title: pH-sensitive polymeric cisplatin-ion complex with styrene-maleic acid copolymer exhibits tumor-selective drug delivery and antitumor activity as a result of the enhanced permeability and retention effect.
abstract: Cisplatin (CDDP) is widely used to treat various cancers. However, its distribution to normal tissues causes serious adverse effects. For this study, we synthesized a complex of styrene-maleic acid copolymer (SMA) and CDDP (SMA-CDDP), which formed polymeric micelles, to achieve tumor-selective drug delivery based on the enhanced permeability and retention (EPR) effect. SMA-CDDP is obtained by regulating the pH of the reaction solution of SMA and CDDP. The mean SMA-CDDP particle size was 102.5 nm in PBS according to electrophoretic light scattering, and the CDDP content was 20.1% (w/w). The release rate of free CDDP derivatives from the SMA-CDDP complex at physiological pH was quite slow (0.75%/day), whereas it was much faster at pH 5.5 (4.4%/day). SMA-CDDP thus had weaker in vitro toxicity at pH 7.4 but higher cytotoxicity at pH 5.5. In vivo pharmacokinetic studies showed a 5-fold higher tumor concentration of SMA-CDDP than of free CDDP. SMA-CDDP had more effective antitumor potential but lower toxicity than did free CDDP in mice after i.v. administration. Administration of parental free CDDP at 4 mg/kg×3 caused a weight loss of more than 5%; SMA-CDDP at 60 mg/kg (CDDP equivalent)×3 caused no significant weight change but markedly suppressed S-180 tumor growth. These findings together suggested using micelles of the SMA-CDDP complex as a cancer chemotherapeutic agent because of beneficial properties-tumor-selective accumulation and relatively rapid drug release at the acidic pH of the tumor-which resulted in superior antitumor effects and fewer side effects compared with free CDDP.
authors.affiliation: Department of Clinical Pharmacology, Yamaguchi University Graduate School of Medicine, Minami-kogushi 1-1-1, Yamaguchi 755-8505, Japan; Department of Pharmacy, Yamaguchi University Hospital, Minami-kogushi 1-1-1, Yamaguchi 755-8505, Japan.
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Saisyo
authors.affiliation: Research Institution of DDS, Sojo University, Ikeda 4-22-1, Nishi-ku, Kumamoto 860-0082, Japan; Faculty of Pharmaceutical Sciences, Sojo University, Ikeda 4-22-1, Nishi-ku, Kumamoto 860-0082, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Research Institution of DDS, Sojo University, Ikeda 4-22-1, Nishi-ku, Kumamoto 860-0082, Japan; Faculty of Pharmaceutical Sciences, Sojo University, Ikeda 4-22-1, Nishi-ku, Kumamoto 860-0082, Japan; Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, Anhui, China. Electronic address: fangjun@ph.sojo-u.ac.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University, Ikeda 4-22-1, Nishi-ku, Kumamoto 860-0082, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsukigawa
authors.affiliation: Department of Pharmacology & Toxicology, Otago School of Medical Sciences, University of Otago, Dunedin 9016, New Zealand; Aljawhara center for Molecular Medicine, Arabian Gulf University, Manama, Bahrain.
authors.forename: Khaled
authors.initials: K
authors.lastname: Greish
authors.affiliation: Department of Clinical Pharmacology, Yamaguchi University Graduate School of Medicine, Minami-kogushi 1-1-1, Yamaguchi 755-8505, Japan; Department of Pharmacy, Yamaguchi University Hospital, Minami-kogushi 1-1-1, Yamaguchi 755-8505, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Furukawa
authors.affiliation: Research Institution of DDS, Sojo University, Ikeda 4-22-1, Nishi-ku, Kumamoto 860-0082, Japan. Electronic address: hirmaeda@ph.sojo-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods; D065546:Drug Liberation; D000067493:Dynamic Light Scattering; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008298:Maleates / Q000737:chemistry*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010539:Permeability; D011108:Polymers / Q000737:chemistry*; D013053:Spectrophotometry; D020058:Styrene / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D008298:Maleates; D011108:Polymers; D020058:Styrene; C030272:maleic acid; D002945:Cisplatin
keywords: Cisplatin; EPR effect; Styrene-maleic acid copolymer; Tumor environment-sensitive drug delivery; Tumor-selective drug delivery