Effects of mannose density on in vitro and in vivo cellular uptake and RNAi efficiency of polymeric nanoparticles

• Published in: Biomaterials Vol. 52; pp. 229 - 239
• Main Authors: Chu, Shuang, Tang, Cui, Yin, Chunhua
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.06.2015
• Subjects: Administration, Oral; Advanced Basic Science; Animals; Biomedical materials; Cell Line; Cellular; Cellular uptake; Chitosan - chemistry; Cysteine - chemistry; Density; Dentistry; Drug Carriers - chemistry; Gene delivery; Gene expression; Gene silencing; In vitro testing; Inflammation - metabolism; Ligands; Liver - metabolism; Liver - pathology; Macrophages, Peritoneal - metabolism; Male; Mannose; Mannose - chemistry; Mannose density; Mice; Mice, Inbred C57BL; Nanoparticles - chemistry; Particle Size; Polymeric nanoparticles; Polymers - chemistry; RAW 264.7 Cells; RNA Interference; RNA, Small Interfering - metabolism; Surgical implants; Tumor Necrosis Factor-alpha - administration & dosage; Tumor Necrosis Factor-alpha - chemistry; Uptakes; Gene delivery; Gene silencing; Cellular uptake; Polymeric nanoparticles; Mannose density
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2015.02.044

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.