Advanced therapeutic strategy: A single-dose injection of a dual-loaded 6-mercaptopurine gelatin-based hydrogel for effective inhibition of tumor growth.

The suboptimal aqueous solubility and pronounced systemic toxicity pose significant constraints on the clinical utility of 6-mercaptopurine (6-MP). This study presents an innovative approach using injectable sustained-release hydrogels for localized drug delivery. A gelatin-based anticancer hydrogel (Gel-MP@Gel@6-MP) was developed to deliver 6-MP through both physical encapsulation and chemical coupling via CS bonds, providing a multistage sustained release platform. In vitro experiments demonstrated that physically encapsuled drug achieved rapid release within 4 h, comparable to intravenous administration kinetics. Furthermore, in the presence of glutathione (GSH), nucleophilic attack triggered slow release of S-(6-purinyl) glutathione (PG) and a minor amount of 6-MP, with sustained release observed for up to 96 h. This suggests that, in contrast to conventional delivery methods, the proposed system not only facilitates an initial high-concentration drug release lasting hours, but also enables the sustained release of drug fragments over an extended period of several days, owing to the gradual cleavage of chemical bonds following one single injection. Ultimately, in vivo antitumor studies revealed superior tumor inhibition with Gel-MP@Gel@6-MP compared to free 6-MP. This dual drug loading strategy significantly prolongs drug action duration and obviates the necessity for repeated drug administrations, thereby revealing the diverse modes of drug administration.