Targeted vancomycin delivery via in situ albumin conjugation and acid-triggered drug release for reduced nephrotoxicity.

Vancomycin has long been considered as the last-resort antibiotic for tacking extremely severe infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, its clinical application is limited by dose-limiting nephrotoxicity. In this study, we report a novel in situ albumin conjugation and acid sensitive prodrug strategy to selectively release vancomycin at the infection site, thereby minimizing the accumulation of vancomycin in the kidney and thus reducing its nephrotoxicity. We synthesized and evaluated four vancomycin prodrugs 13a-d and found that 13c effectively bound to plasma albumin in vitro, and released vancomycin rapidly at the infection site. Its therapeutic effect against MRSA USA300 infection was comparable to that of free vancomycin at 10 mg/kg. In vivo safety assessments demonstrated that 13c did not exhibit significant nephrotoxicity at 50 mg/kg, whereas vancomycin caused obvious nephrotoxicity at the same dose. This work represents the first example of utilizing albumin for targeted delivery of antibiotic to the bacterial infection site to mitigate the common dose-limiting nephrotoxicity of vancomycin, and this strategy may also be applicable to other aminoglycoside antibiotics with nephrotoxicity.