Chitosan coated curcumin nanocrystals augment pharmacotherapy via improved pharmacokinetics and interplay of NFκB, Keap1 and Nrf2 expression in Gram negative sepsis

Abstract

Background and purpose: Gram negative sepsis is a leading cause of mortality in cases of complicated intra-abdominal infections due to the deficit of clinically viable options for therapy. The purpose of the present study was to investigate the potential of intracorporeal chitosan coated curcumin nanocrystals (Chi-CUR-NC-4b) as a parenteral therapeutic approach against endotoxemia-induced sepsis. Experimental approaches: curcumin (CUR) nanocrystals were fabricated by high pressure homogenization and coated with chitosan. These nanocrystals were evaluated for physiochemical and pharmacokinetic parameters. Comparative evaluations were also made between Chi-CUR-NC-4b and CUR in LPS-stimulated HepG2 and J774 cells, as well as in the murine model of LPS-induced sepsis for PK, pharmacodynamic parameters and survival studies. Key results: Chi-CUR-NC 4b (D 95% and zeta potential 443 ± 15.76 nm and +28.82 ± 1.52 mV, respectively) was found to neutralize LPS and it enhanced plasma drug concentration (16 times compared to CUR solution) with improved levels in the organs of interest, i.e. lungs and liver. In vitro and in vivo pharmacodynamic studies demonstrated that the protective effects were mediated by the up-regulation of Nrf2 (enhanced antioxidant activity, i.e. via elevated levels of SOD and GST) as well as via the down-regulation of NFκB, leading to reduced cytokine secretion in the murine model of sepsis. Furthermore, reduction in tissue injury (attributed to reduced neutrophil migration indicated by myeloperoxidase levels) also contributed to enhanced survival in the murine model of LPS-induced endotoxemia. Conclusions and implications: these results together prove that the developed curcumin-bearing nano-formulation could serve as a valuable option for the therapeutic intervention of sepsis and associated hyper-inflammatory disorders.