HSP32 (HO-1) inhibitor, copoly(styrene-maleic acid)-zinc protoporphyrin IX, a water-soluble micelle as anticancer agent: In vitro and in vivo anticancer effect

Abstract

We reported previously the antitumor effect of heme oxygenase-1 (HO-1) inhibition by zinc protoporphyrin IX (ZnPP). ZnPP per se is poorly water soluble and thus cannot be used as anticancer chemotherapeutic. Subsequently, we developed water-soluble micelles of ZnPP using styrene-maleic acid copolymer (SMA), which encapsulated ZnPP (SMA-ZnPP). In this report, the in vitro and in vivo therapeutic effects of SMA-ZnPP are described. In vitro experiments using 11 cultured tumor cell lines and six normal cell lines revealed a remarkable cytotoxicity of SMA-ZnPP against various tumor cells; average IC50 is about 11.1 μM, whereas the IC50 to various normal cells is significantly higher, that is, more than 50 μM. In the pharmacokinetic study, we found that SMA-ZnPP predominantly accumulated in the liver tissue after i.v. injection, suggesting its applicability for liver cancer. As expected, a remarkable antitumor effect was achieved in the VX-2 tumor model in the liver of rabbit that is known as one the most difficult tumor models to cure. Antitumor effect was also observed in murine tumor xenograft, that is, B16 melanoma and Meth A fibrosarcoma. Meanwhile, no apparent side effects were found even at the dose of ∼7 times higher concentration of therapeutics dose. These findings suggest a potential of SMA-ZnPP as a tool for anticancer therapy toward clinical development, whereas further investigations are warranted. © 2012 Elsevier B.V. All rights reserved.