The biomimetic chitosan derivatives synthesized by chemical coupling of L-arginine onto chitosan with low molecular weight, named Arg-CS, which was prepared by mimicking the arginine-rich peptides, to achieve the permeability performance of Cell-penetrating peptides (CPPs). The physicochemical properties of the Arg-CSs were characterized via Attenuated total reflection Fourier transform infrared (ATR-FTIR) and 1H-nuclear magnetic resonance spectroscopy (1H NMR), and high-performance liquid chromatography (HPLC). The thermal stability of Arg-CS was improved by approximately 80 °C, compared to the pure chitosan. The maximum cumulative amounts of aspirin for Arg-CS 4.7 k, Arg-CS 5.2 k, and Arg-CS 6.3 k were 32.85 µg/cm2, 22.98 µg/cm2, and 17.51 µg/cm2 at 8 h, respectively, presenting a phenomenon of increasing of aspirin permeation with decreasing molecular weight of Arg-CS. Arg-CS with low molecular weight was more conducive to improve the penetration of aspirin by changing the secondary structure of keratin from β-sheets to random coil. The molecular docking also suggested that Arg-CS had stronger affinity to keratin by strong hydrogen bond interactions. These results indicated that the nonirritant and thermally stable Arg-CS with lower molecular weight can be used to enhance the permeation of aspirin and applied in the field of transdermal drug delivery.
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