Design, Synthesis, and Characterization of Novel Pyrazole Cross-Linked Chitosan Derivatives Modified with Zinc Oxide Nanoparticles for Boosting Their Anticancer Activity

A new series of chitosan-based pyrazole derivatives was successfully prepared via crosslinking chitosan using either malonopyrazole (MPy-Cs) or thiopyrazole (TPy-Cs). Three derivatives of TPy-Cs were produced based on their content of TPy, namely TPy-Cs1, TPy-Cs2, and TPy-Cs3 of crosslinking degrees of 71, 48, and 29%, respectively. Further, various weight ratios of ZnO nanoparticles were loaded into some of these derivatives to obtain the corresponding ZnONP bio-composites. FTIR, XRD, SEM, and TEM techniques were employed to emphasize the chemical, internal, and morphological structure of these derivatives. Although MPy-Cs derivatives did not show any activity against all the examined cancer cell lines, TPy-Cs derivatives exhibited an appreciable anticancer activity which greatly improved with increasing their TPy content, i.e., from TPy-Cs3 to TPy-Cs1. The TPy-Cs1 displayed IC₅₀ (14.4 μg/mL) against the HN9 cell line that was comparable to the Doxorubicin (DOX) standard drug (12.6 μg/mL). Among all the prepared composites, TPy-Cs3/ZnONPs-5% was the most potent anticancer candidate against all the tested cancer cell lines, although it does not exceed the anticancer activity of DOX. Tpy-Cs2 and its ZnONP composites were safe on normal human skin fibroblast (HSF) cell lines. Thus, the inclusion of both TPy and ZnONPs into the chitosan matrix fostered its anticancer efficiency.