title: Effects of mannose density on in vitro and in vivo cellular uptake and RNAi efficiency of polymeric nanoparticles.
abstract: To evaluate the effects of mannose density on in vitro and in vivo cellular uptake and RNA interference (RNAi) efficiency of polymeric nanoparticles (NPs) in macrophages, mannose-modified trimethyl chitosan-cysteine (MTC) conjugates with mannose densities of 4%, 13%, and 21% (MTC-4, MTC-13, and MTC-21) were synthesized. Tumor necrosis factor-alpha (TNF-α) siRNA loaded MTC NPs with particle sizes of ∼150 nm exhibited desired structural stability and effectively protected siRNA from enzymatic degradation. Generally, cellular uptake and RNAi efficiency were affected by mannose density. As expected, MTC-21 NPs presented the maximum in vitro uptake and RNAi efficacy in Raw 264.7 cells among all NPs tested. However, MTC-4 NPs exhibited the optimal in vivo uptake by peritoneal exudate cell macrophages (PECs). In the inflammation model of acute hepatic injury, orally delivered MTC-4 and MTC-13 NPs worked better in silencing TNF-α expression and alleviating liver damage than MTC-21 NPs. As for the ulcerative colitis model, MTC-4 NPs outperformed MTC-13 and MTC-21 NPs with respect to TNF-α knockdown and therapeutic efficacy following oral administration. These results highlighted the importance of ligand density in cellular uptake and RNAi efficiency, which could serve as a guideline in the rational design of targeted nanocarriers for anti-inflammation therapy.
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Chu
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China. Electronic address: tangcui@fudan.edu.cn.
authors.forename: Cui
authors.initials: C
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D048271:Chitosan / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D007249:Inflammation / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000378:metabolism / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D008358:Mannose / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011108:Polymers / Q000737:chemistry*; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D008024:Ligands; D011108:Polymers; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D048271:Chitosan; D003545:Cysteine; D008358:Mannose
keywords: Cellular uptake; Gene delivery; Gene silencing; Mannose density; Polymeric nanoparticles