Dual targeting of inflammation and β-cell dysfunction for therapy of diabetes mellitus

Diabetes Mellitus (DM) is a chronic metabolic disorder characterized by β-cell loss and inflammation. From a therapeutic standpoint, it would be necessary to halt the uncontrolled inflammatory response and to enable the regeneration of the damaged β-cells. In this work, to achieve the latter two drug-loaded nanocarrier systems have been developed and evaluated in-vivo in DM mouse model. For β-cell proliferation, small chitosan (CS) nanoparticles (NPs) (201 ± 30 nm) were loaded with 4b, a selective inhibitor of DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A). To reduce inflammation, large poly lactic-co-glycolic acid (PLGA) microparticles (MPs) (1172 ± 77 nm) were encapsulated with BI-605906, an inhibitor of IKKβ (inhibitor of kappa B kinase beta), acting as an inhibitor of an inhibitor. The EE% values were 90 ± 4.2 % and 87 ± 4.46 % for 4b–CS–NPs and BI-605906-PLGA-MPs, respectively. In-vivo biodistribution studies indicated the ability of both particles to accumulate in the pancreas. For CS-NPs, this was achieved as a function of the increased vascular permeability in DM, whereas for PLGA-MPs, this was achieved as function of macrophage uptake. Treatment with 4b–CS–NPs (but not the unloaded drug) reduced blood glucose levels (BGLs) and elevated cyclin D1 (CD1) gene expression indicating the successful ability of the NP system in promoting β-cells proliferation. Although treatment with free BI-605906 showed a modest reduction in BGLs, BI-605906-PLGA-MPs showed no improvement in BGLs. The latter could possibly be attributed to sub-optimal dosing. These results indicate that 4b–CS–NPs have the potential to lower BGLs by promoting β-cell proliferation and restoring pancreatic function. Further optimization is needed for BI-605906-PLGA-MPs, which may enhance therapeutic outcome by dual therapy. [Display omitted]