Ying Zhao1, Shiyuan Lin1,2, Ruiyue Fang1, Yaling Shi1, Wei Wu1, Wei Zhang1, Hui Chen1. 1. College of Pharmacy, Guilin Medical University, Guilin, 541199, People's Republic of China. 2. Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China.
Abstract
Introduction: In the previous study, nanoparticles coated with trimethyl chitosan (TMC) derivatives (PPTT-NPs) could promote the oral bioavailability of panax notoginseng saponins (PNS). Herein, we chose PPTT-NPs as a model drug to study the property and mechanism of intestinal absorption in vitro and in vivo. Methods: The stability of PPTT-NPs was evaluated using simulated gastric fluid and simulated intestinal fluid. The uptake and transport of PPTT-NPs were investigated in Caco-2 and Caco-2&HT29 co-culture cells. The biosafety, intestinal permeability, adhesion, and absorption mechanism of PPTT-NPs were investigated using SD rats in vivo. The live imaging and biodistribution of PPTT-NPs were observed by IVIS. Furthermore, the effects on CYP3A4 of PPTT-NPs were investigated using testosterone as the probe substrate. Results: The results of the stability assay showed that PPTT-NPs had a strong tolerance to the pH and digestive enzymes in the gastrointestinal environment. In vitro cell experiments showed that the uptake of drugs exhibited a time-dependent. When the ratio of TMC-VB12 and TMC-Cys was 1:3, the uptake capacity of PPTT-NPs was the highest. PPTT-NPs could enhance the paracellular transport of drugs by reversibly opening a tight junction. Animal experiments demonstrated that PPTT-NPs have good biological safety. PPTT-NPs had good adhesion and permeability to small intestinal mucosa. Meanwhile, PPTT-NPs needed energy and various protein to participate in the uptake of drugs. The live imaging of NPs illustrated that PPTT-NPs could prolong the residence time in the intestine. Moreover, TMC-VB12 and TMC-Cys could reduce the metabolism of drugs by inhibiting CYP3A4 to a certain extent. Conclusion: The results show that TMC-VB12 and TMC-Cys are effective in the transport of PPTT-NPs. PPTT-NPs can increase the intestinal adhesion of drugs and exert high permeation by intestinal enterocytes which demonstrate significant and efficient potential for oral delivery of the BCS III drugs.
Introduction: In the previous study, nanoparticles coated with trimethyl chitosan (TMC) derivatives (PPTT-NPs) could promote the oral bioavailability of panax notoginseng saponins (PNS). Herein, we chose PPTT-NPs as a model drug to study the property and mechanism of intestinal absorption in vitro and in vivo. Methods: The stability of PPTT-NPs was evaluated using simulated gastric fluid and simulated intestinal fluid. The uptake and transport of PPTT-NPs were investigated in Caco-2 and Caco-2&HT29 co-culture cells. The biosafety, intestinal permeability, adhesion, and absorption mechanism of PPTT-NPs were investigated using SD rats in vivo. The live imaging and biodistribution of PPTT-NPs were observed by IVIS. Furthermore, the effects on CYP3A4 of PPTT-NPs were investigated using testosterone as the probe substrate. Results: The results of the stability assay showed that PPTT-NPs had a strong tolerance to the pH and digestive enzymes in the gastrointestinal environment. In vitro cell experiments showed that the uptake of drugs exhibited a time-dependent. When the ratio of TMC-VB12 and TMC-Cys was 1:3, the uptake capacity of PPTT-NPs was the highest. PPTT-NPs could enhance the paracellular transport of drugs by reversibly opening a tight junction. Animal experiments demonstrated that PPTT-NPs have good biological safety. PPTT-NPs had good adhesion and permeability to small intestinal mucosa. Meanwhile, PPTT-NPs needed energy and various protein to participate in the uptake of drugs. The live imaging of NPs illustrated that PPTT-NPs could prolong the residence time in the intestine. Moreover, TMC-VB12 and TMC-Cys could reduce the metabolism of drugs by inhibiting CYP3A4 to a certain extent. Conclusion: The results show that TMC-VB12 and TMC-Cys are effective in the transport of PPTT-NPs. PPTT-NPs can increase the intestinal adhesion of drugs and exert high permeation by intestinal enterocytes which demonstrate significant and efficient potential for oral delivery of the BCS III drugs.
Authors: Luiza A Frank; Renata V Contri; Ruy C R Beck; Adriana R Pohlmann; Silvia S Guterres Journal: Wiley Interdiscip Rev Nanomed Nanobiotechnol Date: 2015-01-30