Synthesis of Doxorubicin α-Linolenic Acid Conjugate and Evaluation of Its Antitumor Activity

被引：39
作者：
Liang, Chun-hui [1 ,3 ]
Ye, Wei-liang [1 ]
Zhu, Chun-lai [1 ]
Na, Ren [1 ]
Cheng, Ying [1 ]
Cui, Han [1 ]
Liu, Dao-zhou [1 ]
Yang, Zhi-fu [2 ]
Zhou, Si-yuan [1 ]
机构：
[1] Fourth Mil Med Univ, Sch Pharm, Dept Pharmaceut, Xian 710032, Peoples R China
[2] Fourth Mil Med Univ, Xijing Hosp, Dept Pharm, Xian 710032, Peoples R China
[3] Xian Childrens Hosp, Dept Pharm, Xian 710002, Peoples R China
来源：
MOLECULAR PHARMACEUTICS | 2014年 / 11卷 / 05期
关键词：
doxorubicin; alpha-linolenic acid; palmitic acid; pH sensitive; tumor targeting; POLYUNSATURATED FATTY-ACIDS; BREAST-CANCER CELLS; DOCOSAHEXAENOIC ACID; IN-VITRO; DRUG-DELIVERY; OXIDATIVE STRESS; CELLULAR UPTAKE; PACLITAXEL; EFFICACY; RESVERATROL;
D O I：
10.1021/mp4004139
中图分类号：
R-3 [医学研究方法]; R3 [基础医学];
学科分类号：
1001 ;
摘要：
Doxorubicin (DOX) is a broad-spectrum antitumor drug used in the clinic. However, it can cause serious heart toxicity. To increase the therapeutic index of DOX and to attenuate its toxicity toward normal tissues, we conjugated DOX with either alpha-linolenic acid (LNA) or palmitic acid (PA) by a hydrazone or an amide bond to produce DOX-hyd-LNA, DOX-ami-LNA, DOX-hyd-PA, and DOX-ami-PA. The cytotoxicity of DOX-hyd-LNA on HepG2, MCF-7, and MDA-231 cells was higher compared to that of DOX, DOX-ami-LNA, DOX-hyd-PA, and DOX-ami-PA. The cytotoxicity of DOX-hyd-LNA on HUVECs was lower than that of DOX. DOX-hyd-LNA released significantly more DOX in pH 5.0 medium than it did in pH 7.4 medium. DOX-hyd-LNA induced more apoptosis in MCF-7 and HepG2 cells than DOX or DOX-ami-LNA. Significantly more DOX was released from DOX-hyd-LNA in both MCF-7 and HepG2 cells compared with DOX-ami-LNA. Compared to free DOX, a biodistribution study showed that DOX-hyd-LNA greatly increased the content of DOX in tumor tissue and decreased the content of DOX in heart tissue after it was intravenously administered. DOX-hyd-LNA improved the survival rate, prolonged the life span, and slowed the growth of the tumor in tumor-bearing nude mice. These results indicate that DOX-hyd-LNA improved the therapeutic index of DOX. Therefore, DOX-hyd-LNA is a potential compound for use as a cancer-targeting therapy.
引用
收藏
页码：1378 / 1390
页数：13
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