pH-Responsive Carbonate-Coupled β-Cyclodextrin Nanocarriers for Levofloxacin Delivery to Enhance Antibiotic Bioavailability

Conventional antibiotics (e.g., levofloxacin) are typically administered orally or by injection for systemic delivery, resulting in a broad therapeutic distribution with poor tissue specificity and consequently low bioavailability at the infection site. In addition, the inherent toxicity and side effects of antibiotics may cause damage to healthy tissues and organs. To address these limitations, we designed an acid-sensitive nanodrug carrier that leverages the mildly acidic microenvironment of infection sites. The carrier was constructed via thiol-ene click reaction between maleimide-containing carbonate conjugates and thiolated β-cyclodextrins, forming a covalent coupling network. The synthesis of the carbonate conjugate and the structure of the carbonate-conjugated β-cyclodextrin nanocarriers (CCCN) were systematically characterized and confirmed using nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (XRPD), surface tensiometry, dynamic light scattering (DLS) and scanning electron microscope (SEM). Drug release studies demonstrated that levofloxacin-loaded CCCN exhibited pronounced pH-responsive release behavior, achieving a cumulative release of 50% within 30 h under acidic conditions, while showing slow release under neutral condition. Antibacterial assays further validated the pH-responsive mechanism: under acidic conditions, the minimum inhibitory concentration (12 h) of the drug-loaded nanocarriers against bacteria was 12.5 μg/mL, and the inhibition zone was significantly larger compared with that under neutral condition. This study confirms that CCCNs can effectively achieve site-specific antibiotic release in acidic infected tissues, significantly enhancing bioavailability, and providing a promising strategy to overcome the poor targeting and side effects associated with traditional antibiotics.