title: Brain-targeted co-delivery of therapeutic gene and peptide by multifunctional nanoparticles in Alzheimer's disease mice.
abstract: Multifunctional nanocarriers are increasingly promising for disease treatment aimed to regulate multiple pathological dysfunctions and overcome barriers in drug delivery. Here we develop a multifunctional nanocarrier for Alzheimer's disease (AD) treatment by achieving therapeutic gene and peptide co-delivery to brain based on PEGylated dendrigraft poly-l-lysines (DGLs) via systemic administration. The dendritic amine-rich structure of DGLs provides plenty reaction sites and positive charge for drug loading. Successful co-delivery of drugs overcoming the blood-brain barrier by brain-targeted ligand modification was demonstrated both in vitro and in vivo. The pharmacodynamics study of the system following multiple-dosing treatment was verified in transgenic AD mice. Down-regulation of the key enzyme in amyloid-β formation was achieved by delivering non-coding RNA plasmid. Simultaneous delivery of the therapeutic peptide into brain leads to reduction of neurofibrillary tangles. Meanwhile, memory loss rescue in AD mice was also observed. Taken together, the multifunctional nanocarrier provides an excellent drug co-delivery platform for brain diseases.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, PR China.
authors.forename: Sai
authors.initials: S
authors.lastname: An
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, PR China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, PR China.
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, PR China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, PR China.
authors.forename: Haojun
authors.initials: H
authors.lastname: Ma
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Bin
authors.initials: B
authors.lastname: Ji
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, PR China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 201203, PR China. Electronic address: jiangchen@fudan.edu.cn.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry; D011107:Polylysine / Q000031:analogs & derivatives / Q000737:chemistry; D022661:RNA, Untranslated / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D004337:Drug Carriers; D010455:Peptides; D022661:RNA, Untranslated; C443714:polylysine-graft-(poly(ethylene glycol)); D011107:Polylysine; D011092:Polyethylene Glycols
keywords: Alzheimer's disease; Aβ; Brain-targeted delivery; Gene therapy; Non-coding RNA; Tau-fibril