Carrier Effects on Antitumor Activity and Neurotoxicity of AZ10992, a Paclitaxel–Carboxymethyl Dextran Conjugate, in a Mouse Model

Abstract

AZ10992 is a novel paclitaxel–carboxymethyl (CM) dextran conjugate via a Gly–Gly–Phe–Gly linker with the molecular weight (MW) of 150 kDa. Our previous studies demonstrated that AZ10992 exerts strong antitumor activity against the human tumor xenografts that are highly refractory to paclitaxel, attributable to passive tumor targeting of released paclitaxel. This study examines the effects of carrier MW, anionic charge and drug-contents on the antitumor effects of AZ10992. To study antitumor effects, colon26 carcinoma-bearing BALB/c female mice received repeated (3 injections administered with 7 d intervals) intravenous administration of non-polymer-bound paclitaxel or paclitaxel–CM dextran conjugates. The results indicated that the conjugate comprising dextran T-110 (MW 110 kDa) with the degree of substitution (DS) value for the CM group of 0.50—0.55 per glucose residue and the drug contents of 5.5—6.5% (w/w) would be appropriate for AZ10992 regarding antitumor activity. Maximal tolerated dose (MTD) of AZ10992 was more than twice of non-polymer-bound paclitaxel. Furthermore, normal BALB/c female mice were treated with repeated (3 injections administered with 2 d intervals) intravenous administration of non-polymer-bound paclitaxel or AZ10992 at 50 mg/kg/d (based on the amount of paclitaxel to CM dextran) to study neurotoxicity. AZ10992 did not induce degeneration of myelin or swelling of Schwann cells in sciatic nerves.