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Abstract: Macromolecular prodrugs of three non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen, ketoprofen, and naproxen, were prepared by the covalent attachment of the drugs onto chondroitin sulfate (ChS) using PEG 1000 as a spacer. Drug–PEG adducts were synthesized using 1,1′-carbonyl diimidazole as a coupling agent in dimethyl sulfoxide, followed by the reaction with ChS in highly dilute aqueous solution at pH 6.8 via N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) as a conjugation agent. The drug–ChS conjugates were confirmed by FTIR, 1H NMR and 13C NMR and the molar percent of drug substitution onto ChS was characterized by 1H NMR using the peak areas of the three protons of –ΦCHCH 3 on the drugs to those of –NHCOCH 3 on ChS. All drug–ChS conjugates are water-soluble. The release amounts of the free drugs from their corresponding drug–ChS conjugates were evaluated in the presence or absence of either esterase or chondroitinase, and the both enzymes in pH 7.4 Tris-buffer solutions at 37°C by high performance liquid chromatography (HPLC). Keto–ChS conjugates released ∼100% ketoprofen within 12h in the presence of esterase, but the combination with chondroitinase did not accelerate the release rate. The degradation of Keto–ChS conjugates by chondroitinase was confirmed by gel permeation chromatography (GPC). The Keto–ChS conjugates still retained the enzymatic recognition even at the substitution of ketoprofen as high as 56mol%. The inhibition percent of carrageenan-induced edema of Keto–ChS-56 was comparable to that of a simple blend of ChS and ketoprofen, suggesting that biologically active ChS and ketoprofen could be liberated from the conjugate. [Copyright &y& Elsevier]