Synthesis of an Enzyme‐Triggered Chitosan‐Based Drug Delivery System for Peri‐Implantitis Prevention

Dental implants have become a leading solution for tooth loss, yet bacterial infections remain a major complication. Antibacterial implant coatings are an important approach to reduce or prevent bacterial infections at the implant. Given the oral cavity's complex microbiome and the importance of some commensal bacteria, it is crucial to develop antibacterial implant coatings that release the active ingredient only when needed. In this work, an enzyme-triggered drug delivery coating based on chitosan with ciprofloxacin as antibiotic was synthesized. The ciprofloxacin is covalently bound via a self-immolative linker with an enzyme-labile group. The linker-drug conjugate was bound to modified chitosan through a Diels-Alder click reaction. A stable drug-delivering coating was assembled on titanium by alternating cationic chitosan with the drug with anionic alginate using layer-by-layer dip-coating. Ellipsometry was used to characterize the coating and demonstrating its stability. The function of the enzyme-labile self-immolative linker was clearly demonstrated by release experiments and detection of genuine ciprofloxacin using UHPLC/HRAM-MS and MS/MS. Furthermore, its biocompatibility was confirmed. After enzymatic activation, the coating exhibited antibacterial activity against an A. naeslundii biofilm. This provides proof of principle for this enzyme-responsive approach to drug delivery.