Abstract
The presence of a thick waxy envelop, the drug efflux and the maintenance of a reductive environment via mycothione reductase pathway help Mycobacterium tuberculosis (M.tb) to survive intracellularly and serve as major contributing factors towards development of drug resistance. Bearing this in mind, in this work cholesterol conjugated thiolated stereocomplexed nanomicelles (thPEI(CH)-ScM) were prepared to increase the transport of rifampicin into M.tb (H37-Rv) infected alveolar macrophages along with efflux pump and mycothione reductase (Mtr) inhibition. Rifampicin-loaded cholesterol decorated thPEI(CH)ScM showed improved in vitro drug release, intestinal mucopenetration, macrophage uptake, mycobacterial inhibition potential and biocompatibility compared to cholesterol conjugated stereocomplexed nanomicelles (PEI(CH)-ScM) and stereocomplexed nanomicelles (ScM). The minimum inhibitory concentration (MIC) of thPEI(CH)-ScM against M.tb (H37-Rv) was found to be significantly lower than that of the free drug and ScM. These thiolated micelles also exhibited efflux pump inhibition and prolonged retention in alveolar macrophages along with Mtr inhibition with an inhibitor constant (Ki) value of 2.74 and half-maximum inhibition concentration (IC50) of 4.73 lg/ml. In vivo studies demonstrated significantly higher reduction in M.tb (H37-Rv) CFU by thPEI(CH)-ScM, a preferential uptake in lungs along with improved pharmacokinetics and reduced dosing frequency compared to PEI(CH)-ScM and ScM. Thus, rifampicin-loaded thPEI(CH)-ScM can be regarded as a stable, biocompatible and efficient nanocarrier system with better drug uptake due to cholesterol conjugation as well as improved drug retention and accumulation within infected alveolar macrophages via efflux pump and Mtr inhibition. (c) 2022 The Author(s). Published by Elsevier B.V.