Targeted intracellular delivery of antitubercular bioactive(s) to Mtb infected macrophages via transferrin functionalized nanoliposomes

[Display omitted] •Two antitubercular drug(s) with different solubility characteristics were entrapped in aqueous core of SUVs using 2-hydroxylpropyl-β-cyclodextrin (HP-β-CD) - Rifampicin (RIF) complexation for solubilization of RIF.•Subsequently, SUVs were functionalized using transferrin (Tf) as a targeting ligand which resulted into better therapeutic efficacy as reflected in residual parasitic load in infected macrophages as well as cellular uptake studies conducted on the developed formulation(s).•It was found to be better stable, lyophilizable, reproducible on reconstitution, capable to overcome/avert drug resistance.•It can be formulated as dry powder insufflations for pulmonary delivery specifically used for pulmonary tuberculosis. The packaging of antimicrobials/chemotherapeutics into nanoliposomes can enhance their activity while minimizing toxicity. However, their use is still limited owing to inefficient/inadequate loading strategies. Several bioactive(s) which are non ionizable, and poorly aqueous soluble cannot be easily encapsulated into aqueous core of liposomes by using conventional means. Such bioactive(s) however could be encapsulated in the liposomes by forming their water soluble molecular inclusion complex with cyclodextrins. In this study, we developed Rifampicin (RIF) − 2-hydroxylpropyl-β-cyclodextrin (HP-β-CD) molecular inclusion complex. The HP-β-CD-RIF complex interaction was assessed by using computational analysis (molecular modeling). The HP-β-CD-RIF complex and Isoniazid were co-loaded in the small unilamellar vesicles (SUVs). Further, the developed system was functionalized with transferrin, a targeting moiety. Transferrin functionalized SUVs (Tf-SUVs) could preferentially deliver their payload intracellularly in the endosomal compartment of macrophages. In in vitro study on infected Raw 264.7 macrophage cells revealed that the encapsulated bioactive(s) could eradicate the pathogen more efficiently than free bioactive(s). In vivo studies further revealed that the Tf-SUVs could accumulate and maintain intracellular bioactive(s) concentrations in macrophages. The study suggests Tf-SUVs as a promising module for targeted delivery of a drug combination with improved/optimal therapeutic index and effective clinical outcomes.