Antitumor Properties and Toxicity of Dextran-methotrexate Conjugates are Dependent on the Molecular Weight of the Carrier

Abstract

Methotrexate (MTX) is widely utilized in the clinical treatment of many forms of cancer. However, the drug has a short plasma half-life and causes toxic effects on normal proliferating cells. Conjugation with carriers is a possible way to alter these disadvantageous pharmacokinetics. Our aim was to synthesize dextran-MTX (D-MTX) conjugates, using carriers with molecular weights (Mw) ranging from 10 kDa to 500 kDa. Their in vitro and in vivo properties were compared with free MTX. The in vitro studies revealed that D-MTX conjugates had 4- to 10-fold lower antiproliferative effects against neoplastic cell lines compared to free MTX. There was a negative relationship between the Mw of the carrier and the antiproliferative effect of the respective conjugate. The data obtained in a mouse leukemia P388 in vivo model suggested that a lower in vitro antiproliferative effect of the conjugates does not result in diminished antileukemic activity in vivo. The toxicity of the conjugates was greater in comparison with the parent drug and tended to rise with increasing Mw. However, no superiority over free MTX in terms of an antileukemic effect was demonstrated. In particular, the D-MTX conjugate based on the dextran with Mw 10 kDa showed a comparable antileukemic effect with an even lower toxicity than that of free MTX. The data suggest that at least the toxicity of conjugates is dependent on the Mw of the carrier. This fact should be taken into account when designing new anticancer polymer-drug compounds.