Skip to main content
SpringerLink
Log in

Temperature-sensitive polymeric nanogels encapsulating with β-cyclodextrin and ICG complex for high-resolution deep-tissue ultrasound-switchable fluorescence imaging

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

Abstract

One of the thorny problems currently impeding the applications of the fluorescence imaging technique is the poor spatial resolution in deep tissue. Ultrasound-switchable fluorescence (USF) imaging is a novel imaging tool that has recently been explored to possibly surmount the above-mentioned bottleneck. Herein, a β-cyclodextrin/indocyanine green (ICG) complex-encapsulated poly(N-isopropylacrylamide) (PNIPAM) nanogel was synthesized and studied for ex vivo/in vivo deep tissue/high-resolution near infrared USF (NIR-USF) imaging. To be specific, our results revealed that the average diameter of the as-prepared nanogels was significantly decreased to ~ 32 nm from ~ 335 nm compared to the reported ICG-PNIPAM nanoparticles. Additionally, the excitation/ emission characteristics of the ICG itself in present nanogels were almost completely retained, and the resultant nanogel exhibited high physiological stability and positive biocompatibility. In particular, the signal-to-noise ratio of the USF image for the PNIPAM/ β-cyclodextrin/ICG nanogel (33.01 ± 2.42 dB) was prominently higher than that of the ICG-PNIPAM nanoparticles (18.73 ± 0.33 dB) in 1.5-cm-thick chicken breast tissues. The NIR-USF imaging in 3.5-cm-thick chicken breast tissues was achieved using this new probe. The ex vivo NIR-USF imaging of the mouse liver was also successfully obtained. Animal experiments showed that the present nanogels were able to be effectively accumulated into U87 tumor-bearing mice via enhanced permeability and retention effects, and the high-resolution NIR-USF imaging of in vivo tumor was efficiently acquired. The metabolism and in vivo biodistribution of the nanogels were evaluated. Overall, the results suggest that the current nanogel is a highly promising NIR-USF probe for deep tissue and high-resolution USF imaging.

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. Shou, K. Q.; Qu, C. R.; Sun, Y.; Chen, H.; Chen, S.; Zhang, L.; Xu, H. B.; Hong, X. C.; Yu, A. X.; Cheng, Z. Multifunctional biomedical imaging in physiological and pathological conditions using a NIR-II probe. Adv. Funct. Mater.2017, 27, 1700995.

    Google Scholar 

  2. Carr, J. A.; Franke, D.; Caram, J. R.; Perkinson, C. F.; Saif, M.; Askoxylakis, V.; Datta, M.; Fukumura, D.; Jain, R. K.; Bawendi, M. G. et al. Shortwave infrared fluorescence imaging with the clinically approved near-infrared dye indocyanine green. Proc. Natl. Acad. Sci. USA2018, 115, 4465–4470.

    CAS  Google Scholar 

  3. Hong, G. S.; Antaris, A. L.; Dai, H. J. Near-infrared fluorophores for biomedical imaging. Nat. Biomed. Eng.2017, 1, 0010.

    CAS  Google Scholar 

  4. Qi, J.; Sun, C. W.; Li, D. Y.; Zhang, H. Q.; Yu, W. B.; Zebibula, A.; Lam, J. W. Y.; Xi, W.; Zhu, L.; Cai, F. H. et al. Aggregation-induced emission luminogen with near-infrared-II excitation and nearinfrared- I emission for ultradeep intravital two-photon microscopy. ACS Nano2018, 12, 7936–7945.

    CAS  Google Scholar 

  5. Frangioni, J. V. In vivo near-infrared fluorescence imaging. Curr. Opin. Chem. Biol.2003, 7, 626–634.

    CAS  Google Scholar 

  6. Yuan, B. H.; Liu, Y.; Mehl, P. M.; Vignola, J. Microbubble-enhanced ultrasound-modulated fluorescence in a turbid medium. Appl. Phys. Lett.2009, 95, 181113.

    Google Scholar 

  7. Huynh, N. T.; Hayes-Gill, B. R.; Zhang, F.; Morgan, S. P. Ultrasound modulated imaging of luminescence generated within a scattering medium. J. Biomed. Opt.2013, 18, 20505.

    Google Scholar 

  8. Lin, Y. T.; Bolisay, L. D.; Ghijsen, M.; Kwong, T. C.; Gulsen, G. Temperature-modulated fluorescence tomography in a turbid media. Appl. Phys. Lett.2012, 100, 073702.

    Google Scholar 

  9. Lin, Y. T.; Kwong, T. C.; Bolisay, L.; Gulsen, G. Temperaturemodulated fluorescence tomography based on both concentration and lifetime contrast. J. Biomed. Opt.2012, 17, 056007.

    Google Scholar 

  10. Yuan, B. H.; Uchiyama, S.; Liu, Y.; Nguyen, K. T.; Alexandrakis, G. -resolution imaging in a deep turbid medium based on an ultrasound-switchable fluorescence technique. Appl. Phys. Lett.2012, 101, 033703.

    Google Scholar 

  11. Ahmad, J.; Jayet, B.; Hill, P. J.; Mather, M. L.; Dehghani, H.; Morgan, S. P. Ultrasound-mediation of self-illuminating reporters improves imaging resolution in optically scattering media. Biomed. Opt. Express2018, 9, 1664–1679.

    CAS  Google Scholar 

  12. Xu, X.; Liu, H. L.; Wang, L. V. Time-reversed ultrasonically encoded optical focusing into scattering media. Nat. Photonics2011, 5, 154–157.

    CAS  Google Scholar 

  13. Yu, S.; Cheng, B. B.; Yao, T. F.; Xu, C. C.; Nguyen, K. T.; Hong, Y.; Yuan, B. H. New generation ICG-based contrast agents for ultrasound-switchable fluorescence imaging. Sci. Rep.2016, 6, 35942.

    CAS  Google Scholar 

  14. Kwong, T. C. A new modality for high resolution diffuse optical imaging: Temperature modulated fluorescence tomography. Ph.D. Dissertation, University of California, Irvine, USA, 2017.

    Google Scholar 

  15. Yao, T. F.; Yu, S.; Liu, Y.; Yuan, B. H. Ultrasound-switchable fluorescence imaging via an EMCCD camera and a Z-scan method. IEEE J. Sel. Top. Quantum Electron.2019, 25, 7102108.

    Google Scholar 

  16. Yao, T. F.; Yu, S.; Liu, Y.; Yuan, B. H. In vivo ultrasound-switchable fluorescence imaging. Sci. Rep.2019, 9, 9855.

    Google Scholar 

  17. Pei, Y. B.; Wei, M. Y.; Cheng, B. B.; Liu, Y.; Xie, Z. W.; Nguyen, K.; Yuan, B. H. High resolution imaging beyond the acoustic diffraction limit in deep tissue via ultrasound-switchable NIR fluorescence. Sci. Rep.2014, 4, 4690.

    Google Scholar 

  18. Rodriguez, V. B.; Henry, S. M.; Hoffman, A. S.; Stayton, P. S.; Li, X. D.; Pun, S. H. Encapsulation and stabilization of indocyanine green within poly(styrene-alt-maleic anhydride) block-poly(styrene) micelles for near-infrared imaging. J. Biomed. Opt.2008, 13, 014025.

    Google Scholar 

  19. Shan, W. J.; Chen, R. H.; Zhang, Q.; Zhao, J.; Chen, B. B.; Zhou, X.; Ye, S. F.; Bi, S. L.; Nie, L. M.; Ren, L. Improved stable indocyanine green (ICG)-mediated cancer optotheranostics with naturalized hepatitis B core particles. Adv. Mater.2018, 30, 1707567.

    Google Scholar 

  20. Saxena, V.; Sadoqi, M.; Shao, J. Degradation kinetics of indocyanine green in aqueous solution. J. Pharm. Sci.2003, 92, 2090–2097.

    CAS  Google Scholar 

  21. Holzer, W.; Mauerer, M.; Penzkofer, A.; Szeimies, R. M.; Abels, C.; Landthaler, M.; Bäumler, W. Photostability and thermal stability of indocyanine green. J. Photochem. Photobiol. B1998, 47, 155–164.

    CAS  Google Scholar 

  22. Jambhekar, S. S.; Breen, P. Cyclodextrins in pharmaceutical formulations II: Solubilization, binding constant, and complexation efficiency. Drug Discovery Today2016, 21, 363–368.

    CAS  Google Scholar 

  23. Liu, R. L.; Zhang, Z. Q.; Jing, W. H.; Wang, L.; Luo, Z. M.; Chang, R. M.; Zeng, A. G.; Du, W.; Chang, C.; Fu, Q. β-Cyclodextrin anchoring onto pericarpium granati-derived magnetic mesoporous carbon for selective capture of lopid in human serum and pharmaceutical wastewater samples. Mater. Sci. Eng. C2016, 62, 605–613.

    CAS  Google Scholar 

  24. Barros, T. C.; Toma, S. H.; Toma, H. E.; Bastos, E. L.; Baptista, M. S. Polymethine cyanine dyes in β-cyclodextrin solution: Multiple equilibria and chemical oxidation. J. Phys. Org. Chem.2010, 23, 893–903.

    CAS  Google Scholar 

  25. DeDora, D. J.; Suhrland, C.; Goenka, S.; Chowdhury, S. M.; Lalwani, G.; Mujica-Parodi, L. R.; Sitharaman, B. Sulfobutyl ether β-cyclodextrin (Captisol®) and methyl β-cyclodextrin enhance and stabilize fluorescence of aqueous indocyanine green. J. Biomed. Mater. Res. Part B: Appl. Biomater.2016, 104, 1457–1464.

    CAS  Google Scholar 

  26. Niki, E. Action of ascorbic acid as a scavenger of active and stable oxygen radicals. Am. J. Clin. Nutr.1991, 54, 1119S–1124S.

  27. Liu, R. L.; Wang, Y.; Ge, X. L.; Yu, P.; Liu, H. Q.; Wang, M. C.; Lu, W.; Fu, Q. Polydopamine/polyethyleneimine complex adhered to micrometer-sized magnetic carbon fibers for high-efficiency hemoperfusion. J. Biomater. Sci. Polym. Ed.2017, 28, 1444–1468.

    CAS  Google Scholar 

  28. Blackburn, W. H.; Andrew Lyon, L. Size-controlled synthesis of monodisperse core/shell nanogels. Colloid Polym. Sci.2008, 286, 563–569.

    CAS  Google Scholar 

  29. Freitag, R.; Garret-Flaudy, F. Salt effects on the thermoprecipitation of poly-(N-isopropylacrylamide) oligomers from aqueous solution. Langmuir2002, 18, 3434–3440.

    CAS  Google Scholar 

  30. Dai, Y. L.; Xu, C.; Sun, X. L.; Chen, X. Y. Nanoparticle design strategies for enhanced anticancer therapy by exploiting the tumour microenvironment. Chem. Soc. Rev.2017, 46, 3830–3852.

    CAS  Google Scholar 

  31. Bhavane, R.; Starosolski, Z.; Stupin, I.; Ghaghada, K. B.; Annapragada, A. NIR-II fuorescence imaging using indocyanine green nanoparticles. Sci. Rep.2018, 8, 14455.

    Google Scholar 

  32. Zhu, Q. S.; Chen, L. B.; Zhu, P. Y.; Luan, J. F.; Mao, C.; Huang, X. H.; Shen, J. Preparation of PNIPAM-g-P (NIPAM-co-St) microspheres and their blood compatibility. Colloids Surf. B: Biointerfaces2013, 104, 61–65.

    CAS  Google Scholar 

  33. Cheng, B. B.; Bandi, V.; Wei, M. Y.; Pei, Y. B.; D’Souza, F.; Nguyen, K. T.; Hong, Y.; Yuan, B. H. High-resolution ultrasound-switchable fluorescence imaging in centimeter-deep tissue phantoms with high signal-to-noise ratio and high sensitivity via novel contrast agents. PLoS One2016, 11, e0165963.

    Google Scholar 

  34. Zhao, J. Y.; Zhong, D.; Zhou, S. B. NIR-I-to-NIR-II fluorescent nanomaterials for biomedical imaging and cancer therapy. J. Mater. Chem. B2018, 6, 349–365.

    CAS  Google Scholar 

  35. Yuan, A.; Wu, J. H.; Tang, X. L.; Zhao, L. L.; Xu, F.; Hu, Y. Q. Application of near-infrared dyes for tumor imaging, photothermal, and photodynamic therapies. J. Pharm. Sci.2013, 102, 6–28.

    CAS  Google Scholar 

  36. Resch-Genger, U.; Grabolle, M.; Cavaliere-Jaricot, S.; Nitschke, R.; Nann, T. Quantum dots versus organic dyes as fluorescent labels. Nat. Methods2008, 5, 763–775.

    CAS  Google Scholar 

  37. Hong, G. S.; Lee, J. C.; Robinson, J. T.; Raaz, U.; Xie, L. M.; Huang, N. F.; Cooke, J. P.; Dai, H. J. Multifunctional In vivo vascular imaging using near-infrared II fluorescence. Nat. Med.2012, 18, 1841–1846.

    CAS  Google Scholar 

  38. Bhavane, R.; Starosolski, Z.; Stupin, I.; Ghaghada, K. B.; Annapragada, A. NIR-II fluorescence imaging using indocyanine green nanoparticles. Sci. Rep.2018, 8, 14455.

    Google Scholar 

  39. Wang, Y. F.; Liu, G. Y.; Sun, L. D.; Xiao, J. W.; Zhou, J. C.; Yan, C. H. Nd3+-sensitized upconversion nanophosphors: Efficient In vivo bioimaging probes with minimized heating effect. ACS Nano2013, 7, 7200–7206.

    CAS  Google Scholar 

  40. Chen, G. Y.; Shen, J.; Ohulchanskyy, T. Y.; Patel, N. J.; Kutikov, A.; Li, Z. P.; Song, J.; Pandey, R. K.; Ågren, H.; Prasad, P. N. et al. (α-NaYbF4:Tm3+)/CaF2 core/shell nanoparticles with efficient nearinfrared to near-infrared upconversion for high-contrast deep tissue bioimaging. ACS Nano2012, 6, 8280–8287.

    CAS  Google Scholar 

  41. Yu, M. X.; Zheng, J. Clearance pathways and tumor targeting of imaging nanoparticles. ACS Nano2015, 9, 6655–6674.

    CAS  Google Scholar 

  42. Imamura, T.; Saitou, T.; Kawakami, R. In vivo optical imaging of cancer cell function and tumor microenvironment. Cancer Sci.2018, 109, 912–918.

    CAS  Google Scholar 

  43. Vanparijs, N.; Nuhn, L.; De Geest, B. G. Transiently thermoresponsive polymers and their applications in biomedicine. Chem. Soc. Rev.2017, 46, 1193–1239.

    CAS  Google Scholar 

  44. Zeng, Y.; Zhu, J.; Wang, J. Q.; Parasuraman, P.; Busi, S.; Nauli, S. M.; Wáng, Y. X. J.; Pala, R.; Liu, G. Functional probes for cardiovascular molecular imaging. Quant. Imaging Med. Surg.2018, 8, 838–852.

    Google Scholar 

Download references

Acknowledgements

This work was supported in part by funding from the CPRIT RP170564 (Baohong Yuan) and the NSF CBET-1253199 (Baohong Yuan).

Author information

Author notes

  1. Ruilin Liu and Tingfeng Yao contributed equally to this work.

Authors and Affiliations

  1. Ultrasound and Optical Imaging Laboratory, Department of Bioengineering, the University of Texas at Arlington, Arlington, TX, 76019, USA

    Ruilin Liu, Tingfeng Yao, Yang Liu, Shuai Yu, Liqin Ren & Baohong Yuan

  2. Joint Biomedical Engineering Program, the University of Texas at Arlington and the University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Ruilin Liu, Tingfeng Yao, Yang Liu, Shuai Yu, Liqin Ren, Yi Hong, Kytai T. Nguyen & Baohong Yuan

  3. Department of Bioengineering, the University of Texas at Arlington, Arlington, TX, 76019, USA

    Yi Hong & Kytai T. Nguyen

Authors
  1. Ruilin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tingfeng Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuai Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Liqin Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kytai T. Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Baohong Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Baohong Yuan.

Ethics declarations

All animal studies were approved by the University of Texas at Arlington’s Institutional Animal Care and Use Committee and performed in accordance with their guidance and regulations.

Electronic supplementary material

12274_2020_2752_MOESM1_ESM.pdf

Temperature-sensitive polymeric nanogels encapsulating with β-cyclodextrin and ICG complex for high-resolution deep-tissue ultrasound-switchable fluorescence imaging

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, R., Yao, T., Liu, Y. et al. Temperature-sensitive polymeric nanogels encapsulating with β-cyclodextrin and ICG complex for high-resolution deep-tissue ultrasound-switchable fluorescence imaging. Nano Res. 13, 1100–1110 (2020). https://doi.org/10.1007/s12274-020-2752-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-020-2752-6

Keywords

Search

Navigation