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

### **Jaishree Garhyan 1, Surender Mohan 1, Vinoth Rajendran 2,3 and Rakesh Bhatnagar 1,4,\***


Received: 22 March 2020; Accepted: 26 April 2020; Published: 13 May 2020

**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 e fficiency 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 e fficacy 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 sugges<sup>t</sup> that BTLs may play an important role in developing a clinical strategy for the clearance of dormant Mtb post-chemotherapy in BM cells.

**Keywords:** BM-MSCs; Mtb; bone-homing; stem cell niche; latent tuberculosis; relapse; liposomes
