Metal–Organic Frameworks Harness Cu Chelating and Photooxidation Against Amyloid β Aggregation in Vivo

Abstract

Recently, photooxygenation of amyloid β (Aβ) has emerged as an effective way to inhibit Aβ aggregation in Alzheimer's disease (AD) treatment. However, their further application has been highly obstructed by self‐aggregation, no metal chelating ability, and poor protein‐enrichment capacity. Herein, porphyrinic metal–organic frameworks (PMOFs) are utilized as a superior CuII chelating and photooxidation agent for inhibiting Aβ aggregation. We selected only four classical kinds of POMFs (Zr–MOF, Al–MOF, Ni–MOF, Hf–MOF) for further investigation in our study, which are stable in physiological conditions and exhibit excellent biocompatibility. Among them, Hf–MOF was the most efficient Aβ photooxidant. A possible explanation about the difference in capacity of 1O2 generation of these four PMOFs has been provided according to the experimental results and DFT calculations. Furthermore, Hf–MOFs are modified with Aβ‐targeting peptide, LPFFD. This can not only enhance Hf–MOFs targeting cellular Aβ to decrease Aβ‐induced cytotoxicity, but also improve Aβ photooxidation in the complicated living environment. More intriguingly, in vivo studies indicate that the well‐designed LPFFD modified Hf–MOFs can decrease Aβ‐induced neurotoxicity and extend the longevity of the commonly used transgenic AD model Caenorhabditis elegans CL2006. Our work may open a new avenue for using MOFs as neurotoxic‐metal‐chelating and photo‐therapeutic agents for AD treatment.

Target-driven supramolecular self-assembly for selective amyloid-β photooxygenation against Alzheimer's disease

“…Furthermore, the photooxygenation of Ab was investigated by using 2,4-dinitrophenylhydrazine (DNPH), a sensitive reagent for carbonyl groups of protein samples. 7,47 As shown in Fig. 3b and S12, † only the carbonyl modication in Ab samples prominently increased aer preincubation of Ab, BSA, and HSA with the PKNPs, respectively.…”

Nitrogen‐Doped Carbonized Polymer Dots: A Potent Scavenger and Detector Targeting Alzheimer's β‐Amyloid Plaques

“…The untreated CL2006 nematodes completely paralyzed and died within 11 d, while CPDs treatment attenuated Aβ‐induced toxicity and postponed the complete death to 17 d (Figure 6c). The lifespan increase was comparable to or superior over those with other nano‐agents, such as Hf‐metal–organic frameworks (Hf‐MOFs), BP@BTA (BP: black phosphorus, BTA: 4‐(6‐methyl‐1,3‐benzothiazol‐2‐yl)phenylamine), and UCNP@C 60 ‐pep (UCNP: upconversion nanoparticle, pep: Aβ‐target peptide KLVFF), [ 17,85,86 ] which extended lifespan of CL2006 strain by 3, 4, and 5 days, respectively. The results demonstrated the potential of CPDs as a potent in vivo scavenger and detector targeting the Aβ 42 deposits.…”

Alzheimer's Therapeutic Strategy: Photoactive Platforms for Suppressing the Aggregation of Amyloid β Protein

“…The LPFFD-modified Hf-MOFs can alleviate Aβ toxicity and lengthen the lifespan of C. elegans CL2006, which is a model animal of AD. This work cast insights into the specially-designed MOFs as neurotoxic-metal chelating and PDT agent (Yu et al, 2019).…”

“…In 2019, we synthesized β-NaYF4:Yb/Er@SiO 2 @RB by conjugating UCNPs with rose Bengal to degrade preformed Aβ aggregates under a 980 nm NIR light. The results revealed that UCNPs could effectively photo-degrade Aβ42 fibrils, which demonstrated UCNP's potential application in the treatment of amyloid diseases (Yu et al, 2019 ). The development of NIR photosensitizers for degenerative disease is just in its infancy.…”