Cross-Linked Agarose by Reaction with Sodium Trimetaphosphate for Controlled Drug Release

Agarose is an abundant and biocompatible natural polysaccharide, whose promising properties in the biomedical field can be modulated by chemical modifications. Thus, the aim of this research was to cross-link commercial agarose with sodium trimetaphosphate in aqueous sodium hydroxide solution (pH 12). The influence of the addition of sodium sulfate and sodium borohydride in the percentage of phosphorylation, determined by ion exchange chromatography (AEC) with conductometric detection and the molecular weight, were investigated. Nine derivatives (AG1-AG9) were obtained with different cross-linking degrees. Native agarose and the phosphorylated derivatives were characterized by infrared and NMR spectroscopy, rheological behavior, and scanning electron microscopy. It was found that phosphorylation efficiency is directly influenced by the agarose:sodium trimetaphosphate molar ratio and reaction time. 31 P NMR spectra of the derivatives gave only a signal at 0.4 ppm consistent with the presence of monophosphodiester linkages. Phosphorus content was also estimated by 31 P NMR, employing a coaxial insert tube, giving a good correlation with the values obtained by AEC. The conditions employed did not produce significant polymer degradation, maintaining high mass recovery percentages. The molecular weights of the products indicated moderate polydispersity indexes (2.4 ± 0.2), consistent with the predominance of intramolecular cross-linking. The incorporation of phosphate groups significantly impacted the mechanical and viscoelastic properties of the materials. Rheological tests indicated variations in the gelling temperatures associated with the degree of cross-linking, while the melting temperatures remained similar. Scanning electron microscopy morphological analysis showed a clear evolution from slightly porous lamellar matrices to highly porous three-dimensional networks, consistent with a higher density of cross-links. Studies of selegiline release from films in Franz cells confirmed that at least one of the phosphorylated derivatives presented potentiality for controlled release.