title: Release studies from smart hydrogels as carriers for piroxicam and copper(II)-oxicam complexes as anti-inflammatory and anti-cancer drugs. X-ray structures of new copper(II)-piroxicam and -isoxicam complex molecules.
abstract: Piroxicam H(2)PIR (H(2)PIR, 4-hydroxy-2-methyl-N-pyridin-2-yl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide), [Cu(HPIR)(2)(H(2)O)(2)] previously prepared and tested from this laboratory and at National Institute of Health, National Cancer Institute, Developmental Therapeutic Program, NIH-NCI-DTP, USA [R. Cini, G. Tamasi, S. Defazio, M.B. Hursthouse, J. Inorg. Biochem. 101 (2007) 1140-1152, and references cited therein], [Cu(HMEL)(2)(DMF)] (H(2)MEL, 4-hydroxy-2-methyl-N-(5-methyl-1,3-thiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide; DMF, N,N-dimethylformamide), [Cu(HISO)(2)] (H(2)ISO, 4-hydroxy-2-methyl-N-(5-methylisoxazol-3-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide), and [Cu(HTEN)(2)(H(2)O)(2)] (H(2)TEN, 4-hydroxy-2-methyl-N-pyridin-2-yl-2H-thieno[2,3-e][1,2]thiazine-3-carboxamide 1,1-dioxide), were loaded on CMH2 hydrogel (co-1:10-poly(N-methacryloyl-L-histidine-co-N-isopropylacrylamide) cross-linked with N,N'-ethylene-bis-acrylamide (EBA) 2%) and the kinetics of release of Cu-HPIR species in several media were studied. The release of Cu(HPIR)(2) in DMSO from CMH2 hydrogel after swelling and loading from DMSO followed a diffusion controlled process. The release of Cu(HPIR)/Cu(HPIR)(2) from dried CMH2 hydrogel after swelling and loading from THF solution, then soaking into water/DMSO 95:5 v/v (pH 5.6) followed a relaxation controlled and diffusion controlled mechanism. The amount of Cu(HPIR)(2) released in the medium reached 0.03 microg Cu/mg gel/mL, i.e. ca 0.8 microM within 48 h that compares well with the IC(50) values reported for metal based drugs like carboplatin (diammino(1,1-cyclobutandicarboxylato)platinum(II)) against certain human tumor cell lines. The release studies performed by monitoring both the absorbance values at 362 nm (sensitive to metal-bound HPIR(-)) and the content of Cu via AAS, showed an excellent agreement with the Cu(HPIR)(2) or Cu(HPIR)(2) stoichiometry, depending on the delivery medium. Corresponding studies were performed for other Cu(oxicam-H)(2) species in different delivery media.
authors.affiliation: Dipartimento di Scienze e Tecnologie Chimiche e dei Biosistemi, Università degli Studi di Siena, Via Aldo Moro 2, 53100-Siena, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Tamasi
authors.forename: Federica
authors.initials: F
authors.lastname: Serinelli
authors.forename: Marco
authors.initials: M
authors.lastname: Consumi
authors.forename: Agnese
authors.initials: A
authors.lastname: Magnani
authors.forename: Mario
authors.initials: M
authors.lastname: Casolaro
authors.forename: Renzo
authors.initials: R
authors.lastname: Cini
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry*; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D010894:Piroxicam / Q000031:analogs & derivatives* / Q000737:chemistry*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D020100:Hydrogels; D009942:Organometallic Compounds; D010894:Piroxicam; D003300:Copper; C013580:isoxicam; D004121:Dimethyl Sulfoxide