Antitumor activity and toxicological properties of doxorubicin conjugated to [alpha],[beta]-poly[(2-hydroxyethyl)-L-aspartamide] administered intraperitoneally in mice.
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.
Cheng
Cheng
C
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China.
Xue
Weihua
W
Diao
Huajia
H
Xia
Suhua
S
Zuo
Longsheng
L
He
Aijun
A
Gao
Fengbo
F
Huang
Zhen
Z
Chen
Jiangning
J
Zhang
Junfeng
J
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008813:Mice, Inbred ICR; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D012510:Sarcoma 180 / Q000188:drug therapy
D000903:Antibiotics, Antineoplastic; D003603:Cytotoxins; D010455:Peptides; C008965:alpha,beta-poly((2-hydroxyethyl)-aspartamide); D004317:Doxorubicin