was to investigate the usefulness of this compound to overcome
cisplatin resistance and to determine whether its encapsulation into
liposomes increases its water solubility, uptake by liver
tumor cells and
cytostatic activity. Highly efficient incorporation of
Bamet-R2 into
liposomes permitted an increase in the concentration of the
drug compared with that in the initial free
solution by more than 6 x 10(6)-fold, which is 10(3)-fold higher than the encapsulation obtained for
cisplatin. A partially
cisplatin-resistant (87-fold) monoclonal cell line (Hepa 1-6/10R) was obtained by 2 subcloning steps of a population of mouse
hepatoma Hepa 1-6 cells grown in step-wise increasing
cisplatin concentrations up to 10 microM. Decreased sensitivity to
cisplatin was accompanied by a 3.2-fold lower
drug accumulation compared to wild-type cells. Uptake was markedly increased by the binding of
cisplatin to
glycocholic acid in both Hepa 1-6 and Hepa 1-6/10R cells. This probably accounts for the partial overcoming (-82%) of resistance when used on Hepa 1-6/10R cells. Inclusion of
Bamet-R2 into
liposomes further increased the amount of the
drug accumulated in both cell types and, hence, enhanced its
cytostatic activity. Since both plain
liposomes and
Bamet-R2 have little toxicity, the formulation of this compound in
liposomes may offer a substantial advantage over
cisplatin in the treatment of
tumors resistant to this anti-neoplastic agent.