oa South African Journal of Chemistry - Carrier-bound Methotrexate. IV. Antiproliferative Activity of Polyaspartamide-MTX Conjugates against Leukemic Lymphoblast Cell Lines
Polymeric conjugates of methotrexate (MTX) with macromolecular carriers, obtained from amine-functionalized polyaspartamides by coupling with one of the drug's carboxyl groups, are used in this preliminary screening project for in vitro cytotoxicity assessment. The water-soluble conjugates, crudely fractionated by aqueous dialysis, possess mass-average molecular masses in the range of 20000-30000. Screens are performed by standard procedures against cultured CEM/S human leukemic lymphoblast cells, a drug-sensitive line, and against CEM/E, its drug-resistant subline, for comparison also against unconjugated MTX. All compounds tested, including the unconjugated drug, display decreasing activity on going from CEM/S to CEM/E, resistance factors (IC50 [CEM/E]/IC50 [CEM/S]) being in the vicinity of 15-20 for MTX as well as for the majority of conjugates. On the other hand, comparisons of IC50 values for conjugates versus free drug, both against CEM/S and CEM/E, show vastly superior antiproliferative performance of the drug in the carrier-anchored state over the free form, with activity factors (IC50 [free MTX]/IC50 [conjugate]) typically in the 10-50 range and higher. On the basis of these promising in vitro findings, the polyaspartamide-MTX conjugates are considered to be excellent candidates for further cell culture and extended in vivo tests.
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