Title : Pulmonary delivery of lovastatin microsphere for tuberculosis pathology: A matrix metalloproteinase targeted approach
Abstract:
Tuberculosis (TB) triggers a strong immune response, leading to extensive lung tissue damage at the infection site, facilitating the transmission of Mycobacterium tuberculosis (Mtb). This excessive inflammation plays a major role in extracellular matrix (ECM) degradation, contributing to high mortality rates in TB patients. Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, are key enzymes involved in ECM breakdown, further exacerbating tissue destruction. In the context of host-directed therapy (HDT), an approach focused on regulating the immune response rather than directly targeting the pathogen—lovastatin (LOV) has been explored for its potential to reduce MMP activity and inflammation. However, its clinical application is limited due to poor solubility and biocompatibility, affecting its therapeutic efficiency. To address these challenges, we developed inhalable gelatin microspheres (GA-MS) encapsulating LOV using spray-drying technology, enhancing solubility and enabling controlled drug release. The optimized microspheres (LOV/GA-MS) had an average particle size of 2.395 ± 0.67 μm, promoting macrophage uptake due to favorable aerodynamic properties. In vitro studies with Mtb-infected macrophages demonstrated that at a concentration of 20 μg/ml, LOV/GA-MS significantly reduced MMP expression and lowered pro-inflammatory cytokine levels, highlighting its anti-inflammatory potential. Additionally, when combined with standard anti-TB drugs, the microspheres exhibited a synergistic effect, improving overall therapeutic efficacy in vitro. These findings suggest that inhalable LOV/GA-MS microspheres could serve as a promising adjunctive HDT strategy for TB by modulating immune responses, targeting inflammation-related mediators, and potentially reducing lung tissue damage, ultimately improving patient outcomes.
