title: In vivo toxicity and immunogenicity of wheat germ agglutinin conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles for intranasal delivery to the brain.
abstract: Biodegradable polymer-based nanoparticles have been widely studied to deliver therapeutic agents to the brain after intranasal administration. However, knowledge as to the side effects of nanoparticle delivery system to the brain is limited. The aim of this study was to investigate the in vivo toxicity and immunogenicity of wheat germ agglutinin (WGA) conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles (WGA-NP) after intranasal instillation. Sprague-Dawley rats were intranasally given WGA-NP for 7 continuous days. Amino acid neurotransmitters, lactate dehydrogenase (LDH) activity, reduced glutathione (GSH), acetylcholine, acetylcholinesterase activity, tumor necrosis factor α (TNF-α) and interleukin-8 (IL-8) in rat olfactory bulb (OB) and brain were measured to estimate the in vivo toxicity of WGA-NP. Balb/C mice were intranasally immunized by WGA-NP and then WGA-specific antibodies in serum and nasal wash were detected by indirect ELISA. WGA-NP showed slight toxicity to brain tissue, as evidenced by increased glutamate level in rat brain and enhanced LDH activity in rat OB. No significant changes in acetylcholine level, acetylcholinesterase activity, GSH level, TNF-α level and IL-8 level were observed in rat OB and brain for the WGA-NP group. WGA-specific antibodies in mice serum and nasal wash were not increased after two intranasal immunizations of WGA-NP. These results demonstrate that WGA-NP is a safe carrier system for intranasal delivery of therapeutic agents to the brain.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Liu
authors.forename: Xiayan
authors.initials: X
authors.lastname: Shao
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Yehong
authors.initials: Y
authors.lastname: Shen
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Feng
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Gao
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jingwei
authors.initials: J
authors.lastname: Li
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000281:Administration, Intranasal; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000097:blood; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004339:Drug Compounding; D004797:Enzyme-Linked Immunosorbent Assay; D005978:Glutathione / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000008:administration & dosage* / Q000276:immunology / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D009830:Olfactory Bulb / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010316:Particle Size; D011091:Polyesters; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000633:toxicity; D011108:Polymers / Q000008:administration & dosage* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014909:Wheat Germ Agglutinins / Q000008:administration & dosage* / Q000276:immunology / Q000633:toxicity
chemical_list: D000596:Amino Acids; D000906:Antibodies; D004337:Drug Carriers; D016209:Interleukin-8; D011091:Polyesters; D011108:Polymers; D014409:Tumor Necrosis Factor-alpha; D014909:Wheat Germ Agglutinins; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); D007770:L-Lactate Dehydrogenase; D000110:Acetylcholinesterase; D005978:Glutathione; D000109:Acetylcholine