Poly(malic acid) Nanoconjugates of Pyrazinoic Acid for Lung Delivery in the Treatment of Tuberculosis.

Abstract

Tuberculosis (TB) remains a major global infection, and TB treatments could be improved by site-specific targeting with delivery systems that allow tissue and cell uptake. To increase the drug concentration at the target sites following lung delivery, polymeric nanoconjugates based on biodegradable poly(malic acid) were designed. Pyrazinoic acid (POA), the active moiety of pyrazinamide─a first-line antituberculosis drug─was covalently bound to poly(malic acid) using a hydrophobic linker at mole ratios of 25%, 50%, and 75%. Three linkers, hexanediol, octanediol, and decanediol, were considered. Independently of the linker or ratio, all the conjugates were able to self-assemble, forming nanoconjugates (NCs) in water with 130-190 nm in diameter. Pyrazinoic acid could be released in a controlled manner without any burst release effect. Its kinetics can be adjusted by modifying the grafting ratio and linker length. No cytotoxicity was observed on RAW 264.7 macrophages up to ∼14 μg/mL of POA. In addition, the nanoconjugates were efficiently taken up by these cells over 5 h. Thanks to their high loading capacity and modulable release profiles, these nanoconjugates hold great promise for more effective treatment of tuberculosis.