Chemical modification of alginate with tosylmethyl isocyanide, propionaldehyde and octylamine via the Ugi reaction for hydrophobic drug delivery

Abstract

To improve the affinity of alginate to the hydrophobic drug molecules, such as ibuprofen, the Ugi four-component condensation reaction involving sodium alginate (SA), tosylmethyl isocyanide, propionaldehyde and octylamine was proposed to synthesize the novel amphiphilic alginate-bisamide derivative (AABD) without any organic solvents and catalysts. The molecular structure and self-aggregate behavior of the resultant AABD was characterized by FT-IR spectrometer, 1H NMR spectrometer, X-ray diffraction, thermal gravimetric analysis, fluorescence spectrophotometer, transmission electron microscope and dynamic light scattering. Meanwhile, the loading and in vitro release of ibuprofen for the AABD microcapsules prepared by the emulsification method as well as their cytotoxicity were also investigated. Experimental results showed that the AABD with the degree of substitution of 19.41% was successfully prepared by the Ugi reaction, and the grafting of hydrophobic side groups on the backbone of alginate was conducive to enhancing its molecular flexibility and colloidal interface activity. Therefore, the AABD could reveal good amphiphilic property with the critical aggregation concentration (CAC) of 0.105 g/L in 0.15 mol/L aqueous NaCl solution, and form the self-aggregated micelle with the average hydrodynamic diameter of 396 nm (PDI\u2009=\u20090.31) and zeta potential at about −\u200962.4 mV. Furthermore, the prepared AABD microcapsules displayed the high encapsulation efficiency and sustained-release property in comparison with the SA microcapsules for the good affinity of AABD to hydrophobic ibuprofen that retarded the drug diffusion. And it also exhibited low cytotoxicity to the murine macrophage RAW264.7 cells. Therefore, the novel amphiphilic AABD synthesized by the Ugi reaction would be of great potentials as the hydrophobic drug carriers for sustained-release formulations.