Mesoporous Nanoparticle-Mediated Ratio-metric & Controlled Release of D-Cycloserine and Levofloxacin: Comparing Chloroacetyl Chloride and Succinyl Chloride Conjugates with Physical Mixture for MDR Tuberculosis Treatment
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Background: The treatment of multi-drug-resistant tuberculosis (MDR-TB) is complicated by resistance to multiple anti-tubercular drugs. This study explores a mesoporous nanoparticle-based approach for the ratiometric and controlled delivery of D-Cycloserine and Levofloxacin to combat MDR-TB. Objective: To synthesize, characterize, and compare the efficacy of mesoporous nanoparticles loaded with D-Cycloserine and Levofloxacin conjugates, using Chloroacetyl Chloride (CAC) and Succinyl Chloride (SCL) as cross-linkers, against a physical mixture for MDR-TB treatment. Methods: Two dual-drug conjugates were synthesized: D-Cycloserine-Chloroacetyl Chloride-Levofloxacin (DCL) and D-Cycloserine-Succinyl Chloride-Levofloxacin (DSL). The conjugates' stability was assessed via hydrolysability testing. Both conjugates, along with a physical mixture of D-Cycloserine and Levofloxacin, were loaded into mesoporous nanoparticles. The nanoparticles were characterized (SEM, FTIR, NMR, particle size, zeta potential, PDI, %EE), and evaluated for in vitro drug release, in vivo pharmacokinetic behavior, and in vitro activity against M. tuberculosis H37Rv. Results: Mesoporous nanoparticles demonstrated favorable characteristics for drug delivery. Notably, nanoparticles loaded with DSL exhibited more sustained drug release. In vitro microbiological studies showed that dual-drug conjugates, particularly DSL-loaded nanoparticles, exhibited superior synergistic activity against M. tuberculosis H37Rv compared to the physical mixture. Conclusion: Mesoporous nanoparticles provide a promising platform for the ratiometric and controlled delivery of D-Cycloserine and Levofloxacin. Conjugation with SCL offers a potential advantage for sustained drug release and enhanced efficacy in MDR-TB treatment compared to CAC conjugates and the physical drug mixture.
