Experimental Study of a Novel Stone-dissolution Controlled-release System for Urinary Tract Stones Combined with Urinary Tract Infection

JIAN Fu-mei; LIANG Dong-mei; LU Pei-zhu; LIU Zhen

Abstract：Objective: This study aims to develop a drug controlled-release system based on nano-hydrogel technology for stone dissolution and evaluate its dual efficacy in synchronously dissolving calcium oxalate stones and inhibiting uropathogenic Escherichia coli. Methods: A pH-responsive chitosan (CS)-sodium alginate (SA)-hydrogel microsphere loaded with potassium sodium hydrogen citrate and fosfomycin (CS/SA@PSHC@CS@F) was constructed using ionic cross-linking. In vitro stone dissolution experiments were conducted to determine drug release kinetics and stone mass reduction rate under different pH environments, and the antibacterial activity against E. coli ATCC 25922 was evaluated using the plate counting method. A rat model of kidney stone combined with infection was established. Stone volume changes were quantified via micro-CT, urinary interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) levels were measured by ELISA, and renal tissue inflammation was scored via histopathological evaluation. Results: The 24-hour cumulative release rate of CS/SA@PSHC@CS@F at pH 5.8 reached 92.3%±4.1%, significantly higher than at pH 7.4 (31.2%±3.7%, P<0.01). At 72 h, the mass reduction rate of calcium oxalate stones in CS/SA@PSHC@CS@F was 68.9%±5.2%, significantly higher than that of the PSHC+F mixture (P<0.01). Antibacterial experiments confirmed that the inhibition rate of biofilm colonies by CS/SA@PSHC@CS@F could reach 82.4%±6.7%, compared to 58.2%±5.3% for F, with a statistically significant difference (P<0.01). Animal experiments showed that the stone volume reduction rate in the CS/SA@PSHC@CS@F group was 62.3%±8.1%, higher than that in the PSHC+F group, and the decrease in urinary IL-6 level after administration was more significant, while there was no significant difference in TNF-α level compared with the other two groups (P>0.05). The renal tissue inflammation score decreased to 2 (1,2) points, showing a significant reduction compared with the other two groups (P<0.05). Conclusion: The novel controlled-release system designed in this study achieves targeted drug release in the stone infection microenvironment through the ion exchange mechanism, simultaneously enhancing stone dissolution efficiency and antibacterial effect, thereby providing a new drug delivery strategy for the treatment of urinary stones combined with infection.