Pharmacoengineered lipid core shell Nanoarchitectonics to mitigate tuberculosis and Potential translational outcome

Abstract

quotMycobacterium tuberculosis causes pulmonary tuberculosis and make it difficult newlineto cure by taking control of natural defence mechanism of alveolar macrophages. newlineEffective delivery at the site of action is essential to mitigate the disease which is newlinepredominant in the Asia and African regions. In addition, most of the anti-tuberculosis newlinedrugs possess first pass metabolism and rapid clearance. Here, we have envisioned to newlinemodulate the alveolar macrophage uptake by passive, active targeting approaches also newlineto reduce the clearance and improve the lymphatic uptake with help of lipid core shell newlinenanoarchitectonics, which were later embedded into the 3D caplets to give a newlinetranslational approach to the delivery system. Appropriate ligan d was selected through newlinethe molecular docking studies such as SP, XP, FID followed by ADMET properties newlinedetermination by QikProp and Protox tools. Selected candidate subjected for the newlinedynamic studies such as RMSD, RMSF and radius of gyration, where the data shown newlineortho stearoyl mannose (OSM) as potential ligand molecule. OSM was synthesised by newlineesterification method, in vitro characterization and uptake in alveolar macrophage cell newlineline measured. Lipid core-shell nanoarchitectonics were fabricated by double newlineemulsification method, the characterization studies revealed that size in-between 200- newline300nm with a positive charge, smooth surface, drug loaded in amorphous status and a newlinebiphasic release pattern observed. The colocalization studies revealed that ligand newlinetethered nanoarchitectonics possess higher uptake in comparison to the naked newlinenanoarchitectonics. Moreover, colocalization were observed in intracellular newlinecompartments such as early, late endosomal and phagolysosomal compartments. newlineFormulations shown statistically significant higher efficiency in smegmatis infected newlineTHP-1 cell line. Pharmacokinetic a biodistribution studies were conducted in SD rats, newlinethe results demonstrated the reduced renal and hepatic clearance rate, increase in the newlinelymphatic uptake which contributed to inc