Background:

Methotrexate is one of the most widely used drugs in the treatment of malignancies for several decades. However, its low plasma half-life, toxicity to normal proliferating cells and other limitations impel scientists to search for improved forms of methotrexate. Conjugation of the drug with macromolecular carriers is one of the strategies frequently applied to improve therapeutic properties of anticancer drugs. We developed several conjugates of methotrexate and raltitrexed with different carriers, namely with fibrinogen, albumin, glycated proteins, dextrans and mannan. Conjugates were synthesized in a reaction of active esters or anhydrides of the drugs with amino or hydroxyl groups of carriers. Conjugates were studied both in vitro and in vivo. The majority of our carrier-methotrexate conjugates revealed improved antitumor activity in vivo against P388 leukemia as compared to original methotrexate. Conjugates of raltitrexed with different carriers were not active in therapy of experimental P388 leukemia.

Methods:

Glycation – lyophilizates containing mixture of glucose or fructose with bovine fibrinogen were heated at 65ºC for 30 min. Conjugates of glycated fibrinogen-MTX were obtained in the reaction with methotrexate anhydride. B₆D₂F₁ mice bearing P388 leukemia were i.p. injected once with free MTX or one of the fibrinogen-methotrexate conjugates at a dose of 40 mg/kg.

 Results:  

Up to 30% of all amino groups in fibrinogen carrier were substituted by “carbohydrate” and 25-45% by methotrexate. Depending on the conjugates used, there were 12-62% of mice survived more than two months after administration of conjugates, while the untreated mice died within two weeks. However, in most groups, some mice died of toxic effects of the conjugates.

            Conclusion: Methotrexate substituted fibrinogen is very effective in experimental tumor treatment. 

This project was supported by Ministry of Science and Higher Education, Poland (N N302 098434)

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