TY - JOUR
T1 - Brain-Targeted Liposomes Loaded with Monoclonal Antibodies Reduce Alpha-Synuclein Aggregation and Improve Behavioral Symptoms in Parkinson's Disease
AU - Sela, Mor
AU - Poley, Maria
AU - Mora-Raimundo, Patricia
AU - Kagan, Shaked
AU - Avital, Aviram
AU - Kaduri, Maya
AU - Chen, Gal
AU - Adir, Omer
AU - Rozencweig, Adi
AU - Weiss, Yfat
AU - Sade, Ofir
AU - Leichtmann-Bardoogo, Yael
AU - Simchi, Lilach
AU - Aga-Mizrachi, Shlomit
AU - Bell, Batia
AU - Yeretz-Peretz, Yoel
AU - Or, Aviv Zaid
AU - Choudhary, Ashwani
AU - Rosh, Idan
AU - Cordeiro, Diogo
AU - Cohen-Adiv, Stav
AU - Berdichevsky, Yevgeny
AU - Odeh, Anas
AU - Shklover, Jeny
AU - Shainsky-Roitman, Janna
AU - Schroeder, Joshua E.
AU - Hershkovitz, Dov
AU - Hasson, Peleg
AU - Ashkenazi, Avraham
AU - Stern, Shani
AU - Laviv, Tal
AU - Ben-Zvi, Ayal
AU - Avital, Avi
AU - Ashery, Uri
AU - Maoz, Ben M.
AU - Schroeder, Avi
N1 - Publisher Copyright:
© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.
PY - 2023/12/21
Y1 - 2023/12/21
N2 - Monoclonal antibodies (mAbs) hold promise in treating Parkinson's disease (PD), although poor delivery to the brain hinders their therapeutic application. In the current study, it is demonstrated that brain-targeted liposomes (BTL) enhance the delivery of mAbs across the blood-brain-barrier (BBB) and into neurons, thereby allowing the intracellular and extracellular treatment of the PD brain. BTL are decorated with transferrin to improve brain targeting through overexpressed transferrin-receptors on the BBB during PD. BTL are loaded with SynO4, a mAb that inhibits alpha-synuclein (AS) aggregation, a pathological hallmark of PD. It is shown that 100-nm BTL cross human BBB models intact and are taken up by primary neurons. Within neurons, SynO4 is released from the nanoparticles and bound to its target, thereby reducing AS aggregation, and enhancing neuronal viability. In vivo, intravenous BTL administration results in a sevenfold increase in mAbs in brain cells, decreasing AS aggregation and neuroinflammation. Treatment with BTL also improve behavioral motor function and learning ability in mice, with a favorable safety profile. Accordingly, targeted nanotechnologies offer a valuable platform for drug delivery to treat brain neurodegeneration.
AB - Monoclonal antibodies (mAbs) hold promise in treating Parkinson's disease (PD), although poor delivery to the brain hinders their therapeutic application. In the current study, it is demonstrated that brain-targeted liposomes (BTL) enhance the delivery of mAbs across the blood-brain-barrier (BBB) and into neurons, thereby allowing the intracellular and extracellular treatment of the PD brain. BTL are decorated with transferrin to improve brain targeting through overexpressed transferrin-receptors on the BBB during PD. BTL are loaded with SynO4, a mAb that inhibits alpha-synuclein (AS) aggregation, a pathological hallmark of PD. It is shown that 100-nm BTL cross human BBB models intact and are taken up by primary neurons. Within neurons, SynO4 is released from the nanoparticles and bound to its target, thereby reducing AS aggregation, and enhancing neuronal viability. In vivo, intravenous BTL administration results in a sevenfold increase in mAbs in brain cells, decreasing AS aggregation and neuroinflammation. Treatment with BTL also improve behavioral motor function and learning ability in mice, with a favorable safety profile. Accordingly, targeted nanotechnologies offer a valuable platform for drug delivery to treat brain neurodegeneration.
KW - Parkinson's disease
KW - brain targeting
KW - central nervous system
KW - lipid nanoparticles
KW - neuroinflammation
UR - http://www.scopus.com/inward/record.url?scp=85174902644&partnerID=8YFLogxK
U2 - 10.1002/adma.202304654
DO - 10.1002/adma.202304654
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C2 - 37753928
AN - SCOPUS:85174902644
SN - 0935-9648
VL - 35
JO - Advanced Materials
JF - Advanced Materials
IS - 51
M1 - 2304654
ER -