Controlled and Selective Photo-oxidation of Amyloid-β Fibrils by Oligomeric p-Phenylene Ethynylenes

Adeline M. Fanni, Daniel Okoye, Florencia A. Monge, Julia Hammond, Fahimeh Maghsoodi, Tye D. Martin, Gabriella Brinkley, M. Lisa Phipps, Deborah G. Evans, Jennifer S. Martinez, David G. Whitten, Eva Y. Chi

Research output: Contribution to journalArticlepeer-review

Abstract

Photodynamic therapy (PDT) has been explored as a therapeutic strategy to clear toxic amyloid aggregates involved in neurodegenerative disorders such as Alzheimer's disease. A major limitation of PDT is off-target oxidation, which can be lethal for the surrounding cells. We have shown that a novel class of oligo-p-phenylene ethynylenes (OPEs) exhibit selective binding and fluorescence turn-on in the presence of prefibrillar and fibrillar aggregates of disease-relevant proteins such as amyloid-β (Aβ) and α-synuclein. Concomitant with fluorescence turn-on, OPE also photosensitizes singlet oxygen under illumination through the generation of a triplet state, pointing to the potential application of OPEs as photosensitizers in PDT. Herein, we investigated the photosensitizing activity of an anionic OPE for the photo-oxidation of Aβ fibrils and compared its efficacy to the well-known but nonselective photosensitizer methylene blue (MB). Our results show that, while MB photo-oxidized both monomeric and fibrillar conformers of Aβ40, OPE oxidized only Aβ40 fibrils, targeting two histidine residues on the fibril surface and a methionine residue located in the fibril core. Oxidized fibrils were shorter and more dispersed but retained the characteristic β-sheet rich fibrillar structure and the ability to seed further fibril growth. Importantly, the oxidized fibrils displayed low toxicity. We have thus discovered a class of novel theranostics for the simultaneous detection and oxidization of amyloid aggregates. Importantly, the selectivity of OPE's photosensitizing activity overcomes the limitation of off-target oxidation of traditional photosensitizers and represents an advancement of PDT as a viable strategy to treat neurodegenerative disorders.

Original languageEnglish (US)
Pages (from-to)14871-14886
Number of pages16
JournalACS Applied Materials and Interfaces
Volume14
Issue number13
DOIs
StatePublished - Apr 6 2022
Externally publishedYes

Keywords

  • Alzheimer's disease
  • amyloid aggregates
  • fibril disassembly
  • oligo- p-phenylene ethylene
  • photo-oxidation

ASJC Scopus subject areas

  • Materials Science(all)

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