Long-acting antituberculous therapeutic nanoparticles target macrophage endosomes.
Bottom Line: Coadministration of nanoformulated RIF and INHP provided a 6-fold increase in therapeutic efficacy compared with equivalent concentrations of native drugs.Notably, nanoformulated RIF and INHP were found to be localized in recycling and late MDM endosomal compartments.Our results demonstrate the potential of antimicrobial nanomedicines to simplify MTB drug regimens.
Affiliation: Department of Pharmacology and Experimental Neuroscience, and.Show MeSH
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Mentions: To assess whether combination therapy would improve antimicrobial activity, MDMs were treated with various concentrations of RIF/INHP combinations of either nanoformulations or NDs before M. smegmatis exposure. We evaluated the effect of individual drug concentration on mycobacterium suppression by varying the concentration of each drug used in combination for both NDs and the nanoformulations (Fig. 3). Comparison of mycobacterium suppression profiles for the nanoformulations and NDs followed a similar trend. Combined RIF/INHP at 300/300 μM exhibited the most sustained antimicrobial efficacy and enhanced antimicrobial activity for both NDs (Fig. 3A) and nanoformulations (Fig. 3B) compared with individual drugs (Fig. 2B, C). Of significance, the 300/300 μM RIF/INHP nanoformulations suppressed mycobacterial replication over a 10 d period. The antimicrobial activity on d 1 and 5 after drug loading for the RIF/INHP nanoformulations was 3- and 5-fold greater than for native RIF/INHP. In the 300/200 μM RIF/INHP treatments the differences in the activity against mycobacterial replication was up to 4-fold higher in the nanoformulation arm when compared with NDs on d 1 and 5 after drug loading. Treatment of MDM with 200/300 μM RIF/INHP resulted in a 2-fold difference in antimicrobial efficacy between the nanoformuations and the NDs. For NDs a concentration of 200 μM of either drug in the combination suppressed mycobacterial infection 1.3- to 1.7-fold on d 1 after drug loading but was diminished by d 5. For nanoformulated drug combinations, a combination of 300/300 μM RIF/INHP provided 4.5- to 5-fold suppression of mycobacterial growth on d 1 and 5 after drug loading, while the 200/300 μM RIF/INHP combination provided only 1.1- to 1.5-fold suppression. Of significance, no mycobacterium suppression was observed for either NDs or the nanoformulations when infection occurred on d 10 after drug loading if the concentration of either drug in the combination was reduced to 200 μM.
Affiliation: Department of Pharmacology and Experimental Neuroscience, and.