TY - JOUR
T1 - Dense hydroxyl polyethylene glycol dendrimer targets activated glia in multiple CNS disorders
AU - Sharma, Anjali
AU - Sharma, Rishi
AU - Zhang, Zhi
AU - Liaw, Kevin
AU - Kambhampati, Siva P.
AU - Porterfield, Joshua E.
AU - Lin, Ku Chien
AU - DeRidder, Louis B.
AU - Kannan, Sujatha
AU - Kannan, Rangaramanujam M.
N1 - Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved.
PY - 2020/1/22
Y1 - 2020/1/22
N2 - Poor transport of neuropharmaceutics through central nervous system (CNS) barriers limits the development of effective treatments for CNS disorders. We present the facile synthesis of a novel neuroinflammation-targeting polyethylene glycol-based dendrimer (PEGOL-60) using an efficient click chemistry approach. PEGOL-60 reduces synthetic burden by achieving high hydroxyl surface density at low generation, which plays a key role in brain penetration and glia targeting of dendrimers in CNS disorders. Systemically administered PEGOL-60 crosses impaired CNS barriers and specifically targets activated microglia/macrophages at the injured site in diverse animal models for cerebral palsy, glioblastoma, and age-related macular degeneration, demonstrating its potential to overcome impaired blood-brain, blood-tumor-brain, and blood-retinal barriers and target key cells in the CNS. PEGOL-60 also exhibits powerful intrinsic anti-oxidant and anti-inflammatory effects in inflamed microglia in vitro. Therefore, PEGOL-60 is an effective vehicle to specifically deliver therapies to sites of CNS injury for enhanced therapeutic outcomes in a range of neuroinflammatory diseases.
AB - Poor transport of neuropharmaceutics through central nervous system (CNS) barriers limits the development of effective treatments for CNS disorders. We present the facile synthesis of a novel neuroinflammation-targeting polyethylene glycol-based dendrimer (PEGOL-60) using an efficient click chemistry approach. PEGOL-60 reduces synthetic burden by achieving high hydroxyl surface density at low generation, which plays a key role in brain penetration and glia targeting of dendrimers in CNS disorders. Systemically administered PEGOL-60 crosses impaired CNS barriers and specifically targets activated microglia/macrophages at the injured site in diverse animal models for cerebral palsy, glioblastoma, and age-related macular degeneration, demonstrating its potential to overcome impaired blood-brain, blood-tumor-brain, and blood-retinal barriers and target key cells in the CNS. PEGOL-60 also exhibits powerful intrinsic anti-oxidant and anti-inflammatory effects in inflamed microglia in vitro. Therefore, PEGOL-60 is an effective vehicle to specifically deliver therapies to sites of CNS injury for enhanced therapeutic outcomes in a range of neuroinflammatory diseases.
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U2 - 10.1126/sciadv.aay8514
DO - 10.1126/sciadv.aay8514
M3 - Article
C2 - 32010790
AN - SCOPUS:85078850094
SN - 2375-2548
VL - 6
JO - Science Advances
JF - Science Advances
IS - 4
M1 - eaay8514
ER -