Abstract In this paper, l‐lysine (Lys), l‐glutamate (Glu), and l‐glutamine (Gln) grafted‐chitosan (CS) polymers (AA‐g‐CS) are prepared by the one‐pot method using EDC/NHS as coupling agents. The introduction of AA into the backbone structure of CS improves its solubility in the pH range of 6.0–7.0. Moreover, AA‐g‐CS/glycerophosphate hydrogel (AA‐g‐CS/GP hydrogel) prepared by physical cross‐linking has better thermosensitivity and can achieve the sol–gel transition in very short order. AA‐g‐CS/GP hydrogel has a dense three‐dimensional network structure, conducing to the loading of the hydrophobic drugs, and its pore size and pore wall are affected by Lys, Glu, and Gln. Berberine hydrochloride (BBH) is encapsulated within the three‐dimensional mesh of the hydrogel. And the addition of BBH has no significant effect on the structure of AA‐g‐CS/GP hydrogel. The optimal parameters for AA‐g‐CS/GP hydrogel loaded BBH (BBH@AA‐g‐CS/GP hydrogel) are the concentration of AA‐g‐CS is 4.5 and the volume ratio of AA‐g‐CS/GP is 1.4/0.6. It is shown that BBH@Lys‐g‐CS/GP hydrogel, BBH@Glu‐g‐CS/GP hydrogel, and BBH@Gln‐g‐CS/GP hydrogel have better‐sustained release effect. Moreover, the sustained release of BBH@Lys‐g‐CS/GP hydrogel is the best, and the cumulative release rate is about 56 in 24 h. Therefore, AA‐g‐CS/GP thermosensitive hydrogel is expected to be an excellent vehicle for sustained release of drugs.
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