Preclinical Evidence of Nanomedicine Formulation to Target Mycobacterium tuberculosis at Its Bone Marrow Niche

Abstract

One-third of the world’s population is estimated to be latently infected with Mycobacterium tuberculosis (Mtb). Recently, we found that dormant Mtb hides in bone marrow mesenchymal stem cells (BM-MSCs) post-chemotherapy in mice model and in clinical subjects. It is known that residual Mtb post-chemotherapy may be responsible for increased relapse rates. However, strategies for Mtb clearance post-chemotherapy are lacking. In this study, we engineered and formulated novel bone-homing PEGylated liposome nanoparticles (BTL-NPs) which actively targeted the bone microenvironment leading to Mtb clearance. Targeting of BM-resident Mtb was carried out through bone-homing liposomes tagged with alendronate (Ald). BTL characterization using TEM and DLS showed that the size of bone-homing isoniazid (INH) and rifampicin (RIF) BTLs were 100 ± 16.3 nm and 84 ± 18.4 nm, respectively, with the encapsulation efficiency of 69.5% ± 4.2% and 70.6% ± 4.7%. Further characterization of BTLs, displayed by sustained in vitro release patterns, increased in vivo tissue uptake and enhanced internalization of BTLs in RAW cells and CD271+BM-MSCs. The efficacy of isoniazid (INH)- and rifampicin (RIF)-loaded BTLs were shown using a mice model where the relapse rate of the tuberculosis was decreased significantly in targeted versus non-targeted groups. Our findings suggest that BTLs may play an important role in developing a clinical strategy for the clearance of dormant Mtb post-chemotherapy in BM cells.

Rifampicin–Liposomes for Mycobacterium abscessus Infection Treatment: Intracellular Uptake and Antibacterial Activity Evaluation

“…The recent discovery that rifabutin, an analogue of rifampicin, is active against Mabs [ 11 ] has stimulated different strategies to reposition rifampicin for the treatment of this difficult non-tuberculous mycobacteria lung disease. In this context, RIF encapsulation in a proper nanocarrier could represent a viable strategy to increase its local concentration and overcome mycobacterial drug inactivation, offering, at the same time, the possibility to increase its stability and water solubility and have a favorable impact on Mabs infection [ 12 ].…”

A novel comprehensive Tuberculosis (TB) control programme methodology based on the nexus of participatory action research inspired public health and precision treatment approach

“…We have been doing the sputum collection and AFB staining since 1994 (19), and also took this experience to Bhutan's TB control program at Mongar Hospital during 1995-1998 (38), where the first observation of TB hiding in bone marrow was observed (38). In 2010, we recruited subjects from the Idu-Mishmi tribe living in a remote mountain range of Arunachal Pradesh, India utilising our KTC network for a TB dormancy study (18) (35). All participants were older than 40 years and gave written informed consent.…”

One Size Fits All? Not in In Vivo Modeling of Tuberculosis Chemotherapeutics

“…Nevertheless, the Cornell model has been extensively utilized, particularly for drug evaluation and attempts to locate the reservoir of Mtb resulting in relapse ( Dhillon et al., 1996 ; Miyazaki et al., 1999 ; Das et al., 2013 ; Liu et al., 2018 ). Operating on the hypothesis that the bone marrow is the source of Mtb in relapse, a recent study described a novel strategy for Mtb clearance post-chemotherapy, using nanoparticle-encapsulated drugs to specifically target and kill bone marrow resident Mtb in the Cornell model ( Garhyan et al., 2020 ).…”