title: Iron Chelation Nanoparticles with Delayed Saturation as an Effective Therapy for Parkinson Disease.
abstract: Iron accumulation in substantia nigra pars compacta (SNpc) has been proved to be a prominent pathophysiological feature of Parkinson's diseases (PD), which can induce the death of dopaminergic (DA) neurons, up-regulation of reactive oxygen species (ROS), and further loss of motor control. In recent years, iron chelation therapy has been demonstrated to be an effective treatment for PD, which has shown significant improvements in clinical trials. However, the current iron chelators are suboptimal due to their short circulation time, side effects, and lack of proper protection from chelation with ions in blood circulation. In this work, we designed and constructed iron chelation therapeutic nanoparticles protected by a zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) to delay the saturation of iron chelators in blood circulation and prolong the in vivo lifetime, with HIV-1 trans-activating transcriptor (TAT) served as a shuttle to enhance the blood-brain barrier (BBB) permeability. We explored and investigated whether the Parkinsonian neurodegeneration and the corresponding symptoms in behaviors and physiologies could be prevented or reversed both in vitro and in vivo. The results demonstrated that iron chelator loaded therapeutic nanoparticles could reverse functional deficits in Parkinsonian mice not only physiologically but also behaviorally. On the contrary, both untreated PD mice and non-TAT anchored nanoparticle treated PD mice showed similar loss in DA neurons and difficulties in behaviors. Therefore, with protection of zwitterionic polymer and prolonged in vivo lifetime, iron chelator loaded nanoparticles with delayed saturation provide a PD phenotype reversion therapy and significantly improve the living quality of the Parkinsonian mice.
authors.affiliation: School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, and ‡Instrumental Analysis Center, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, and ‡Instrumental Analysis Center, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
authors.forename: Xin
authors.identifier: 0000-0003-1779-6407
authors.initials: X
authors.lastname: Jin
authors.affiliation: School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, and ‡Instrumental Analysis Center, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
authors.forename: Dongbo
authors.initials: D
authors.lastname: Guo
authors.affiliation: School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, and ‡Instrumental Analysis Center, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
authors.forename: Gangsheng
authors.initials: G
authors.lastname: Tong
authors.affiliation: School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, and ‡Instrumental Analysis Center, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
authors.forename: Xinyuan
authors.identifier: 0000-0002-2891-837X
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000737:chemistry; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D007502:Iron Chelating Agents; D011109:Polymethacrylic Acids; C115766:poly(2-methacryloyloxyethyl-phosphorylcholine); D010767:Phosphorylcholine; D007501:Iron