The main objective of this study was to investigate polyethylene imine (PEI) based stereocomplexed nanomiceles for intracellular delivery of rifampicin against Mycobacterium bovis (M. bovis) and their in vitro-in vivo evaluation. The formation of Rifampicin (Rif) loaded isotactic (PEI-g-PLLA and PEI-g-PDLA) and stereocomplexed nanomicelles (StM) of PEI conjugated poly l- and poly d-lactic acid via self-assembly was thoroughly explored. Synthesis of polymer graft was confirmed via FTIR and NMR. A 2-fold reduction in CMC of StM was observed along with decreased particle size in comparison to isotactic nanomicelles. In vitro, StM exhibited a higher encapsulation efficiency and 84 % of drug release in 48 h. at pH 5 with minimal initial burst release in comparison to isotactic nanomicelles. Minimum inhibitory concentration (MIC) of StM was found to be four folds lower in contrast to isotactic nanomicelles. Ex vivo studies exhibited a better uptake of StM and minimum cytotoxicity in murine alveolar macrophages. Following oral administration in mice, drug loaded StM exhibited highest distribution in macrophage rich organs, longer half-life, AUC, AUMC and MRT in comparison to isotactic nanomicelles indicating maximum bioavailability and efficacy of StM. In vivo antimycobacterial activity also demonstrated a higher reduction (2.38fold) in M. bovis CFU at reduced dosing frequency by drug loaded StM in comparison to control group. Thus, StM can be regarded as a simple, stable, efficient, and biocompatible carrier system for delivery of rifampicin to intracellular M. bovis with added advantage of reduced dosing frequency and improved patient compliance.
Keywords: Intracellular targeting; Mycobacterium bovis; Poly l-lactic acid; Polyethylene imine; Stereocomplexed nanomicelles.
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