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

被引：38

作者：

Saisyo, Atsuyuki ^{[1
,2
]}

Nakamura, Hideaki ^{[3
,4
]}

Fang, Jun ^{[3
,4
,5
]}

Tsukigawa, Kenji ^{[4
]}

Greish, Khaled ^{[6
,7
]}

Furukawa, Hiroyuki ^{[1
,2
]}

Maeda, Hiroshi ^{[3
]}

机构：

[1] Yamaguchi Univ, Dept Clin Pharmacol, Grad Sch Med, Yamaguchi 7558505, Japan

[2] Yamaguchi Univ, Dept Pharm, Yamaguchi 7558505, Japan

[3] Sojo Univ, Res Inst DDS, Nishi Ku, Kumamoto 8600082, Japan

[4] Sojo Univ, Fac Pharmaceut Sci, Nishi Ku, Kumamoto 8600082, Japan

[5] Anhui Med Univ, Sch Publ Hlth, Dept Toxicol, Hefei 230032, Anhui, Peoples R China

[6] Univ Otago, Dept Pharmacol & Toxicol, Otago Sch Med Sci, Dunedin 9016, New Zealand

[7] Arabian Gulf Univ, Aljawhara Ctr Mol Med, Manama, Bahrain

来源：

COLLOIDS AND SURFACES B-BIOINTERFACES | 2016年 / 138卷

基金：

日本科学技术振兴机构;

关键词：

Cisplatin; Styrene-maleic acid copolymer; Tumor environment-sensitive drug delivery; Tumor-selective drug delivery; EPR effect; HIGH-MOLECULAR-WEIGHT; MACROMOLECULAR THERAPEUTICS; TARGETING EFFICIENCY; ZINC PROTOPORPHYRIN; ANTICANCER AGENTS; SOLID TUMORS; HUMAN BREAST; MICELLES; CANCER; NEOCARZINOSTATIN;

D O I：

10.1016/j.colsurfb.2015.11.032

中图分类号：

Q6 [生物物理学];

学科分类号：

071011 ;

摘要：

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 x 3 caused a weight loss of more than 5%; SMA-CDDP at 60 mg/kg (CDDP equivalent) x 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. (C) 2015 Elsevier B.V. All rights reserved.

引用

页码：128 / 137

页数：10