Skip to main content
SpringerLink
Log in

A cytotoxic amyloid oligomer self-triggered and NIR-enhanced amyloidosis therapeutic system

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

Abstract

We report a new strategy for improving the efficiency of non-specific amyloidosis therapeutic drugs by coating amyloid-responsive lipid bilayers. The approach had drawn inspiration from amyloid oligomer-mediated cell membrane disruption in the pathogenesis of amyloidosis. A graphene-mesoporous silica hybrid (GMS)-supported lipid bilayer (GMS-Lip) system was used as a drug carrier. Drugs were well confined inside the nanocarrier until encountering amyloid oligomers, which could pierce the lipid bilayer coat and cause drug release. To ensure release efficiency, use of a near-infrared (NIR) laser was also introduced to facilitate drug release, taking advantage of the photothermal effect of GMS and thermal sensitivity of lipid bilayers. To facilitate tracking, fluorescent dyes were co-loaded with drugs within GMS-Lip and the NIR laser was used once the oligomer-triggered release had been signaled. Because of the spatially and temporally controllable property of light, the NIR-assisted release could be easily and selectively activated locally, by tracking the fluorescence signal. Our design is based on amyloidosis pathogenesis, the cytotoxic amyloid oligomer self-triggered release via cell membrane disruption, for the controlled release of drug molecules. The results may shed light on the development of pathogenesis-inspired drug delivery systems.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Obici, L.; Perfetti, V.; Palladini, G.; Moratti, R.; Merlini, G. Clinical aspects of systemic amyloid diseases. Biochim. Biophys. Acta, Proteins Proteomics 2005, 1753, 11–22.

    Article  Google Scholar 

  2. Stefani, M.; Dobson, C. M. Protein aggregation and aggregate toxicity: New insights into protein folding, misfolding diseases and biological evolution. J. Mol. Med. 2003, 81, 678–699.

    Article  Google Scholar 

  3. Merlini, G.; Bellotti, V. Molecular mechanisms of amyloidosis. N. Engl. J. Med. 2003, 349, 583–596.

    Article  Google Scholar 

  4. Sacchettini, J. C.; Kelly, J. W. Therapeutic strategies for human amyloid diseases. Nat. Rev. Drug Discovery 2002, 1, 267–275.

    Article  Google Scholar 

  5. Yamin, G.; Ono, K.; Inayathullah, M.; Teplow, D. B. Amyloid beta-protein assembly as a therapeutic target of alzheimer’s disease. Curr. Pharm. Des. 2008, 14, 3231–3246.

    Article  Google Scholar 

  6. Soto, C.; Estrada, L. Amyloid inhibitors and β-sheet breakers. In Alzheimer’s Disease; Harris, J. R.; Fahrenholz, F., Eds.; Springer US: New York, 2005; pp 351–364.

    Google Scholar 

  7. Findeis, M. A. Approaches to discovery and characterization of inhibitors of amyloid beta-peptide polymerization. Biochim. Biophys. Acta–Mol. Basis of Dis. 2000, 1502, 76–84.

    Article  Google Scholar 

  8. Soto, C.; Kindy, M. S.; Baumann, M.; Frangione, B. Inhibition of alzheimer’s amyloidosis by peptides that prevent betasheet conformation. Biochem. Biophys. Res. Commun. 1996, 226, 672–680.

    Article  Google Scholar 

  9. Marzban, L.; Scrocchi, L. A.; Warnock, G. L.; Rosenberg, L.; Fraser, P. E.; Verchere, C. B. Hexapeptide inhibitors of islet amyloid polypeptide aggregation prevent islet amyloid formation and enhance survival of cultured human islets. Diabetes 2005, 54, A391–A391.

  10. Yang, F. S.; Lim, G. P.; Begum, A. N.; Ubeda, O. J.; Simmons, M. R.; Ambegaokar, S. S.; Chen, P. P.; Kayed, R.; Glabe, C. G.; Frautschy, S. A. et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem. 2005, 280, 5892–5901.

    Article  Google Scholar 

  11. Mishra, R.; Bulic, B.; Sellin, D.; Jha, S.; Waldmann, H.; Winter, R. Small-molecule inhibitors of islet amyloid polypeptide fibril formation. Angew. Chem. Int. Ed. 2008, 47, 4679–4682.

    Article  Google Scholar 

  12. Masuda, M.; Suzuki, N.; Taniguchi, S.; Oikawa, T.; Nonaka, T.; Iwatsubo, T.; Hisanaga, S.; Goedert, M.; Hasegawa, M. Small molecule inhibitors of alpha-synuclein filament assembly. Biochemistry 2006, 45, 6085–6094.

    Article  Google Scholar 

  13. Gao, N.; Sun, H. J.; Dong, K.; Ren, J. S.; Duan, T. C.; Xu, C.; Qu, X. G. Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for alzheimer’s disease. Nat. Commun. 2014, 5. 3422.

    Google Scholar 

  14. Kayed, R.; Head, E.; Thompson, J. L.; McIntire, T. M.; Milton, S. C.; Cotman, C. W.; Glabe, C. G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003, 300, 486–489.

    Article  Google Scholar 

  15. Glabe, C. G.; Kayed, R. Common structure and toxic function of amyloid oligomers implies a common mechanism of pathogenesis. Neurology 2006, 66, S74–S78.

  16. Quist, A.; Doudevski, L.; Lin, H.; Azimova, R.; Ng, D.; Frangione, B.; Kagan, B.; Ghiso, J.; Lal, R. Amyloid ion channels: A common structural link for protein-misfolding disease. Proc. Natl. Acad. Sci. USA 2005, 102, 10427–10432.

    Article  Google Scholar 

  17. Last, N. B.; Rhoades, E.; Miranker, A. D. Islet amyloid polypeptide demonstrates a persistent capacity to disrupt membrane integrity. Proc. Natl. Acad. Sci. USA 2011, 108, 9460–9465.

    Article  Google Scholar 

  18. Yang, S. B.; Feng, X. L.; Wang, L.; Tang, K.; Maier, J.; Mullen, K. Graphene-based nanosheets with a sandwich structure. Angew. Chem. Int. Ed. 2010, 49, 4795–4799.

    Article  Google Scholar 

  19. Wang, Y.; Wang, K. Y.; Zhao, J. F.; Liu, X. G.; Bu, J.; Yan, X. Y.; Huang, R. Q. Multifunctional mesoporous silica-coated graphene nanosheet used for chemo-photothermal synergistic targeted therapy of glioma. J. Am. Chem. Soc. 2013, 135, 4799–4804.

    Article  Google Scholar 

  20. Wu, L.; Wang, J. S.; Sun, H. J.; Ren, J. S.; Qu, X. G. Graphene-mesoporous silica-dispersed palladium nanoparticlesbased probe carrier platform for electrocatalytic sensing of telomerase activity at less than single-cell level. Adv. Healthc. Mater. 2014, 3, 588–595.

    Article  Google Scholar 

  21. Richter, R. P.; Berat, R.; Brisson, A. R. Formation of solidsupported lipid bilayers: An integrated view. Langmuir 2006, 22, 3497–3505.

    Article  Google Scholar 

  22. Anderson, T. H.; Min, Y. J.; Weirich, K. L.; Zeng, H. B.; Fygenson, D.; Israelachvili, J. N. Formation of supported bilayers on silica substrates. Langmuir 2009, 25, 6997–7005.

    Article  Google Scholar 

  23. Glasmastar, K.; Larsson, C.; Hook, F.; Kasemo, B. Protein adsorption on supported phospholipid bilayers. Colloid Interface Sci. 2002, 246, 40–47.

    Article  Google Scholar 

  24. Pace, S.; Seantier, B.; Belamie, E.; Lautredou, N.; Sailor, M. J.; Milhiet, P. E.; Cunin, F. Characterization of phospholipid bilayer formation on a thin film of porous SiO2 by reflective interferometric fourier transform spectroscopy (RIFTS). Langmuir 2012, 28, 6960–6969.

    Article  Google Scholar 

  25. Savarala, S.; Ahmed, S.; Ilies, M. A.; Wunder, S. L. Formation and colloidal stability of dmpc supported lipid bilayers on SiO2 nanobeads. Langmuir 2010, 26, 12081–12088.

    Article  Google Scholar 

  26. Liu, M. X.; Gan, L. H.; Chen, L. H.; Xu, Z. J.; Zhu, D. Z.; Hao, Z. X.; Chen, L. W. Supramolecular core–shell nanosilica@ liposome nanocapsules for drug delivery. Langmuir 2012, 28, 10725–10732.

    Article  Google Scholar 

  27. Liu, J. W.; Jiang, X. M.; Ashley, C.; Brinker, C. J. Electrostatically mediated liposome fusion and lipid exchange with a nanoparticle-supported bilayer for control of surface charge, drug containment, and delivery. J. Am. Chem. Soc. 2009, 131, 7567–7569.

    Article  Google Scholar 

  28. Yang, K.; Zhang, S. A.; Zhang, G. X.; Sun, X. M.; Lee, S. T.; Liu, Z. Graphene in mice: Ultrahigh in vivo tumor uptake and efficient photothermal therapy. Nano Lett. 2010, 10, 3318–3323.

    Article  Google Scholar 

  29. Robinson, J. T.; Tabakman, S. M.; Liang, Y. Y.; Wang, H. L.; Casalongue, H. S.; Vinh, D.; Dai, H. J. Ultrasmall reduced graphene oxide with high near-infrared absorbance for photothermal therapy. J. Am. Chem. Soc. 2011, 133, 6825–6831.

    Article  Google Scholar 

  30. Li, M.; Yang, X. J.; Ren, J. S.; Qu, K. G.; Qu, X. G. Using graphene oxide high near-infrared absorbance for photothermal treatment of alzheimer’s disease. Adv. Mater. 2012, 24, 1722–1728.

    Article  Google Scholar 

  31. Volodkin, D. V.; Skirtach, A. G.; Mohwald, H. Near-IR remote release from assemblies of liposomes and nanoparticles. Angew. Chem. Int. Ed. 2009, 48, 1807–1809.

    Article  Google Scholar 

  32. Haan, M. N. Therapy insight: Type 2 diabetes mellitus and the risk of late-onset alzheimer’s disease. Nat. Clin. Pract. Neuro. 2006, 2, 159–166.

    Article  Google Scholar 

  33. Seeliger, J.; Evers, F.; Jeworrek, C.; Kapoor, S.; Weise, K.; Andreetto, E.; Tolan, M.; Kapurniotu, A.; Winter, R. Crossamyloid interaction of Aβ and IAPP at lipid membranes. Angew. Chem. Int. Ed. 2012, 51, 679–683.

    Article  Google Scholar 

  34. Hummers, W. S.; Offeman, R. E. Preparation of graphitic oxide. J. Am. Chem. Soc. 1958, 80, 1339–1339.

    Article  Google Scholar 

  35. Reviakine, I.; Brisson, A. Formation of supported phospholipid bilayers from unilamellar vesicles investigated by atomic force microscopy. Langmuir 2000, 16, 1806–1815.

    Article  Google Scholar 

  36. Riaz, M. Liposomes preparation methods. Pak. J. Pharm. Sci. 1996, 9, 65–77.

    Google Scholar 

  37. Weiner, N.; Martin, F.; Riaz, M. Liposomes as a drug delivery system. Drug Dev. Ind. Pharm. 1989, 15, 1523–1554.

    Article  Google Scholar 

  38. Yu, H. J.; Li, M.; Liu, G. P.; Geng, J.; Wang, J. Z.; Ren, J. S.; Zhao, C. Q.; Qu, X. G. Metallosupramolecular complex targeting an alpha/beta discordant stretch of amyloid beta peptide. Chem. Sci. 2012, 3, 3145–3153.

    Article  Google Scholar 

  39. Geng, J.; Li, M.; Ren, J. S.; Wang, E. B.; Qu, X. G. Polyoxometalates as inhibitors of the aggregation of amyloid beta peptides associated with alzheimer’s disease. Angew. Chem. Int. Ed. 2011, 50, 4184–4188.

    Article  Google Scholar 

  40. Kresge, C. T.; Leonowicz, M. E.; Roth, W. J.; Vartuli, J. C.; Beck, J. S. Ordered mesoporous molecular-sieves synthesized by a liquid-crystal template mechanism. Nature 1992, 359, 710–712.

    Article  Google Scholar 

  41. Troutier, A. L.; Ladaviere, C. An overview of lipid membrane supported by colloidal particles. Adv. Colloid Interface Sci. 2007, 133, 1–21.

    Article  Google Scholar 

  42. Garbuzenko, O.; Barenholz, Y.; Priev, A. Effect of grafted peg on liposome size and on compressibility and packing of lipid bilayer. Chem. Phys. Lipids 2005, 135, 117–129.

    Article  Google Scholar 

  43. Chan, Y. H. M.; Boxer, S. G. Model membrane systems and their applications. Curr. Opin. Chem. Biol. 2007, 11, 581–587.

    Article  Google Scholar 

  44. Lai, C. Y.; Trewyn, B. G.; Jeftinija, D. M.; Jeftinija, K.; Xu, S.; Jeftinija, S.; Lin, V. S. Y. A mesoporous silica nanosphere-based carrier system with chemically removable CdS nanoparticle caps for stimuli-responsive controlled release of neurotransmitters and drug molecules. J. Am. Chem. Soc. 2003, 125, 4451–4459.

    Article  Google Scholar 

  45. Xu, C.; Lin, Y. H.; Wang, J. S.; Wu, L.; Wei, W. L.; Ren, J. S.; Qu, X. G. Nanoceria-triggered synergetic drug release based on CeO2-capped mesoporous silica host–guest interactions and switchable enzymatic activity and cellular effects of CeO2. Adv. Healthc. Mater. 2013, 2, 1591–1599.

    Article  Google Scholar 

  46. Kosik, K. S. Alzheimer’s disease: A cell biological perspective. Science 1992, 256, 780–783.

    Article  Google Scholar 

  47. Blennow, K.; de Leon, M. J.; Zetterberg, H. Alzheimer's disease. The Lancet 2006, 368, 387–403.

    Article  Google Scholar 

  48. Selkoe, D. J. Amyloid β-protein and the genetics of alzheimer’s disease. J. Biol. Chem. 1996, 271, 18295–18298.

    Article  Google Scholar 

  49. Sipe, J. D.; Cohen, A. S. Review: History of the amyloid fibril. J. Struct. Biol. 2000, 130, 88–98.

    Article  Google Scholar 

  50. Yankner, B. A.; Duffy, L. K.; Kirschner, D. A. Neurotrophic and neurotoxic effects of amyloid beta protein: Reversal by tachykinin neuropeptides. Science 1990, 250, 279–282.

    Article  Google Scholar 

  51. Mastrangelo, I. A.; Ahmed, M.; Sato, T.; Liu, W.; Wang, C. P.; Hough, P.; Smith, S. O. High-resolution atomic force microscopy of soluble a beta 42 oligomers. J. Mol. Biol. 2006, 358, 106–119.

    Article  Google Scholar 

  52. Shekhawat, G. S.; Lambert, M. P.; Sharma, S.; Velasco, P. T.; Viola, K. L.; Klein, W. L.; Dravid, V. P. Soluble state high resolution atomic force microscopy study of alzheimer’s beta-amyloid oligomers. Appl. Phys. Lett. 2009, 95. 183701.

    Article  Google Scholar 

  53. Liu, J. N.; Bu, J. W.; Bu, W. B.; Zhang, S. J.; Pan, L. M.; Fan, W. P.; Chen, F.; Zhou, L. P.; Peng, W. J.; Zhao, K. L. et al. Real-time in vivo quantitative monitoring of drug release by dual-mode magnetic resonance and upconverted luminescence imaging. Angew. Chem. Int. Ed. 2014, 53, 4551–4555.

    Article  Google Scholar 

  54. Liu, J. A.; Bu, W. B.; Pan, L. M.; Shi, J. L. NIR-triggered anticancer drug delivery by upconverting nanoparticles with integrated azobenzene-modified mesoporous silica. Angew. Chem. Int. Ed. 2013, 52, 4375–4379.

    Article  Google Scholar 

  55. Belkin, M.; Maffeo, C.; Wells, D. B.; Aksimentiev, A. Stretching and controlled motion of single-stranded DNA in locally heated solid-state nanopores. ACS Nano 2013, 7, 6816–6824.

    Article  Google Scholar 

  56. Urban, A. S.; Fedoruk, M.; Horton, M. R.; Rädler, J. O.; Stefani, F. D.; Feldmann, J. Controlled nanometric phase transitions of phospholipid membranes by plasmonic heating of single gold nanoparticles. Nano Lett. 2009, 9, 2903–2908.

    Article  Google Scholar 

  57. Geng, J.; Li, M.; Wu, L.; Chen, C. E.; Qu, X. G. Mesoporous silica nanoparticle-based H2O2 responsive controlled-release system used for alzheimer’s disease treatment. Adv. Healthc. Mater. 2012, 1, 332–336.

    Article  Google Scholar 

  58. Li, M.; Liu, Z.; Ren, J. S.; Qu, X. G. Inhibition of metalinduced amyloid aggregation using light-responsive magnetic nanoparticle prochelator conjugates. Chem. Sci. 2012, 3, 868–873.

    Article  Google Scholar 

  59. Li, M.; Shi, P.; Xu, C.; Ren, J. S.; Qu, X. G. Cerium oxide caged metal chelator: Anti-aggregation and anti-oxidation integrated H2O2-responsive controlled drug release for potential alzheimer’s disease treatment. Chem. Sci. 2013, 4, 2536–2542.

    Article  Google Scholar 

  60. Shi, P.; Li, M.; Ren, J. S.; Qu, X. G. Gold nanocage-based dual responsive “caged metal chelator” release system: Noninvasive remote control with near infrared for potential treatment of alzheimer’s disease. Adv. Funct. Mater. 2013, 23, 5412–5419.

    Article  Google Scholar 

  61. Liu, H. M.; Wang, H.; Yang, W. J.; Cheng, Y. Y. Disulfide cross-linked low generation dendrimers with high gene transfection efficacy, low cytotoxicity, and low cost. J. Am. Chem. Soc. 2012, 134, 17680–17687.

    Google Scholar 

  62. Pohl, F. M.; Jovin, T. M.; Baehr, W.; Holbrook, J. J. Ethidium bromide as a cooperative effector of a DNA structure. Proc. Natl. Acad. Sci. USA 1972, 69, 3805–3809.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China

    Can Xu, Peng Shi, Meng Li, Jinsong Ren & Xiaogang Qu

  2. University of Chinese Academy of Sciences, Beijing, 100039, China

    Can Xu, Peng Shi & Meng Li

Authors
  1. Can Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peng Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jinsong Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaogang Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jinsong Ren or Xiaogang Qu.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, C., Shi, P., Li, M. et al. A cytotoxic amyloid oligomer self-triggered and NIR-enhanced amyloidosis therapeutic system. Nano Res. 8, 2431–2444 (2015). https://doi.org/10.1007/s12274-015-0753-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-015-0753-7

Keywords

Search

Navigation