PMID- 22576132 OWN - NLM STAT- MEDLINE DCOM- 20121221 LR - 20191210 IS - 1873-3441 (Electronic) IS - 0939-6411 (Linking) VI - 81 IP - 3 DP - 2012 Aug TI - 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. PG - 540-7 LID - 10.1016/j.ejpb.2012.04.016 [doi] AB - 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 IC(50) is about 11.1 muM, whereas the IC(50) to various normal cells is significantly higher, that is, more than 50 muM. 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 approximately 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. CI - Copyright (c) 2012 Elsevier B.V. All rights reserved. FAU - Fang, Jun AU - Fang J AD - Laboratory of Microbiology and Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan. FAU - Greish, Khaled AU - Greish K FAU - Qin, Haibo AU - Qin H FAU - Liao, Long AU - Liao L FAU - Nakamura, Hideaki AU - Nakamura H FAU - Takeya, Motohiro AU - Takeya M FAU - Maeda, Hiroshi AU - Maeda H LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120430 PL - Netherlands TA - Eur J Pharm Biopharm JT - European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V JID - 9109778 RN - 0 (Antineoplastic Agents) RN - 0 (Maleates) RN - 0 (Metalloporphyrins) RN - 0 (Micelles) RN - 0 (Polystyrenes) RN - 0 (copoly(styrene-maleic acid)-zinc protoporphyrin) RN - EC 1.14.14.18 (Heme Oxygenase-1) SB - IM MH - Animals MH - Antineoplastic Agents/administration & dosage/*pharmacology/toxicity MH - Cell Line MH - Cell Line, Tumor MH - Chick Embryo MH - Chlorocebus aethiops MH - Female MH - Heme Oxygenase-1/*antagonists & inhibitors MH - Humans MH - Inhibitory Concentration 50 MH - Injections, Intravenous MH - Liver/metabolism MH - Male MH - Maleates/administration & dosage/*pharmacology/toxicity MH - Metalloporphyrins/administration & dosage/*pharmacology/toxicity MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Micelles MH - Neoplasms/*drug therapy/pathology MH - Polystyrenes/administration & dosage/*pharmacology/toxicity MH - Rabbits MH - Tissue Distribution MH - Xenograft Model Antitumor Assays EDAT- 2012/05/12 06:00 MHDA- 2012/12/22 06:00 CRDT- 2012/05/12 06:00 PHST- 2011/10/27 00:00 [received] PHST- 2012/04/19 00:00 [revised] PHST- 2012/04/21 00:00 [accepted] PHST- 2012/05/12 06:00 [entrez] PHST- 2012/05/12 06:00 [pubmed] PHST- 2012/12/22 06:00 [medline] AID - S0939-6411(12)00130-0 [pii] AID - 10.1016/j.ejpb.2012.04.016 [doi] PST - ppublish SO - Eur J Pharm Biopharm. 2012 Aug;81(3):540-7. doi: 10.1016/j.ejpb.2012.04.016. Epub 2012 Apr 30.