Development and Evaluation of Macrophage Targeted Preactivated Thiolated Nanomedicine for Therapeutic Management of Tuberculosis

Abstract

The contemporary study was intended to synthesize mannose anchored preactivated thiolated chitosan (MPTCh) polymeric scaffold as enveloping and capping/stabilizer biomolecule in order to target Mycobacterium tuberculosis infected macrophages overexpressed with mannose receptors. The surface capping or stabilizing as well as targeting potential of MPTCh polymeric graft or scaffold was evaluated by the synthesis of two types of formulation of nanocarriers i.e., mannose anchored preactivated thiolated chitosan nanocargoes (MPTCh-NCs) and mannose coated preactivated thiolated chitosan capped silver-Rif nanocomposites (MPTCh-AgRif NCs) by employing Rif as a classical anti-mycobacterial drug. The recently developed MPTCh polymeric scaffold was characterized in order to ratify the grafting as well altered physicochemical properties in comparison to unmodified chitosan. The MPTCh polymer capped/enveloped nanocargoes and silver nanocomposites were also characterized for particle size, surface charge, PDI, encapsulation potential, FTIR spectroscopy analysis, differential scanning calorimetry (DCS) X-ray diffraction analysis (XRD), drug release profile as well as stability. The hydrodynamic diameter of the MPTCh-NCs and MPTCh-AgRif-NCs was 390 nm and 106.4 nm respectively. The MPTCh-NCs and MPTCh-AgRif-NCs exhibited low PDI and positive surface charge owing to increased stability due to stabilization potential of MPTCh polymeric scaffold. The slow and gradual swelling and mucoadhesion capacity of thiomeric polymer resulted in sustained in vitro drug release of Rif. The in vitro anti mycobaterial studies via giemsa staining and flow cytometric analysis exhibited efficient pathogen demise in MPTCh-NCs and MPTCh-AgRif-NCs treated Mycobacterium tuberculosis infected macrophages. The permeation enhancement potential of the thiomeric polymer resulted in improved oral bioavailability and pharmacokinetic parameters of Rif by MPTCh-NCs and MPTCh-AgRif-NCs. Both MPTCh-NCs and MPTCh-AgRif-NCs exhibited no evidence of hepatotoxicity with acute oral toxicity evaluation as well as real time PCR analysis. These evidences suggest the possible potential of MPTCh polymeric scaffold as efficient enveloping and capping/stabilizing agent for diverse nanocarriers for intracellular targeting.