Abstract

In order to improve the chemotherapy of tuberculosis, there is an urgent need to enhance the efficacy of existing agents and also to develop more efficient drug delivery systems. Here, we synthesized a novel anti-TB drug complex consisting of zinc and rifampicin (Zn-RIF), and encapsulated it into transferrin-conjugated silver quantum-dots (Zn-RIF-Tf-QD) to improve delivery in macrophages. Successful synthesis of Zn-RIF and Zn-RIF-Tf-QD was confirmed by UV/Vis-spectroscopy, TEM, FTIR, photoluminescence, XRD, XPS, and NMR. The sizes of silver QDs and transferrin-conjugated QDs were found to be in the range of 5–20 nm. Activity assays showed that Zn-RIF-Tf-QD exhibited 10-fold higher antibacterial activity against Mycobacterium smegmatis and Mycobacterium bovis-BCG as compared to Zn-RIF, RIF and Zn. Immunofluorescence studies showed that Zn-RIF-Tf-QD-conjugates were actively endocytosed by macrophages and dendritic cells, but not by lung epithelial cells. Treatment with Zn-RIF-Tf-QD efficiently killed mycobacteria residing inside macrophages without exhibiting cytotoxicity and genotoxicity. Moreover, the conjugates remained stable for upto 48 h, were taken up into the late endosomal compartment of macrophages, and released the drug in a sustainable manner. Our data demonstrate that Zn-RIF-Tf-QDs have a great potential as anti-TB drugs. In addition, transferrin-conjugated QDs may constitute an effective drug delivery system for tuberculosis therapy.

Highlights

  • In order to improve the chemotherapy of tuberculosis, there is an urgent need to enhance the efficacy of existing agents and to develop more efficient drug delivery systems

  • FITC-labeled quantum dots (QDs) were actively internalized by peritoneal macrophages and dendritic cells, but not by A549 lung epithelial cells. These results indicate that zinc and rifampicin (Zn-RIF)-transferrin conjugated QDs (Tf-QDs) are delivered to the macrophages

  • We examined the genotoxicity of Zn-RIF-Tf-QDs against mouse macrophages using the micronuclei and comet assays

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Summary

Introduction

In order to improve the chemotherapy of tuberculosis, there is an urgent need to enhance the efficacy of existing agents and to develop more efficient drug delivery systems. Major limitations associated with the current TB therapy include prolonged treatment duration and the use of high doses of antibiotics, which result in severe adverse effects and non-compliance of the patients. These factors are mainly due to the prevalence of drug resistant bacterial strains. Mycobacteria have developed various strategies to survive and replicate inside macrophages for extended periods of time These strategies include inhibition of phago-lysosome fusion, phagosomal escape, manipulation of phagosomal vesicle environment, and inhibition of oxidative stress responses[4,5,6,7]. Zinc oxide (ZnO) nanoparticles are even more efficient along with reduced toxicity[16]

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