Dual-Sensitive Nanomicelles Enhancing Systemic Delivery of Therapeutically Active Antibodies Specifically into the Brain

Abstract

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.

Blood-brain barrier–penetrating siRNA nanomedicine for Alzheimer’s disease therapy

“…In addition, competitive cellular binding assay of Gal-NP@Cy5-siRNA in general Glut1 inhibitor phloretin treatments showed a dose-dependent uptake in Glut1 highly expressed cells (fig. S4), which is consistent with previous report ( 18 ), indicating Glut1 as the dominant endocytosis pathway. Next, to quantify the efficiency of siRNA silencing of the target gene, BACE1 mRNA and protein expression were examined in Neuro-2a cell samples treated with Gal-NP@siBACE1.…”

“…Our triple-interaction stabilized siRNA nanomedicine demonstrates superior stability performance in blood circulation relative to conventional cationic polymer-based nanomedicines that feature only a single electrostatic interaction (16). Furthermore, exploiting Glut1 recycling by initially inducing hypoglycemia, which elevates Glut1 expression on the luminal plasma membrane of the BBB, facilitates markedly enhanced delivery of glucose-modified nanocarriers across the BBB when Glut1 is recycled to the abluminal membrane of the BBB upon glucose replenishment (17)(18)(19). To facilitate the Glut1 recycling approach, we appreciated that Glut1 stereochemistry allows binding of both d-glucose and d-galactose (20)(21)(22)(23).…”

Programmed and Sequential Disassembly of Multi‐responsive Supramolecular Protein Nanoassemblies: A Detailed Mechanistic Investigation

“…Stimuli‐responsive supramolecular systems hold huge potential for application in the area of biomedical sciences [55–57] . Over the last two decades, several groups have made seminal contributions to this field [58–63] . These supramolecular systems have been constructed using a variety of synthetic and biomolecules such as amphiphilic block‐copolymers, [64–67] amphiphilic dendrimer, [68–72] metal nanoparticles, [73] DNA, [74–76] RNA, [77,78] peptides, [79–82] and carbohydrates [83] .…”

Application of Antibody Fragments Against Aβ With Emphasis on Combined Application With Nanoparticles in Alzheimer’s Disease

“…Besides, they observed that TVNs could prevent production of cytokines caused by the exposure of Aβ40 (Agyare et al, 2014). Another application of combining polymeric nanoparticles and antibody fragment is studied by Xie et al (2020). The system of polymeric nanomicelle (PM) was provided to deliver 3D6-Fab.…”