b936d799cd8a8e981f8d61f6181f6c67 pmc_10574493.pdf d324f693d043b7b5e5d60a7f52c29e9894e87ab0 pmc_10574493.pdf b508daad0373204ef404711045e07a5887b7fc3416dc967368ec5269c2e19ee4 pmc_10574493.pdf Title: Polyoxometalate-Decorated Gold Nanoparticles Inhibit-Amyloid Aggregation and Cross the Blood–Brain Barrier in a physiological Model Subject: Alzheimer’s disease is characterized by a combination of several neuropathological hallmarks, such as extracellular aggregates of beta amyloid (A). Numerous alternatives have been studied for inhibiting A aggregation but, at this time, there are no effective treatments available. Here, we developed the tri-component nanohybrid system AuNPs@POM@PEG based on gold nanoparticles (AuNPs) covered with polyoxometalates (POMs) and polyethylene glycol (PEG). In this work, AuNPs@POM@PEG demonstrated the inhibition of the formation of amyloid fibrils, showing a 75% decrease in A aggregation in vitro. As it is a potential candidate for the treatment of Alzheimer’s disease, we evaluated the cytotoxicity of AuNPs@POM@PEG and its ability to cross the blood–brain barrier (BBB). We achieved a stable nanosystem that is non-cytotoxic below 2.5 nM to human neurovascular cells. The brain permeability of AuNPs@POM@PEG was analyzed in an in vitro microphysiological model of the BBB (BBB-on-a-chip), containing 3D human neurovascular cell co-cultures and microfluidics. The results show that AuNPs@POM@PEG was able to cross the brain endothelial barrier in the chip and demonstrated that POM does not affect the barrier integrity, giving the green light to further studies into this system as a nanotherapeutic. Keywords: nanovehicle; gold nanoparticles; polyoxometalates; -amyloid; blood–brain barrier organ-on-a-chip Author: Marta Perxés Perich, Sujey Palma-Florez, Clara Solé, Sara Goberna-Ferrón, Josep Samitier, Pedro Gómez-Romero, Mònica Mir and Anna Lagunas Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Oct 3 11:53:22 2023 CEST ModDate: Thu Oct 12 16:03:52 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1055548 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- EQJVKE+EURB10 Type 1 Builtin yes yes no 10 0 QMGUTW+VnURWPalladioL-Bold Type 1 Custom yes yes no 14 0 VVSYYB+EURM10 Type 1 Builtin yes yes no 19 0 TPXATO+URWPalladioL-Bold Type 1 Custom yes yes no 23 0 LJZNBX+URWPalladioL-Roma Type 1 Custom yes yes no 28 0 QKVTYY+URWPalladioL-Ital Type 1 Custom yes yes no 32 0 FZLVCN+EURM7 Type 1 Builtin yes yes no 36 0 XILSDV+VnURWPalladioL Type 1 Custom yes yes no 40 0 NPLVPL+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 58 0 OJYQXC+CMSY10 Type 1 Builtin yes yes no 80 0 JAKMJV+PazoMath-Italic Type 1 Builtin yes yes no 87 0 HiddenHorzOCR CID Type 0C Identity-H yes no yes 96 0 Helvetica Type 1 WinAnsi no no no 101 0 Times-Roman Type 1 WinAnsi no no no 102 0 GCMMDL+PalatinoLinotype TrueType WinAnsi yes yes no 115 0 HiddenHorzOCR CID Type 0C Identity-H yes no yes 124 0 Helvetica-Bold Type 1 WinAnsi no no no 129 0 Helvetica Type 1 WinAnsi no no no 130 0 Times-Roman Type 1 WinAnsi no no no 131 0 Helvetica-Oblique Type 1 WinAnsi no no no 132 0 MDJNAF+PalatinoLinotype TrueType WinAnsi yes yes no 152 0 HiddenHorzOCR CID Type 0C Identity-H yes no yes 161 0 Helvetica-Bold Type 1 WinAnsi no no no 166 0 Helvetica Type 1 WinAnsi no no no 167 0 Times-Bold Type 1 WinAnsi no no no 168 0 Times-Roman Type 1 WinAnsi no no no 169 0 Times-Italic Type 1 WinAnsi no no no 170 0 HiddenHorzOCR CID Type 0C Identity-H yes no yes 184 0 Helvetica-Bold Type 1 WinAnsi no no no 189 0 Helvetica Type 1 WinAnsi no no no 190 0 Times-Roman Type 1 WinAnsi no no no 191 0 Times-Italic Type 1 WinAnsi no no no 192 0 Helvetica-Oblique Type 1 WinAnsi no no no 193 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-02-01 02:32:21 CET RepresentationInformation: pmc_10574493.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-01-10 02:27:40 CET Size: 1055548 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 474 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results and Discussion Destination: section.2 Children: Item: Title: Synthesis and Characterization of AuNPs@POM@PEG Destination: subsection.2.1 Item: Title: Evaluation of the Inhibition of A Fibrillization In Vitro by AuNPs@POM@PEG Destination: subsection.2.2 Item: Title: Evaluation of the Cytotoxicity and Permeability of AuNPs@POM@PEG across the Blood Brain-Barrier-on-a-Chip (BBB-oC) In Vitro Model Destination: subsection.2.3 Item: Title: Conclusions Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Chemicals Destination: subsection.4.1 Item: Title: POM Synthesis Destination: subsection.4.2 Item: Title: POM Characterization Destination: subsection.4.3 Item: Title: Gold Nanoparticle Synthesis Destination: subsection.4.4 Item: Title: AuNPs@POM@PEG Functionalization Destination: subsection.4.5 Item: Title: Alexa 647 Functionalization Destination: subsection.4.6 Item: Title: Characterization of AuNPs@PEG@POM Destination: subsection.4.7 Item: Title: amyloid Aggregation Inhibition Destination: subsection.4.8 Item: Title: Cell Culture Destination: subsection.4.9 Item: Title: Cytotoxicity Assays Destination: subsection.4.10 Item: Title: BBB-on-a-Chip Device Fabrication Destination: subsection.4.11 Item: Title: BBB-oC Cell Seeding Destination: subsection.4.12 Item: Title: AuNPs@POM@PEG Permeability Assays in BBB-oC Destination: subsection.4.13 Item: Title: References Destination: section.A. Info: Title: Polyoxometalate-Decorated Gold Nanoparticles Inhibit-Amyloid Aggregation and Cross the Blood Brain Barrier in a physiological Model Author: Marta Perxés Perich, Sujey Palma-Florez, Clara Solé, Sara Goberna-Ferrón, Josep Samitier, Pedro Gómez-Romero, Mònica Mir and Anna Lagunas Subject: Alzheimer’s disease is characterized by a combination of several neuropathological hallmarks, such as extracellular aggregates of beta amyloid (A). Numerous alternatives have been studied for inhibiting A aggregation but, at this time, there are no effective treatments available. Here, we developed the tri-component nanohybrid system AuNPs@POM@PEG based on gold nanoparticles (AuNPs) covered with polyoxometalates (POMs) and polyethylene glycol (PEG). In this work, AuNPs@POM@PEG demonstrated the inhibition of the formation of amyloid fibrils, showing a 75% decrease in A aggregation in vitro. As it is a potential candidate for the treatment of Alzheimer’s disease, we evaluated the cytotoxicity of AuNPs@POM@PEG and its ability to cross the blood brain barrier (BBB). We achieved a stable nanosystem that is non-cytotoxic below 2.5 nM to human neurovascular cells. The brain permeability of AuNPs@POM@PEG was analyzed in an in vitro microphysiological model of the BBB (BBB-on-a-chip), containing 3D human neurovascular cell co-cultures and microfluidics. The results show that AuNPs@POM@PEG was able to cross the brain endothelial barrier in the chip and demonstrated that POM does not affect the barrier integrity, giving the green light to further studies into this system as a nanotherapeutic. 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