Jhilta Agrim, Jadhav Krishna, Sharma Rahul, Singh Raghuraj, Negi Swarnima, Sharma Neelesh, Singh Amit Kumar, Verma Rahul Kumar
Institute of Nano Science and Technology (INST), Sector-81, Mohali, Punjab 140306, India.
Experimental Animal Facility, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra 282004, India.
ACS Appl Bio Mater. 2025 Feb 17;8(2):1533-1546. doi: 10.1021/acsabm.4c01723. Epub 2025 Jan 20.
Tuberculosis (TB) triggers a robust immune response, which leads to significant destruction of the lung tissue at the site of infection, aiding in the transmission of (Mtb) to the hosts. The excessive inflammatory response contributes heavily to extracellular matrix (ECM) damage, which is linked to high mortality rates among TB patients. Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, are pivotal in the breakdown of the ECM, worsening tissue destruction. In the context of host-directed therapy (HDT), a strategy aimed at modulating the immune response rather than directly targeting the pathogen, we evaluated the potential of lovastatin (LOV). LOV has shown promise in reducing MMP activity and inflammation, which could alleviate the immune-mediated pathology in TB. However, its clinical use has been limited due to poor solubility and biocompatibility, reducing its therapeutic efficacy. To overcome these limitations, we designed inhalable gelatin microspheres (GA-MS) loaded with LOV using the spray-drying technology. This approach improved the solubility and allowed for the controlled release of the drug. The resulting LOV-loaded gelatin microspheres (LOV/GA-MS) had an optimal particle size of 2.395 ± 0.67 μm, facilitating macrophage uptake due to their aerodynamic properties. In studies using Mtb-infected macrophages, LOV/GA-MS effectively suppressed MMP expression and reduced levels of pro-inflammatory cytokines at a concentration of 20 μg/mL, demonstrating substantial anti-inflammatory potential. Moreover, these microspheres showed a synergistic effect when combined with standard anti-TB drugs, enhancing the overall therapeutic efficacy in experiments. The findings suggest that inhalable LOV/GA-MS microspheres represent a promising adjunctive host-directed therapy for TB. By modulating the host's immune response and targeting key inflammatory mediators such as MMPs, this approach could mitigate lung tissue damage, improve clinical outcomes, and provide a more holistic treatment option for TB.
结核病（TB）引发强烈的免疫反应，这会导致感染部位的肺组织遭到严重破坏，有助于结核分枝杆菌（Mtb）传播给宿主。过度的炎症反应在很大程度上导致细胞外基质（ECM）损伤，这与结核病患者的高死亡率相关。基质金属蛋白酶（MMPs），尤其是MMP - 2和MMP - 9，在ECM的分解中起关键作用，会加剧组织破坏。在宿主导向疗法（HDT）的背景下，这是一种旨在调节免疫反应而非直接针对病原体的策略，我们评估了洛伐他汀（LOV）的潜力。LOV已显示出降低MMP活性和炎症的前景，这可能减轻结核病中免疫介导的病理状况。然而，由于其溶解性和生物相容性差，其临床应用受到限制，降低了其治疗效果。为克服这些限制，我们使用喷雾干燥技术设计了负载LOV的可吸入明胶微球（GA - MS）。这种方法提高了溶解度并实现了药物的控释。所得的负载LOV的明胶微球（LOV/GA - MS）的最佳粒径为2.395±0.67μm，由于其空气动力学特性便于巨噬细胞摄取。在使用Mtb感染的巨噬细胞的研究中，LOV/GA - MS在浓度为20μg/mL时有效抑制MMP表达并降低促炎细胞因子水平，显示出显著的抗炎潜力。此外，这些微球与标准抗结核药物联合使用时显示出协同作用，在实验中提高了整体治疗效果。研究结果表明，可吸入的LOV/GA - MS微球是一种有前景的结核病辅助宿主导向疗法。通过调节宿主的免疫反应并靶向关键的炎症介质如MMPs，这种方法可以减轻肺组织损伤，改善临床结果，并为结核病提供更全面的治疗选择。
