Synthesis of doxorubicin α-linolenic acid conjugate and evaluation of its antitumor activity.
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 α-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.
Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University , Xi'an 710032, China.
Chun-Hui
CH
Liang
Wei-Liang
WL
Ye
Chun-Lai
CL
Zhu
Ren
R
Na
Ying
Y
Cheng
Han
H
Cui
Dao-Zhou
DZ
Liu
Zhi-Fu
ZF
Yang
Si-Yuan
SY
Zhou
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008113:Liver Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D019308:Palmitic Acid / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays; D017962:alpha-Linolenic Acid / Q000737:chemistry*
D000970:Antineoplastic Agents; D006835:Hydrazones; D017962:alpha-Linolenic Acid; D019308:Palmitic Acid; D004317:Doxorubicin