Dual-Sensitive Nanomicelles Enhancing Systemic Delivery of Therapeutically Active Antibodies Specifically into the Brain.
Jinbing XieDaniel Gonzalez-CarterTheofilus A TockaryNoriko NakamuraYonger XueMakoto NakakidoHiroki AkibaAnjaneyulu DirisalaXueying LiuKazuko TohTao YangZengtao WangShigeto FukushimaJunjie LiSabina QuaderKouhei TsumotoTakanori YokotaYasutaka AnrakuKazunori KataokaPublished in: ACS nano (2020)
Delivering therapeutic antibodies into the brain across the blood-brain barrier at a therapeutic level is a promising while challenging approach in the treatment of neurological disorders. Here, we present a polymeric nanomicelle (PM) system capable of delivering therapeutically effective levels of 3D6 antibody fragments (3D6-Fab) into the brain parenchyma for inhibiting Aβ aggregation. PM assembly was achieved by charge-converting 3D6-Fab through pH-sensitive citraconylation to allow complexation with reductive-sensitive cationic polymers. Brain targeting was achieved by functionalizing the PM surface with glucose molecules to allow interaction with recycling glucose transporter (Glut)-1 proteins. Consequently, 41-fold enhanced 3D6-Fab accumulation in the brain was achieved by using the PM system compared to free 3D6-Fab. Furthermore, therapeutic benefits were obtained by successfully inhibiting Aβ1-42 aggregation in Alzheimer's disease mice systemically treated with 3D6-Fab-loaded glucosylated PM. Hence, this nanocarrier system represents a promising method for effectively delivering functional antibody agents into the brain and treating neurological diseases.
Keyphrases
- resting state
- particulate matter
- white matter
- air pollution
- cerebral ischemia
- drug delivery
- functional connectivity
- heavy metals
- polycyclic aromatic hydrocarbons
- signaling pathway
- cancer therapy
- water soluble
- type diabetes
- metabolic syndrome
- multiple sclerosis
- subarachnoid hemorrhage
- adipose tissue
- skeletal muscle
- blood glucose
- mild cognitive impairment
- replacement therapy
- drug release
- high fat diet induced