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

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...

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Bibliographic Details
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
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Summary: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
ISSN:0021-8995
1097-4628
DOI:10.1002/app.2027