Carrier-bound methotrexate. I. Water-soluble polyaspartamide-methotrexate conjugates with ester links in the polymer-drug spacer

• Published in: Journal of applied polymer science 2001-11, Vol.82 (8), p.1844-1849
• Main Authors: Meirim, M. G., Neuse, E. W., N'Da, D. D.
• Format: Article
• Language: English
• Subjects: Agents; antifolate agent; Applied sciences; Aromatic compounds; bioavailability; Biological and medical sciences; Diseases; Esters; Exact sciences and technology; General pharmacology; macromolecular carrier; Macromolecules; Medical sciences; methotrexate; Natural polymers; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Physicochemistry of polymers; Polyamides; polymer-drug conjugation; Proteins; Purification; Reaction kinetics; Solubility; Water
• ISSN: 0021-8995; 1097-4628
• DOI: 10.1002/app.2027

The antifolate‐type anticancer drug methotrexate (MTX) has for many years, in numerous laboratories, been a “workhorse” drug for conjugation with natural and synthetic macromolecular carriers for the purpose of enhancing bioavailability and lowering toxic side effects. In the project here described the polymer–drug conjugation strategy is utilized for the preparation of water‐soluble polyaspartamide–methotrexate conjugates in which the drug is carrier‐anchored through short spacers containing ester groups as biofissionable links. To this end, polyaspartamide carriers 1, poly‐α,β‐D,L‐N‐(2‐hydroxyethyl)aspartamide, and 2, poly‐α,β‐D,L‐N‐[2‐(2‐hydroxyethoxy)ethyl]aspartamide, are treated with MTX in DMF solution in the presence of a carbodiimide coupling agent and 4‐(dimethylamino)pyridine catalyst. The molar MTX/OH feed ratios, 0.28 and lower, are chosen in these coupling reactions so as to provide conjugates featuring drug‐loading levels in the approximate range of 3–16 mol % MTX, roughly corresponding to 6–28% by mass. The water‐soluble product polymers are purified by aqueous dialysis, collected in the solid state by freeze‐drying, and structurally characterized by 1H–NMR spectroscopy. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 82: 1844–1849, 2001