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 [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.