Functionalized Upconversion Nanoparticles for Disassembly of β‑Amyloid Aggregation with Near-Infrared Excitation

doi:10.6023/A21050194

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, confusion, and a variety of cognitive disabilities. The self-assembly and aggregation of β-amyloid (Aβ) peptides is a main feature of the brain of Alzheimer's disease, which can aggravate the nerve damage and cognitive impairment of AD patients. Therefore, inhibition of the aggregation of Aβ peptides is recognized as a potential strategy to alleviate AD. Photodynamic therapy (PDT) is a creative method that has wide applications in suppressing amyloid aggregation or eliminating the amyloid aggregates. However, most photosensitizers are excited by ultraviolet and visible light, have a low penetration depth in biological tissues, and cause serious tissue damage, which limits their application in biomedicine. Herein, we report a dual-targeting upconversion nanoprobe excited by near-infrared light to inhibit the Aβ aggregation process. The core-shell structured upconversion nanoparticles NaYF₄:Yb,Er,Gd,Tm@NaYF₄ are used as light converters, and the photosensitizer chlorin-e6 (Ce6) is loaded through the hydrophobic coating of the amphiphilic polymer 1,2-distearoylsn-glycero-3-phosphoethanolamine-N- [maleimide(polyethyleneglycol)-2000] (DSPE-PEG-MAL). A blood-brain barrier targeting peptide, TGN, and a Aβ target peptide, QSH, are simultaneously modified on the surface of nanoparticles via the specific reaction between maleimide and sulfhydryl groups. The results indicate that UCNPs can transfer the excited-state energy to the photosensitizer Ce6 through luminescence resonance energy transfer (LRET) process under the excitation of near-infrared light irradiation. After transition to the excited state, Ce6 further interact with the surrounding oxygen molecules to produce singlet oxygen (¹O₂) and irreversibly oxidize β-amyloid, thus effectively disassembling Aβ aggregates and reducing the cytotoxicity associated with Aβ. In addition, UCNPs-Ce6-TQ not only exhibits good biocompatibility, but also can effectively cross the blood-brain barrier and target Aβ₄₂. This nanoprobe may be a powerful tool to inhibit the accumulation of Aβ in the brain and alleviate the neurotoxic damage caused by Aβ.

Key words: near infrared, upconversion nanoparticles, photodynamic therapy, beta-amyloid, Alzheimer's disease

Cite this article

Ju Huang, Zhen Li, Zhihong Liu. Functionalized Upconversion Nanoparticles for Disassembly of β‑Amyloid Aggregation with Near-Infrared Excitation[J]. Acta Chimica Sinica, 2021, 79(8): 1049-1057.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 6

Figure 1. The mechanism diagram of the upconversion nanoparticles with dual-targeting and loaded photosensitizer to inhibit Aβ aggregation under near-infrared light irradiation. Under near-infrared light (980 nm) excitation, the upconversion nanoparticles emit 655 nm visible light to excite the photosensitizer Ce6 to produce singlet oxygen (1O2) to irreversibly oxidize Aβ peptides, thereby effectively disassembling Aβ aggregates

Figure 2. Transmission electron microscope images of (a) NaYF4:Yb,Er,Gd,Tm and (b) NaYF4:Yb,Er,Gd,Tm@NaYF4. Histograms of the size distribution of (c) NaYF4:Yb,Er,Gd,Tm and (d) NaYF4:Yb,Er,Gd,Tm@NaYF4

Figure 3. (a) The UV absorption spectrum of the photosensitizer Ce6 overlaps with the upconversion emission spectrum of UCNPs-PEG in aqueous under near-infrared light excitation. (b) The upconversion luminescence spectra of UCNPs before and after loading the photosensitizer Ce6. (c) UV-vis absorbance spectra of UCNPs (1 mg/mL) loaded with different concentrations (0~110 μg/mL) of Ce6. (d) Comparison between the UV-vis absorption spectra of UCNPs-Ce6-TQ, photosensitizer and the two peptide chains labeled with the dyes

Figure 4. UCNPs-Ce6-TQ photooxidation inhibits Aβ aggregates in vitro. (a) Fluorescence intensity of ThT at 480 nm. (b) Circular dichroism spectrum of natural Aβ peptides and Aβ peptides co-incubated with UCNPs-Ce6-TQ under dark or near-infrared light conditions. (c~e) AFM images of natural Aβ peptides (20 μmol/L) and Aβ peptides co-incubated with UCNPs-Ce6-TQ in the dark or under near-infrared light conditions. DLS particle size distribution of (f) natural Aβ peptide and (g) Aβ peptide co-incubated with UCNPs-Ce6-TQ under near-infrared light irradiation

Figure 5. (a) Scheme showing the design of the blood-brain barrier model. (b) In vitro BBB permeability of UCNPs-Ce6 and UCNPs-Ce6-TQ

Figure 6. MTT analysis to evaluate the biocompatibility of UCNPs-Ce6-TQ and the inhibition of Aβ peptide-induced cytotoxicity under near-infrared light excitation. (a) Cell viability analysis of UCNPs-Ce6-TQ incubated with PC12 cells at different concentrations (0, 0.1, 0.2, 0.3, 0.4 and 0.5 mg/mL.) (b) Cell viability of PC12 incubated with natural Aβ peptides and Aβ peptides treated with different concentrations of UCNPs-Ce6-TQ under dark or near-infrared light irradiation conditions

References 56

[1]	Alzheimer's, association, Alzheimer's Dementia 2016, 12, 459. doi: 10.1016/j.jalz.2016.03.001
[2]	Savelieff, M. G.; Nam, G.; Kang, J.; Lee, H. J.; Lee, M.; Lim, M. H. Chem. Rev. 2019, 119, 1221. doi: 10.1021/acs.chemrev.8b00138 pmid: 30095897
[3]	Iadanza, M. G.; Jackson, M. P.; Hewitt, E. W.; Ranson, N. A.; Radford, S. E. Nat. Rev. Mol. Cell Bio. 2018, 19, 755. doi: 10.1038/s41580-018-0060-8
[4]	Hardy, J.; Selkoe, D. J. Science 2002, 297, 353. pmid: 12130773
[5]	Sun, H.; Liu, J.; Li, S. -L.; Zhou, L. -Y.; Wang, J. -W.; Liu, L. -B.; Lv, F. -T.; Gu, Q.; Hu, B. -Y.; Ma, Y. -G.; Wang, S. Angew. Chem. Int. Ed. 2019, 58, 5988. doi: 10.1002/anie.v58.18
[6]	Fan, L. -Y.; Mao, C. -Y.; Hu, X. -C.; Zhang, S.; Yang, Z. -H.; Hu, Z. -H.; Sun, H. -F.; Fan, Y.; Dong, Y. -L.; Yang, J.; Shi, C. -H.; Xu, Y. -M. Front. Neurol. 2019, 10, 1312. doi: 10.3389/fneur.2019.01312
[7]	De Strooper,, B.; Vassar,, R.; Golde,, T. Nat. Rev. Neurol. 2010, 6, 99. doi: 10.1038/nrneurol.2009.218 pmid: 20139999
[8]	Wilquet, V.; De Strooper, B. Curr. Opin. Neurobiol. 2004, 14, 582. doi: 10.1016/j.conb.2004.08.001
[9]	Haass, C.; Selkoe, D. J. Nat. Rev. Mol. Cell Bio. 2007, 8, 101. doi: 10.1038/nrm2101
[10]	Lee, S. J.C.; Nam, E.; Lee, H. J.; Savelieff, M. G.; Lim, M. H. Chem. Soc. Rev. 2017, 46, 310. doi: 10.1039/C6CS00731G
[11]	Ehrnhoefer, D. E.; Bieschke, J.; Boeddrich, A.; Herbst, M.; Masino, L.; Lurz, R.; Engemann, S.; Pastore, A.; Wanker, E. E. Nat. Struct. Mol. Biol. 2008, 15, 558. doi: 10.1038/nsmb.1437 pmid: 18511942
[12]	Taniguchi, A.; Sasaki, D.; Shiohara, A.; Iwatsubo, T.; Tomita, T.; Sohma, Y.; Kanai, M. Angew. Chem. Int. Ed. 2014, 53, 1382. doi: 10.1002/anie.v53.5
[13]	Lee, B. I.; Lee, S.; Suh, Y. S.; Lee, J. S.; Kim, A. -k.; Kwon, O. Y.; Yu, K.; Park, C. B. Angew. Chem. Int. Ed. 2015, 54, 11472. doi: 10.1002/anie.v54.39
[14]	Suh, J. -M.; Kim, G.; Kang, J.; Lim, M. H. Inorg. Chem. 2019, 58, 8. doi: 10.1021/acs.inorgchem.8b02813
[15]	Guan, Y. -J.; Du, Z.; Gao, N.; Cao, Y.; Wang, X. -H.; Scott, P.; Song, H. -L.; Ren, J. -S.; Qu, X. -G. Sci. Adv. 2018, 4, eaao6718. doi: 10.1126/sciadv.aao6718
[16]	Goyal, D.; Shuaib, S.; Mann, S.; Goyal, B. ACS Comb. Sci. 2017, 19, 55. doi: 10.1021/acscombsci.6b00116
[17]	Xiong, N.; Dong, X. -Y.; Zheng, J.; Liu, F. -F.; Sun, Y. ACS Appl. Mater. Inter. 2015, 7, 5650. doi: 10.1021/acsami.5b00915
[18]	Niu, L.; Liu, L.; Xi, W. -H.; Han, Q. -S.; Li, Q.; Yu, Y.; Huang, Q. -X.; Qu, F. -Y.; Xu, M.; Li, Y. -B.; Du, H. -W.; Yang, R.; Cramer, J.; Gothelf, K. V.; Dong, M. -D.; Besenbacher, F.; Zeng, Q. -D.; Wang, C.; Wei, G-H.; G-H., Y. -L. ACS Nano 2016, 10, 4143. doi: 10.1021/acsnano.5b07396
[19]	Han, Q. -S.; Cai, S. -F.; Yang, L.; Wang, X. -H.; Qi, C.; Yang, R.; Wang, C. ACS Appl. Mater. Inter. 2017, 9, 21116. doi: 10.1021/acsami.7b03816
[20]	Zhang, Z. -M.; Wang, J.; Song, Y. -X.; Wang, Z. -K.; Dong, M. -D.; Liu, L. Colloid. Surface. B 2019, 181, 341. doi: 10.1016/j.colsurfb.2019.05.053
[21]	Zhang, J. -Y.; Liu, J. -P.; Zhu, Y. -Y.; Xu, Z. -A.; Xu, J.; Wang, T. -T.; Yu, H. -J.; Zhang, W. Chem. Commun. 2016, 52, 12044. doi: 10.1039/C6CC06175C
[22]	Ke, P. C.; Pilkington, E. H.; Sun, Y.; Javed, I.; Kakinen, A.; Peng, G.; Ding, F.; Davis, T. P. Adv. Mater. 2020, 32, 1901690. doi: 10.1002/adma.v32.18
[23]	Yu, D. -Q.; Liu, C.; Zhang, H. -C.; Ren, J. -S.; Qu, X. -G. Chem. Sci. 2021, 12, 4963. doi: 10.1039/D0SC07067J
[24]	Du, Z.; Li, M.; Ren, J. -S.; Qu, X. -G. Acc. Chem. Res. 2021, 54, 2172. doi: 10.1021/acs.accounts.1c00055
[25]	Furtado, D.; Björnmalm, M.; Ayton, S.; Bush, A. I.; Kempe, K.; Caruso, F. Adv. Mater. 2018, 30, 1801362. doi: 10.1002/adma.v30.46
[26]	Ali, I. U.; Chen, X. ACS Nano 2015, 9, 9470. doi: 10.1021/acsnano.5b05341
[27]	Yan, T.; Liu, Z. -H.; Song, X. -Y.; Zhang, S. -S. Acta Chim. Sinica 2020, 78, 657 (in Chinese.) doi: 10.6023/A20040132
	( 闫涛, 刘振华, 宋昕玥, 张书圣化学学报 2020, 78, 657.) doi: 10.6023/A20040132
[28]	Li, M. -L.; Peng, X. -J. Acta Chim. Sinica 2016, 74, 959 (in Chinese.) doi: 10.6023/A16100553
	( 李明乐, 彭孝军, 化学学报, 2016, 74, 959.) doi: 10.6023/A16100553
[29]	Liu, W.; Dong, X. -Y.; Liu, Y.; Sun, Y. Acta Biomater. 2021, 123, 93. doi: 10.1016/j.actbio.2021.01.018
[30]	Lee, B. I.; Chung, Y. J.; Park, C. B. Biomaterials 2019, 190-191, 121. doi: 10.1016/j.biomaterials.2018.10.043
[31]	Tang, Y. -F.; Pei, F.; Lu, X. -M.; Fan, Q. -L.; Huang, W. Adv. Opt. Mater. 2019, 7, 1900917. doi: 10.1002/adom.v7.21
[32]	Liu, H. -W.; Zhu, L. -M.; Lou, X. -F.; Yuan, L.; Zhang, X. -B. Acta Chim. Sinica 2020, 78, 1240 (in Chinese.) doi: 10.6023/A20070323
	( 刘红文, 朱隆民, 娄霄峰, 袁林, 张晓兵, 化学学报, 2020, 78, 1240.) doi: 10.6023/A20070323
[33]	Yang, Y.; Liu, H. -L.; Han, M. -J.; Sun, B. -B.; Li, J. -B. Angew. Chem. Int. Ed. 2016, 55, 13538. doi: 10.1002/anie.201605905
[34]	Dong, H.; Du, S. -R.; Zheng, X. -Y.; Lyu, G. -M.; Sun, L. -D.; Li, L. -D.; Zhang, P. -Z.; Zhang, C.; Yan, C. -H. Chem. Rev. 2015, 115, 10725. doi: 10.1021/acs.chemrev.5b00091 pmid: 26151155
[35]	Chen, G. -Y.; Qiu, H. -L.; Prasad, P. N.; Chen, X. -Y. Chem. Rev. 2014, 114, 5161. doi: 10.1021/cr400425h
[36]	Zhou, J.; Liu, Z.; Li, F. -Y. Chem. Soc. Rev. 2012, 41, 1323. doi: 10.1039/C1CS15187H
[37]	Zheng, W.; Huang, P.; Tu, D. -T.; Ma, E.; Zhu, H. -M.; Chen, X. -Y. Chem. Soc. Rev. 2015, 44, 1379. doi: 10.1039/c4cs00178h pmid: 25093303
[38]	Wang, P. -P.; Liang, T.; Zuo, M. -M.; Li, Z.; Liu, Z. -H. Acta Chim. Sinica 2020, 78, 797 (in Chinese.) doi: 10.6023/A20050146
	( 王培培, 梁涛, 左苗苗, 李贞, 刘志洪, 化学学报, 2020, 78, 797.) doi: 10.6023/A20050146
[39]	Idris, N. M.; Jayakumar, M. K.G.; Bansal, A.; Zhang, Y. Chem. Soc. Rev. 2015, 44, 1449. doi: 10.1039/C4CS00158C
[40]	Yang, D. -M.; Ma, P. A.; Hou, Z. -Y.; Cheng, Z. -Y.; Li, C. -X.; Lin, J. Chem. Soc. Rev. 2015, 44, 1416. doi: 10.1039/C4CS00155A
[41]	Hao, C. -L.; Wu, X. -L.; Sun, M. -Z.; Zhang, H. -Y.; Yuan, A. -M.; Xu, L. -G.; Xu, C. -L.; Kuang, H. J. Am. Chem. Soc. 2019, 141, 19373. doi: 10.1021/jacs.9b09360
[42]	Zhu, X. -J.; Li, J. -C.; Qiu, X. -C.; Liu, Y.; Feng, W.; Li, F. -Y. Nat. Commun. 2018, 9, 2176. doi: 10.1038/s41467-018-04571-4
[43]	Zhao, J.; Chu, H. -Q.; Zhao, Y.; Lu, Y.; Li, L. -L. J. Am. Chem. Soc. 2019, 141, 7056. doi: 10.1021/jacs.9b01931
[44]	Xu, J.; Xu, L. -G.; Wang, C. -Y.; Yang, R.; Zhuang, Q.; Han, X.; Dong, Z. -L.; Zhu, W. -W.; Peng, R.; Liu, Z. ACS Nano 2017, 11, 4463. doi: 10.1021/acsnano.7b00715
[45]	Zhou, Y. -Q.; Peng, Z. -L.; Seven, E. S.; Leblanc, R. M. J. Control. Release 2018, 270, 290. doi: 10.1016/j.jconrel.2017.12.015
[46]	Li, J. -W.; Feng, L.; Fan, L.; Zha, Y.; Guo, L-R.; Zhang, Q. -Z.; Chen, J.; Pang, Z. -Q.; Wang, Y. -C.; Jiang, X. -G.; Yang, V. C.; Wen, L. -P.. Biomaterials 2011, 32, 4943. doi: 10.1016/j.biomaterials.2011.03.031
[47]	Yang, L. -C.; Sun, J.; Xie, W. -J.; Liu, Y. -N.; Liu, J. J. Mater. Chem. B 2017, 5, 5954. doi: 10.1039/C6TB02952C
[48]	Wiesehan, K.; Buder, K.; Linke, R. P.; Patt, S.; Stoldt, M.; Unger, E.; Schmitt, B.; Bucci, E.; Willbold, D. ChemBioChem 2003, 4, 748. pmid: 12898626
[49]	Zhang, C.; Zheng, X. -Y.; Wan, X.; Shao, X. -Y.; Liu, Q. -F.; Zhang, Z. -M.; Zhang, Q. -Z. J. Control. Release 2014, 192, 317. doi: 10.1016/j.jconrel.2014.07.050
[50]	Zhang, C.; Wan, X.; Zheng, X. -Y.; Shao, X. -Y.; Liu, Q. -F.; Zhang, Q. -Z.; Qian, Y. Biomaterials 2014, 35, 456. doi: 10.1016/j.biomaterials.2013.09.063 pmid: 24099709
[51]	Biancalana, M.; Koide, S. BBA-Proteins Proteomics 2010, 1804, 1405. doi: 10.1016/j.bbapap.2010.04.001
[52]	Younan, N. D.; Viles, J. H. Biochemistry 2015, 54, 4297. doi: 10.1021/acs.biochem.5b00309
[53]	Bartolini, M.; Bertucci, C.; Bolognesi, M. L.; Cavalli, A.; Melchiorre, C.; Andrisano, V. ChemBioChem 2007, 8, 2152. pmid: 17939148
[54]	Abbott, N. J.; Patabendige, A. A.; Dolman, D. E.; Yusof, S. R.; Begley, D. J. Neurobiol. Dis. 2010, 37, 13. doi: 10.1016/j.nbd.2009.07.030 pmid: 19664713
[55]	Srinivasan, B.; Kolli, A. R.; Esch, M. B.; Abaci, H. E.; Shuler, M. L.; Hickman, J. J. J. Lab. Autom. 2015, 20, 107. doi: 10.1177/2211068214561025 pmid: 25586998
[56]	Wei, Y.; Lu, F. -Q.; Zhang, X. -R.; Chen, D. -P. Chem. Mater. 2006, 18, 5733. doi: 10.1021/cm0606171

近红外光激发功能化上转换纳米颗粒用于解聚Aβ聚集体