Chunbai He1, Lichen Yin, Cui Tang, Chunhua Yin. 1. State Key Laboratory of Genetic Engineering Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai, 200433, China.
Abstract
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.
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 injurymice. 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.
Authors: Gregory J Tesz; Myriam Aouadi; Matthieu Prot; Sarah M Nicoloro; Emilie Boutet; Shinya U Amano; Anca Goller; Mengxi Wang; Chang-An Guo; William E Salomon; Joseph V Virbasius; Rebecca A Baum; Mark J O'Connor; Ernesto Soto; Gary R Ostroff; Michael P Czech Journal: Biochem J Date: 2011-06-01 Impact factor: 3.857
Authors: Myriam Aouadi; Gregory J Tesz; Sarah M Nicoloro; Mengxi Wang; My Chouinard; Ernesto Soto; Gary R Ostroff; Michael P Czech Journal: Nature Date: 2009-04-30 Impact factor: 49.962