An immunoregulator nanomedicine approach for the treatment of tuberculosis

Introduction: A nanoparticle composed of a poly (lactic-co-glycolic acid) (PLGA) core and a chitosan (CS) shell with surface-adsorbed 1,3 beta-glucan (beta-glucan) was synthesized. The exposure response of CS-PLGA nanoparticles (0.1 mg/mL) with surface-bound beta-glucan at 0, 5, 10, 15, 20, or 25 ng or free beta-glucan at 5, 10, 15, 20, or 25 ng/mL in macrophage in vitro and in vivo was investigated. TNFa increased at 10 and 15 ng surface-bound beta-glucan on CS-PLGA nanoparticles (0.1 mg/mL) and at 20 and 25 ng/mL of free beta-glucan both at 24 h and 48 h. Secretion of TNFa protein and ROS production increased at 5, 10, 15, and 20 ng surface-bound beta-glucan on CS-PLGA nanoparticles and at 20 and 25 ng/mL of free beta-glucan at 24 h. Laminarin, a Dectin-1 antagonist, prevented the increase in cytokine gene expression induced by CS-PLGA nanoparticles with surface-bound beta-glucan at 10 and 15 ng, indicating a Dectin-1 receptor mechanism. Efficacy studies showed a significant reduction in intracellular accumulation of mycobacterium tuberculosis (Mtb) in monocytederived macrophages (MDM) incubated with on CS-PLGA (0.1 mg/ml) nanoparticles with 5, 10, and 15 ng surface-bound beta-glucan or with 10 and 15 ng/mL of free beta-glucan. beta-glucan-CS-PLGA nanoparticles inhibited intracellular Mtb growth more than free beta-glucan alone supporting the role of beta-glucan-CS-PLGA nanoparticles as stronger adjuvants than free beta-glucan. In vivo studies demonstrate that oropharyngeal aspiration (OPA) of CS-PLGA nanoparticles with nanogram concentrations of surface-bound beta-glucan or free beta-glucan increased TNFa gene expression in alveolar macrophages and TNFa protein secretion in bronchoalveolar lavage supernatants. Discussion: Data also demonstrate no damage to the alveolar epithelium or changes in the murine sepsis score following exposure to beta-glucan-CS-PLGA nanoparticles only, indicating safety and feasibility of this nanoparticle adjuvant platform to mice by OPA.

Automated summary

A nanoparticle composed of PLGA core and CS shell with surface-adsorbed beta-glucan was synthesized and its effects on macrophages were investigated in vitro and in vivo. The nanoparticle led to increased TNFa levels and ROS production. It also showed efficacy in reducing intracellular accumulation of Mtb and had stronger adjuvant effects compared to free beta-glucan. In vivo studies demonstrated the safety and feasibility of the nanoparticle adjuvant platform.