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Synthesis and NMR Characterization of New Hyaluronan-Based NO Donors

Chiara Di Meo,^† Donatella Capitani,^‡ Luisa Mannina,^‡^§ Enzo Brancaleoni,^‡ Devis Galesso, Gilda De Luca, and Vittorio Crescenzi*^†

Department of Chemistry, University of Rome La Sapienza, p.le Aldo Moro 5, 00185 Rome, Italy, Institute of Chemical Methodologies, CNR, Research Area of Rome, Via Salaria Km 29,300, 00016 Monterotondo Stazione, Rome, Italy, S.T.A.A.M. Department, University of Molise, 86100 Campobasso, Italy, and Fidia Farmaceutici SpA, Via Ponte della Fabbrica 3/a, I-35031 Abano Terme, Padua, Italy

Biomacromolecules, 2006, 7 (4), pp 1253–1260

DOI: 10.1021/bm050904i

Publication Date (Web): March 10, 2006

†

University of Rome “La Sapienza”.

‡

Institute of Chemical Methodologies.

University of Molise.

Fidia Farmaceutici SpA.

To whom correspondence should be addressed. E-mail: vittorio.crescenzi@uniroma1.it.

Abstract

Nitric oxide (NO) and hyaluronic acid (HA), two species widely different in terms of molecular complexity and biological competence, are both known to play an important role in the wound healing process. To combine the properties of HA and NO, we synthesized new NO-donors based on hyaluronic acid derivatives exhibiting a controlled NO-release under physiological conditions (in vitro tests). Since two molecules of NO can form a covalent bond with secondary amines to yield structures, named NONO-ates, able to release NO in solution, we used spermidine bound to HA as the NO-linker. The HA−spermidine derivative was obtained by controlled HA amidation in aqueous media, activating the biopolymer carboxylate groups with a water soluble carbodiimide. The resulting derivative, soluble in water, was fully characterized by high field ¹H and ¹³C NMR spectroscopy. The amount of grafting of spermidine on HA was determined by integration of suitable ¹H NMR signals. In addition, cross-linked derivatives of HA were synthesized by the Ugi's four-component reaction using formaldehyde, cyclohexylisocyanide, and spermidine. The HA−spermidine networks were characterized by ¹³C CP-MAS NMR spectroscopy. The degree of cross-linking of the networks was also determined. Finally, the release of NO from the swollen hydrogels freshly saturated with NO, in contact with aqueous media, was monitored by means of UV spectrophotometric measurements.

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