Nanoparticle Encapsulated Lipopeptide Conjugate of Antitubercular Drug Isoniazid: In Vitro Intracellular Activity and in Vivo Efficacy in a Guinea Pig Model of Tuberculosis

Abstract

Considering that Mycobacterium tuberculosis (Mtb) can survive in host phagocytes for decades and currently applied drugs are largely ineffective in killing intracellular Mtb, novel targeted delivery approaches to improve tuberculosis chemotherapy are urgently needed. In order to enhance the efficacy of a clinically used antitubercular agent (isoniazid, INH) a novel lipopeptide carrier was designed based on the sequence of tuftsin, which has been reported as a macrophage-targeting molecule. The conjugate showed relevant in vitro activity on Mtb H37Rv culture with low cytotoxicity and hemolytic activity on human cells. The conjugate directly killed intracellular Mtb and shows much greater efficacy than free INH. To improve bioavailability, the conjugate was encapsulated into poly(lactide-co-glycolide) (PLGA) nanoparticles and tested in vivo in a guinea pig infection model. External clinical signs, detectable mycobacterial colonies in the organs, and the histopathological findings substantiate the potent chemotherapeutic effect of orally administered conjugate-loaded nanoparticles.

In vitro biological evaluation of new antimycobacterial salicylanilide-tuftsin conjugates

“…Palmitoylated tuftsin conjugate of INH (pal-T5(INH) 2 , where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820) 2 ) found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity [40,41]. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH) 2 conjugate significantly inhibited the intracellular M. tuberculosis [42]. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity [41,42].…”

“…Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH) 2 conjugate significantly inhibited the intracellular M. tuberculosis [42]. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity [41,42].…”

Chemical structure and in vitro cellular uptake of luminescent carbon quantum dots prepared by solvothermal and microwave assisted techniques

“…According to the mean fluorescence value, relevant concentration-dependent internalization was observed for both CDQ2 and CDQ3 nanodots ( . It has been shown that hydrophobicity can increase internalization rates of both drugs [69] and nanoparticles [70]. CQD3 was shown to have a more apolar character than CQD2 that could contribute to its higher uptake.…”

Delivery of antituberculosis drugs to Mycobacterium tuberculosis H37Rv infected macrophages via polylactide-co-glycolide (PLGA) nanoparticles

“…Regardless of the overall accessibility of tuberculosis (TB) drugs, long length of the treatment, genuine unfavorable impacts, poor patient consistence and the rise of multidrug safe strains, demonstrates that the recognizable proof of novel antituberculars, the adjustment of existing medications and the improvement of new medication conveyance frameworks to abbreviate TB chemotherapy are direly required. 9 Nanotechnology gives the best stage to pharmacology which gives a conclusion to end answer for the outlining of medication conveyance framework which is fit to target phagocytic cells defiled by intracellular pathogens, e.g. mycobacteria.…”