Chitosan, a glucosamine polymer usually derived from the shells of crustaceans, has shown substantial potential in drug delivery primarily through both nanoparticle formation and polymer-drug conjugation routes. The ability of chitosan to destabilize cell membranes not only allows it to effectively deliver drugs into human cells but also gives it antibacterial properties by preventing nutrient uptake in bacterial cells. However, its insolubility at physiological pH and lack of reactive sites significantly limits its pharmacological applicability. Thus, in this work, we present a straightforward process for the functionalization of chitosan through the attachment of carboxylic acid groups, starting with the amidification of its amino group and concluding with the addition of a 3,4-dihydroxybenzoic acid linker by azo coupling. Fourier transmission infrared spectroscopy (FTIR) analysis was used to confirm the products of each step. Subsequent spectral analysis showed an 11% degree of linker substitution. As proof of concept, we attached methoxypolyethylene glycol-NH2 (mPEG-NH2), which has been shown to be able to penetrate cell membranes and further improve the attachment of other molecules to cell membranes, to the linker through NHS/EDC coupling. When tested on Escherichia coli (E. coli), the PEG-chitosan copolymer showed significantly higher bactericidal activity compared to unmodified chitosan, indicating the successful functionalization of chitosan. Furthermore, our novel functionalization method allows for the attachment of a wide variety of molecules to chitosan, including drugs, targeting peptides, and other polymers, providing a versatile foundation for the further implementation of chitosan in antimicrobial and drug delivery applications.

Novel synthesis of PEG-chitosan copolymers through a 3,4-dihydroxybenzoic acid linker for enhanced antibacterial activity: An adaptable approach

ACS Spring 2022

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