阿霉素偶联至聚[(2-羟乙基)-L-天冬酰胺]的抗肿瘤活性和毒理学性质,以腹腔内给药的方式用于小鼠。

Antitumor activity and toxicological properties of doxorubicin conjugated to [alpha],[beta]-poly[(2-hydroxyethyl)-L-aspartamide] administered intraperitoneally in mice.

机构信息

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China.

出版信息

Anticancer Drugs. 2010 Apr;21(4):362-71. doi: 10.1097/cad.0b013e3283355227.

Abstract

A polymer-drug conjugate was developed by conjugating doxorubicin (DOX) to [alpha],[beta]-poly[(2-hydroxyethyl)-L-aspartamide] (PHEA) with a succinic spacer. The suitability of PHEA-DOX in intraperitoneal chemotherapy was investigated both in vitro and in vivo. The results showed that the release rate of DOX from PHEA-DOX in S180 ascites was faster than that in mouse serum or in buffer solutions. An in-vivo antitumor study revealed that PHEA-DOX was more effective than DOX against solid S180 tumor after intraperitoneal injection at the same dose of 10 or 15 mg (DOX eq.)/kg, respectively. At a high dose of 28 mg (DOX eq.)/kg, which was lethal for free DOX to mice, PHEA-DOX could inhibit 61.5% of solid S180 tumor growth and markedly prolonged the survival time of ascetic S180-bearing mice. The toxicological effects of PHEA-DOX injected intraperitoneally in normal mice were assessed by using LD50, body weight increment, electrocardiography, blood biochemical indices, and myocardium histology, giving evidence that PHEA-DOX displayed considerably reduced systemic and cardiotoxicity compared with free DOX. All results suggest that PHEA-DOX has great potential for intraperitoneal chemotherapy because of its high therapeutic effects and few adverse side effects.

摘要

一种聚合物-药物偶联物是通过用琥珀酸间隔臂将阿霉素(DOX)与[α],[β]-聚[[(2-羟乙基)-L-天冬酰胺](PHEA)偶联而开发的。研究了 PHEA-DOX 在腹腔内化疗中的适用性,包括在体外和体内。结果表明,PHEA-DOX 在 S180 腹水的 DOX 释放率比在小鼠血清或缓冲液中的释放率更快。体内抗肿瘤研究表明,与相同剂量 10 或 15 mg(DOX eq.)/kg 的 DOX 相比,PHEA-DOX 经腹腔注射对实体 S180 肿瘤更有效。在高剂量 28 mg(DOX eq.)/kg 时,游离 DOX 对小鼠致死,PHEA-DOX 可抑制 61.5%的实体 S180 肿瘤生长,并显著延长腹水 S180 荷瘤小鼠的存活时间。通过使用 LD50、体重增加、心电图、血液生化指标和心肌组织学评估 PHEA-DOX 在正常小鼠腹腔内注射的毒理学作用,证明与游离 DOX 相比,PHEA-DOX 具有明显降低的全身毒性和心脏毒性。所有结果表明,由于 PHEA-DOX 具有高治疗效果和较少的不良反应,因此它具有很大的腹腔内化疗潜力。

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