Brain delivery of fibronectin through bioactive phosphorous dendrimers for Parkinson’s disease treatment via cooperative modulation of microglia  

作　　者：Waicong Dai Mengsi Zhan Yue Gao Huxiao Sun Yu Zou Regis Laurent Serge Mignani Jean-Pierre Majoral Mingwu Shen Xiangyang Shi 

机构地区：[1]State Key Laboratory for Modification of Chemical Fibers and Polymer Materials,Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine,College of Biological Science and Medical Engineering,Donghua University,Shanghai,201620,PR China [2]Laboratoire de Chimie de Coordination du CNRS,205 Route de Narbonne,CEDEX 4,31077,Toulouse,France [3]Universit´e Toulouse,118 Route de Narbonne,CEDEX 4,31077,Toulouse,France [4]CQM-Centro de Química da Madeira,Universidade da Madeira,Campus Universit´ario da Penteada,9020-105,Funchal,Portugal

出　　处：《Bioactive Materials》2024年第8期45-54,共10页生物活性材料（英文）

基　　金：supported by the National Natural Science Foundation of China(52350710203 and U23A2096);the Science and Technology Commission of Shanghai Municipality(21490711500,23WZ2503300,23520712500 and 20DZ2254900);the National Key R&D Program(2022YFE0196900);the Shanghai Education Commission through the leading talent program.S.M.and X.S.also acknowledge the support by the Fundaçao para a Ciencia e a Tecnologia(FCT)with Portuguese Government funds through the CQM Base Fund-UIDB/00674/2020(DOI:10.54499/UIDB/00674/2020);Programmatic Fund-UIDP/00674/2020(DOI:10.54499/UIDP/00674/2020).

摘　　要：Effective treatment of Parkinson’s disease(PD),a prevalent central neurodegenerative disorder particularly affecting the elderly population,still remains a huge challenge.We present here a novel nanomedicine formulation based on bioactive hydroxyl-terminated phosphorous dendrimers(termed as AK123)complexed with fibronectin(FN)with anti-inflammatory and antioxidative activities.The created optimized AK123/FN nanocomplexes(NCs)with a size of 223 nm display good colloidal stability in aqueous solution and can be specifically taken up by microglia through FN-mediated targeting.We show that the AK123/FN NCs are able to consume excessive reactive oxygen species,promote microglia M2 polarization and inhibit the nuclear factor-kappa B signaling pathway to downregulate inflammatory factors.With the abundant dendrimer surface hydroxyl terminal groups,the developed NCs are able to cross blood-brain barrier(BBB)to exert targeted therapy of a PD mouse model through the AK123-mediated anti-inflammation for M2 polarization of microglia and FN-mediated antioxidant and anti-inflammatory effects,thus reducing the aggregation ofα-synuclein and restoring the contents of dopamine and tyrosine hydroxylase to normal levels in vivo.The developed dendrimer/FN NCs combine the advantages of BBB-crossing hydroxyl-terminated bioactive per se phosphorus dendrimers and FN,which is expected to be extended for the treatment of different neurodegenerative diseases.

关 键 词：Phosphorous dendrimers FIBRONECTIN Parkinson’s disease Blood brain barrier Combination therapy 

分 类 号：O62[理学—有机化学]