Self-Assembled Curcumin-Poly(carboxybetaine methacrylate) Conjugates : Potent Nano-Inhibitors against Amyloid β-Protein Fibrillogenesis and Cytotoxicity
Fibrillogenesis of amyloid β-protein (Aβ) is a pathological hallmark of Alzheimer's disease, so inhibition of Aβ aggregation is considered as an important strategy for the precaution and treatment of AD. Curcumin (Cur) has been recognized as an effective inhibitor of Aβ fibrillogenesis, but its...
| Veröffentlicht in: | Langmuir : the ACS journal of surfaces and colloids. - 1992. - 35(2019), 5 vom: 05. Feb., Seite 1846-1857 |
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| Format: | Online-Aufsatz |
| Sprache: | English |
| Veröffentlicht: |
2019
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| Zugriff auf das übergeordnete Werk: | Langmuir : the ACS journal of surfaces and colloids |
| Schlagworte: | Journal Article Research Support, Non-U.S. Gov't Amyloid beta-Peptides Methacrylates Peptide Fragments Polymethacrylic Acids amyloid beta-protein (1-42) polycarboxybetaine methacrylate Betaine 3SCV180C9W mehr... |
| Zusammenfassung: | Fibrillogenesis of amyloid β-protein (Aβ) is a pathological hallmark of Alzheimer's disease, so inhibition of Aβ aggregation is considered as an important strategy for the precaution and treatment of AD. Curcumin (Cur) has been recognized as an effective inhibitor of Aβ fibrillogenesis, but its potential application is limited by its poor bioavailability. Herein, we proposed to conjugate Cur to a zwitterionic polymer, poly(carboxybetaine methacrylate) (pCB), and synthesized three CurpCB conjugates of different degrees of substitution (DS, 1.9-2.9). Cur@pCB conjugates self-assembled into nanogels of 120-190 nm. The inhibition effects of Cur@pCB conjugates on the fibrillation and cytotoxicity of Aβ42 was investigated by extensive biophysical and biological analyses. Thioflavin T fluorescence assays and atomic force microscopic observations revealed that the Cur@pCB conjugates were much more efficient than molecular curcumin on inhibiting Aβ42 fibrillation, and cytotoxicity assays also indicated the same tendency. Of the three conjugates, Cur1@pCB of the lowest DS (1.97) exhibited the best performance; 5 μM Cur1@pCB functioned similarly with 25 μM free curcumin. Moreover, 5 μM Cur1@pCB increased the cell viability by 43% but free curcumin at the same concentration showed little effect. It is considered that the highly hydrated state of the zwitterionic polymers resulted in the superiority of Cur@pCB over free curcumin. Namely, the dense hydration layer on the conjugates strongly stabilized the bound Aβ on curcumin anchored on the polymer, suppressing the conformational transition of the protein to β-sheet-rich structures. This was demonstrated by circular dichroism spectroscopy, in which Cur1@pCB was proven to be the strongest in the three conjugates. The research has thus revealed a new function of zwitterionic polymer pCBMA and provided new insights into the development of more potent nanoinhibitors for suppressing Aβ fibrillogenesis and cytotoxicity |
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| Beschreibung: | Date Completed 08.06.2020 Date Revised 03.07.2020 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1520-5827 |
| DOI: | 10.1021/acs.langmuir.8b01921 |