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

A polymer–drug conjugate was developed by conjugating doxorubicin (DOX) to α,β-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.