Skip to main content
SpringerLink
Log in

Two-photon AIE probe conjugated theranostic nanoparticles for tumor bioimaging and pH-sensitive drug delivery

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

Abstract

Nanoparticles armed with chemotherapy drug and fluorescence probe have become an effective anticancer strategy for their advantages in cancer diagnosis and treatment. However, fluorophore for diagnostic medicine with deep penetration depth and high resolution are still very rare, while rational designs are also required to improve the tumor retention and target-site drug delivery. Herein, a two-photon fluorophore with aggregation-induced emission and large two-photon absorption cross-section has been designed for two-photon bioimaging, and a novel theranostic nanoplatform is also constructed based on doxorubicin and the two-photon fluorophore conjugated copolymer, P(TPMA-co-AEMA)-PEI(DA)-Blink-PEG (PAEEBlink-DA). The micelles maintain a “stealth” property during blood circulation and is activated in the acidic tumor microenvironment, which triggers the charge-conversion and results in enhanced micellar internalization. Meanwhile, PAEMA chains can convert from hydrophobicity to hydrophilicity with accelerated drug release and particle size expansion. The enlarged particle size would potentially extend the retention time of these micelles. Moreover, a great AIE active two-photon bioimaging with tissue penetration depth up to 150 µm is observed and the in vivo biodistribution of nanoparticles can be traced. The in vivo antitumor results further indicate the obvious reduction of adverse effect and enhanced treatment effect of these micelles, proving that these PAEEBlink-DA micelles would be a potential candidate for tumor theranostic applications.

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. Ni, Y.; Wu, J. S. Far-red and near infrared bodipy dyes: Synthesis and applications for fluorescent pH probes and bio-imaging. Org. Biomol. Chem. 2014, 12, 3774–3791.

    Article  Google Scholar 

  2. Keeble, J.; Goh, C. C.; Wang, Y. L.; Weninger, W.; Ng, L. G. Intravital multiphoton imaging of immune cells. In Advances in Bio-Imaging: From Physics to Signal Understanding Issues. Loménie, N.; Racoceanu, D.; Gouaillard, A., Eds.; Springer: Berlin, Heidelberg, 2012; pp 3–16.

    Chapter  Google Scholar 

  3. Hong, Y. N.; Lam, J. W. Y.; Tang, B. Z. Aggregation-induced emission. Chem. Soc. Rev. 2011, 40, 5361–5388.

    Article  Google Scholar 

  4. Reisch, A.; Klymchenko, A. S. Fluorescent polymer nanoparticles based on dyes: Seeking brighter tools for bioimaging. Small 2016, 12, 1968–1992.

    Article  Google Scholar 

  5. Yuan, Y. Y.; Kwok, R. T. K.; Tang, B. Z.; Liu, B. Targeted theranostic platinum(IV) prodrug with a built-in aggregation-induced emission light-up apoptosis sensor for noninvasive early evaluation of its therapeutic responses in situ. J. Am. Chem. Soc. 2014, 136, 2546–2554.

    Article  Google Scholar 

  6. Luo, J. D.; Xie, Z. L.; Lam, J. W. Y.; Cheng, L.; Chen, H. Y.; Qiu, C. F.; Kwok, H. S.; Zhan, X. W.; Liu, Y. Q.; Zhu, D. B. et al. Aggregation-induced emission of 1-methyl-1, 2, 3, 4, 5-pentaphenylsilole. Chem. Commun. 2001, 1740–1741.

    Google Scholar 

  7. Jayaram, D. T.; Ramos-Romero, S.; Shankar, B. H.; Garrido, C.; Rubio, N.; Sanchez-Cid, L.; Gómez, S. B.; Blanco, J.; Ramaiah, D. In vitro and in vivo demonstration of photodynamic activity and cytoplasm imaging through TPE nanoparticles. ACS Chem. Biol. 2016, 11, 104–112.

    Article  Google Scholar 

  8. Theer, P.; Hasan, M. T.; Denk, W. Two-photon imaging to a depth of 1,000 µm in living brains by use of a Ti:Al2O3 regenerative amplifier. Opt. Lett. 2003, 28, 1022–1024.

    Article  Google Scholar 

  9. Helmchen, F.; Denk, W. Deep tissue two-photon microscopy. Nat. Methods 2005, 2, 932–940.

    Article  Google Scholar 

  10. Jiang, M. J.; Gu, X. G.; Lam, J. W. Y.; Zhang, Y. L.; Kwok, R. T. K.; Wong, K. S.; Tang, B. Z. Two-photon AIE bio-probe with large stokes shift for specific imaging of lipid droplets. Chem. Sci. 2017, 8, 5440–5446.

    Article  Google Scholar 

  11. Roberts, W. G.; Palade, G. E. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J. Cell Sci. 1995, 108, 2369–2379.

    Google Scholar 

  12. Luo, Y. P.; Jiang, F.; Cole, T. B.; Hradil, V. P.; Reuter, D.; Chakravartty, A.; Albert, D. H.; Davidsen, S. K.; Cox, B. F.; McKeegan, E. M. et al. A novel multi-targeted tyrosine kinase inhibitor, linifanib (ABT-869), produces functional and structural changes in tumor vasculature in an orthotopic rat glioma model. Cancer Chemother. Pharmacol. 2012, 69, 911–921.

    Article  Google Scholar 

  13. Larson, D. R.; Zipfel, W. R.; Williams, R. M.; Clark, S. W.; Bruchez, M. P.; Wise, F. W.; Webb, W. W. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science 2003, 300, 1434–1436.

    Article  Google Scholar 

  14. Wang, D.; Su, H. F.; Kwok, R. T. K.; Hu, X. L.; Zou, H.; Luo, Q. X.; Lee, M. M. S.; Xu, W. H.; Lam, J. W. Y.; Tang, B. Z. Rational design of a water-soluble NIR AIEgen, and its application in ultrafast wash-free cellular imaging and photodynamic cancer cell ablation. Chem. Sci. 2018, 9, 3685–3693.

    Article  Google Scholar 

  15. Ge, Z. S.; Liu, S. Y. Functional block copolymer assemblies responsive to tumor and intracellular microenvironments for site-specific drug delivery and enhanced imaging performance. Chem. Soc. Rev. 2013, 42, 7289–7325.

    Article  Google Scholar 

  16. Miyata, K.; Christie, R. J.; Kataoka, K. Polymeric micelles for nano-scale drug delivery. React. Funct. Polym. 2011, 71, 227–234.

    Article  Google Scholar 

  17. Zhao, J. Y.; Zhong, D.; Zhou, S. B. NIR-I-to-NIR-II fluorescent nanomaterials for biomedical imaging and cancer therapy. J. Mater. Chem. B 2018, 6, 349–365.

    Article  Google Scholar 

  18. Wang, Y.; Wei, G. Q.; Zhang, X. B.; Huang, X. H.; Zhao J. Y.; Guo, X.; Zhou, S. B. Multistage targeting strategy using magnetic composite nanoparticles for synergism of photothermal therapy and chemotherapy. Small 2014, 14, 1702994.

    Article  Google Scholar 

  19. Fang, J.; Nakamura, H.; Maeda, H. The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv. Drug Deliv. Rev. 2011, 63, 136–151.

    Article  Google Scholar 

  20. Sun, Q. H.; Zhou, Z. X.; Qiu, N. S.; Shen, Y. Q. Rational design of cancer nanomedicine: Nanoproperty integration and synchronization. Adv. Mater. 2017, 29, 1606628.

    Article  Google Scholar 

  21. Stewart, M. P.; Sharei, A.; Ding, X. Y.; Sahay, G.; Langer, R.; Jensen, K. F. In vitro and ex vivo strategies for intracellular delivery. Nature 2016, 538, 183–192.

    Article  Google Scholar 

  22. Sanhai, W. R.; Sakamoto, J. H.; Canady, R.; Ferrari, M. Seven challenges for nanomedicine. Nat. Nanotechnol. 2008, 3, 242–244.

    Article  Google Scholar 

  23. Shi, J. J.; Kantoff, P. W.; Wooster, R.; Farokhzad, O. C. Cancer nanomedicine: Progress, challenges and opportunities. Nat. Rev. Cancer 2016, 17, 20–37.

    Article  Google Scholar 

  24. Chen, G. Y.; Roy, I.; Yang, C. H.; Prasad, P. N. Nanochemistry and nanomedicine for nanoparticle-based diagnostics and therapy. Chem. Rev. 2016, 116, 2826–2885.

    Article  Google Scholar 

  25. Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2007, 2, 751–760.

    Article  Google Scholar 

  26. Sugihara, S.; Blanazs, A.; Armes, S. P.; Ryan, A. J.; Lewis, A. L. Aqueous dispersion polymerization: A new paradigm for in situ block copolymer self-assembly in concentrated solution. J. Am. Chem. Soc. 2011, 133, 15707–15713.

    Article  Google Scholar 

  27. Wang, S.; Huang, P.; Chen, X. Y. Hierarchical targeting strategy for enhanced tumor tissue accumulation/retention and cellular internalization. Adv. Mater. 2016, 28, 7340–7364.

    Article  Google Scholar 

  28. Zhang, Y.; Cai, K. M.; Li, C.; Guo, Q.; Chen, Q. J.; He, X.; Liu, L. S.; Zhang, Y. J.; Lu, Y. F.; Chen, X. L. et al. Macrophage-membrane-coated nanoparticles for tumor-targeted chemotherapy. Nano Lett. 2018, 18, 1908–1915.

    Article  Google Scholar 

  29. Guo, X.; Wei, X.; Jing, Y. T.; Zhou, S. B. Size changeable nanocarriers with nuclear targeting for effectively overcoming multidrug resistance in cancer therapy. Adv. Mater. 2015, 27, 6450–6456.

    Article  Google Scholar 

  30. Guo, X.; Shi, C. L.; Yang, G.; Wang, J.; Cai, Z. H.; Zhou, S. B. Dual-responsive polymer micelles for target-cell-specific anticancer drug delivery. Chem. Mater. 2014, 26, 4405–4418.

    Article  Google Scholar 

  31. Huang, Y.; Tang, Z. H.; Zhang, X. F.; Yu, H. Y.; Sun, H.; Pang, X.; Chen, X. S. pH-triggered charge-reversal polypeptide nanoparticles for cisplatin delivery: Preparation and in vitro evaluation. Biomacromolecules 2013, 14, 2023–2032.

    Article  Google Scholar 

  32. Liu, G. Y.; Li, M.; Zhu, C. S.; Jin, Q.; Zhang, Z. C.; Ji, J. Charge-conversional and pH-sensitive PEGylated polymeric micelles as efficient nanocarriers for drug delivery. Macromol. Biosci. 2014, 14, 1280–1290.

    Article  Google Scholar 

  33. Xu, P. S.; Van Kirk, E. A.; Zhan, Y. H.; Murdoch, W. J.; Radosz, M.; Shen, Y. Q. Targeted charge-reversal nanoparticles for nuclear drug delivery. Angew. Chem. 2007, 119, 5087–5090.

    Article  Google Scholar 

  34. Lee, E. S.; Gao, Z. G.; Bae, Y. H. Recent progress in tumor pH targeting nanotechnology. J. Control. Release. 2008, 132, 164–170.

    Article  Google Scholar 

  35. Lu, Y.; Aimetti, A. A.; Langer, R.; Gu, Z. Bioresponsive materials. Nat. Rev. Mater. 2016, 2, 16075.

    Article  Google Scholar 

  36. Hu, J. M.; Zhang, G. Y.; Ge, Z. S.; Liu, S. Y. Stimuli-responsive tertiary amine methacrylate-based block copolymers: Synthesis, supramolecular self-assembly and functional applications. Prog. Polym. Sci. 2014, 39, 1096–1143.

    Article  Google Scholar 

  37. Lee, E. S.; Na, K.; Bae, Y. H. Super pH-sensitive multifunctional polymeric micelle. Nano Lett. 2005, 5, 325–329.

    Article  Google Scholar 

  38. Mindell, J. A. Lysosomal acidification mechanisms. Annu. Rev. Physiol. 2012, 74, 69–86.

    Article  Google Scholar 

  39. Gu, J. X.; Cheng, W. P.; Liu, J. G.; Lo, S. Y.; Smith, D.; Qu, X. Z.; Yang, Z. Z. pH-triggered reversible “stealth” polycationic micelles. Biomacromolecules 2008, 9, 255–262.

    Article  Google Scholar 

  40. Yoshio, O.; Reiko, A.; Toyoki, K. Reaction of the azomethine moiety buried in bilayer membranes. Bull. Chem. Soc. Jpn. 1983, 56, 802–808.

    Article  Google Scholar 

  41. Ma, B. X.; Zhuang, W. H.; Wang, Y. N.; Luo, R. F.; Wang, Y. B. pH-sensitive doxorubicin-conjugated prodrug micelles with charge-conversion for cancer therapy. Acta Biomater. 2018, 70, 186–196.

    Article  Google Scholar 

  42. Zhou, K. J.; Wang, Y. G.; Huang, X. N.; Luby-Phelps, K.; Sumer, B. D.; Gao, J. M. Tunable, ultrasensitive pH-responsive nanoparticles targeting specific endocytic organelles in living cells. Angew. Chem., Int. Ed. 2011, 50, 6109–6114.

    Article  Google Scholar 

  43. Zhuang, W. H.; Xu, Y. Y.; Li, G. C.; Hu, J.; Ma, B. X.; Yu, T.; Su, X.; Wang, Y. B. Redox and pH dual-responsive polymeric micelles with aggregation-induced emission feature for cellular imaging and chemotherapy. ACS Appl. Mater. Interfaces 2018, 10, 18489–18498.

    Article  Google Scholar 

  44. Hu, J.; Zhuang, W. H.; Ma, B. X.; Su, X.; Yu, T.; Li, G. C.; Hu, Y. F.; Wang, Y. B. Redox-responsive biomimetic polymeric micelle for simultaneous anticancer drug delivery and aggregation-induced emission active imaging. Bioconjugate Chem. 2018, 29, 1897–1910.

    Article  Google Scholar 

Download references

Acknowledgements

This research was financially supported by the National Natural Science Foundation of China (No. 21502129), the National 111 Project of Introducing Talents of Discipline to Universities (No. B16033), China Postdoctoral Science Foundation Funded Project (Nos. 2017M612956 and 2018T110969), the Key Technology Support Program of Sichuan Province (No. 2016SZ0004), and the State Key Laboratory of Polymer Materials Engineering (No. sklpme2018-3-05). We are grateful for the help of Mr. Chenghui Li (Analytical & Testing Center, Sichuan University) taking laser scanning confocal images.

Author information

Author notes

  1. Boxuan Ma and Weihua Zhuang contributed equally to this work.

Authors and Affiliations

  1. National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China

    Boxuan Ma, Weihua Zhuang, Haiyang He, Xin Su, Tao Yu, Jun Hu, Li Yang, Gaocan Li & Yunbing Wang

Authors
  1. Boxuan Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weihua Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Haiyang He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Li Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gaocan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yunbing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Li Yang or Gaocan Li.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, B., Zhuang, W., He, H. et al. Two-photon AIE probe conjugated theranostic nanoparticles for tumor bioimaging and pH-sensitive drug delivery. Nano Res. 12, 1703–1712 (2019). https://doi.org/10.1007/s12274-019-2426-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-019-2426-4

Keywords

Search

Navigation