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 formulat...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.展开更多
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)+2 种基金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).
文摘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.
