Trimethyl chitosan-cysteine nanoparticles for systemic delivery of TNF-α siRNA via oral and intraperitoneal routes.

PURPOSE

The lack of effective delivery vehicles impedes in vivo applications of siRNA. The trimethyl chitosan-cysteine (TC) nanoparticles (NPs) were developed for in vivo delivery of tumor necrosis factor α (TNF-α) siRNA via oral gavage and intraperitoneal injection.

METHODS

The nanoparticles formulated from TC conjugate of 100, 200, and 500 kDa were prepared through ionic gelation with sodium tripolyphosphate, termed as TC100 NPs, TC200 NPs, and TC500 NPs, respectively. They were evaluated in terms of stability, siRNA protection, cellular uptake and TNF-α knockdown in peritoneal exudates macrophage cells (PECs), and in vivo TNF-α silencing in acute hepatic injury mice.

RESULTS

TC100 NPs exhibited poor stability in simulated physiological environment compared to TC200 NPs and TC500 NPs. Compared to TC500 NPs, TC200 NPs could significantly enhance in vitro and in vivo cellular uptake by PECs and facilitate cytoplasmic siRNA release, resulting in high in vitro and in vivo TNF-α knockdown. Superior TNF-α suppressing level was obtained with TC200 NPs via oral gavage rather than intraperitoneal injection.

CONCLUSIONS

The efficacies of in vivo TNF-α silencing were related to the molecular weight of TC conjugate and the administration route, which would assist in the rational design of siRNA vehicles.