Photo-triggered nucleus targeting for cancer drug delivery


Here, we report a strategy to deliver drug nanoparticles into cells with nucleus-targeting ability under a spatiotemporal control. The nanoparticles were constructed through self-assembly of photoresponsive prodrugs and free drugs. By incorporating a nucleus localization sequence in the system, drug nanoparticles could be delivered into nuclei upon visible light irradiation. The drug nanoparticles showed high drug loading capacity and specific nucleus-targeting ability, which efficiently killed cancer cells. This self-assembly strategy could be applied to other hydrophobic drugs and targeting ligands for photo-controlled organelle-targeted drug delivery.

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  1. [1]

    Shi, J. J.; Kantoff, P. W.; Wooster, R.; Farokhzad, O. C. Cancer nanomedicine: Progress, challenges and opportunities. Nat. Rev. Cancer 2017, 17, 20–37.

    CAS  Article  Google Scholar 

  2. [2]

    Nichols, J. W.; Bae, Y. H. EPR: Evidence and fallacy. J. Control. Release 2014, 190, 451–464.

    CAS  Article  Google Scholar 

  3. [3]

    Yan, J.; Zhu, R. Y.; Wu, F.; Zhao, Z. Y.; Ye, H.; Hou, M. Y.; Liu, Y.; Yin, L. C. iRGD-reinforced, photo-transformable nanoclusters toward cooperative enhancement of intratumoral penetration and antitumor efficacy. Nano Res. 2020, 13, 2706–2715.

    CAS  Article  Google Scholar 

  4. [4]

    Lee, E. S.; Gao, Z. G.; Kim, D.; Park, K.; Kwon, I. C.; Bae, Y. H. Super pH-sensitive multifunctional polymeric micelle for tumor pHe specific TAT exposure and multidrug resistance. J. Control. Release 2008, 129, 228–236.

    CAS  Article  Google Scholar 

  5. [5]

    Barhoumi, A.; Wang, W. P.; Zurakowski, D.; Langer, R. S.; Kohane, D. S. Photothermally targeted thermosensitive polymer-masked nanoparticles. Nano Lett. 2014, 14, 3697–3701.

    CAS  Article  Google Scholar 

  6. [6]

    Yang, Y.; Liu, J. J.; Sun, X. Q.; Feng, L. Z.; Zhu, W. W.; Liu, Z.; Chen, M. W. Near-infrared light-activated cancer cell targeting and drug delivery with aptamer-modified nanostructures. Nano Res. 2016, 9, 139–148.

    CAS  Article  Google Scholar 

  7. [7]

    Wang, Y. F.; Kohane, D. S. External triggering and triggered targeting strategies for drug delivery. Nat. Rev. Mater. 2017, 2, 17020.

    CAS  Article  Google Scholar 

  8. [8]

    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.

    CAS  Article  Google Scholar 

  9. [9]

    Rwei, A. Y.; Wang, W. P.; Kohane, D. S. Photoresponsive nanoparticles for drug delivery. Nano Today 2015, 10, 451–467.

    CAS  Article  Google Scholar 

  10. [10]

    Li, Y. F.; Zhang, Y. M.; Wang, W. P. Phototriggered targeting of nanocarriers for drug delivery. Nano Res. 2018, 11, 5424–5438.

    CAS  Article  Google Scholar 

  11. [11]

    Li, J.; Sun, C. Y.; Tao, W.; Cao, Z. Y.; Qian, H. S.; Yang, X. Z.; Wang, J. Photoinduced PEG deshielding from ROS-sensitive linkage-bridged block copolymer-based nanocarriers for on-demand drug delivery. Biomaterials 2018, 170, 147–155.

    CAS  Article  Google Scholar 

  12. [12]

    Rajendran, L.; Knölker, H. J.; Simons, K. Subcellular targeting strategies for drug design and delivery. Nat. Rev. Drug Discov. 2010, 9, 29–42.

    CAS  Article  Google Scholar 

  13. [13]

    Kim, K. Y.; Jin, H. Y.; Park, J.; Jung, S. H.; Lee, J. H.; Park, H.; Kim, S. K.; Bae, J.; Jung, J. H. Mitochondria-targeting self-assembled nanoparticles derived from triphenylphosphonium-conjugated cyanostilbene enable site-specific imaging and anticancer drug delivery. Nano Res. 2017, 11, 1082–1098.

    Article  Google Scholar 

  14. [14]

    Zhang, W. J.; Hu, X. L.; Shen, Q.; Xing, D. Mitochondria-specific drug release and reactive oxygen species burst induced by polyprodrug nanoreactors can enhance chemotherapy. Nat. Commun. 2019, 10, 1704.

    Article  Google Scholar 

  15. [15]

    Lv, W.; Zhang, Z.; Zhang, K. Y.; Yang, H. R.; Liu, S. J.; Xu, A. Q.; Guo, S.; Zhao, Q.; Huang, W. A mitochondria-targeted photosensitizer showing improved photodynamic therapy effects under hypoxia. Angew. Chem., Int. Ed. 2016, 55, 9947–9951.

    CAS  Article  Google Scholar 

  16. [16]

    Hua, X. W.; Bao, Y. W.; Wu, F. G. Fluorescent carbon quantum dots with intrinsic nucleolus-targeting capability for nucleolus imaging and enhanced cytosolic and nuclear drug delivery. ACS Appl. Mater. Interfaces 2018, 10, 10664–10677.

    CAS  Article  Google Scholar 

  17. [17]

    Cheng, H.; Yuan, P.; Fan, G. L.; Zhao, L. P.; Zheng, R. R.; Yang, B.; Qiu, X. Z.; Yu, X. Y.; Li, S. Y.; Zhang, X. Z. Chimeric peptide nanorods for plasma membrane and nuclear targeted photosensitizer delivery and enhanced photodynamic therapy. Appl. Mater. Today 2019, 16, 120–131.

    CAS  Article  Google Scholar 

  18. [18]

    Zhou, Z. X.; Shen, Y. Q.; Tang, J. B.; Fan, M. H.; Van Kirk, E. A.; Murdoch, W. J.; Radosz, M. Charge-reversal drug conjugate for targeted cancer cell nuclear drug delivery. Adv. Funct. Mater. 2009, 19, 3580–3589.

    CAS  Article  Google Scholar 

  19. [19]

    Wang, Y.; Niu, G. L.; Zhai, S. D.; Zhang, W. J.; Xing, D. Specific photoacoustic cavitation through nucleus targeted nanoparticles for high-efficiency tumor therapy. Nano Res. 2020, 13, 719–728.

    Article  Google Scholar 

  20. [20]

    Leung, C. W. T.; Wang, Z. M.; Zhao, E. G.; Hong, Y. N.; Chen, S. J.; Kwok, R. T. K.; Leung, A. C. S.; Wen, R. S.; Li, B. S.; Lam, J. W. Y. et al. A lysosome-targeting aiegen for autophagy visualization. Adv. Healthc Mater. 2016, 5, 427–431.

    CAS  Article  Google Scholar 

  21. [21]

    Daum, S.; Reshetnikov, M. S. V.; Sisa, M.; Dumych, T.; Lootsik, M. D.; Bilyy, R.; Bila, E.; Janko, C.; Alexiou, C.; Herrmann, M. et al. Lysosome-targeting amplifiers of reactive oxygen species as anticancer prodrugs. Angew. Chem., Int. Ed. 2017, 56, 15545–15549.

    CAS  Article  Google Scholar 

  22. [22]

    Panasci, L.; Paiement, J. P.; Christodoulopoulos, G.; Belenkov, A.; Malapetsa, A.; Aloyz, R. Chlorambucil drug resistance in chronic lymphocytic leukemia: The emerging role of DNA repair. Clin. Cancer Res. 2001, 7, 454–461.

    CAS  Google Scholar 

  23. [23]

    Sui, M. H.; Liu, W. W.; Shen, Y. Q. Nuclear drug delivery for cancer chemotherapy. J. Control Release 2011, 155, 227–236.

    CAS  Article  Google Scholar 

  24. [24]

    Lin, Q.; Bao, C.; Cheng, S.; Yang, Y.; Ji, W.; Zhu, L. Target-activated coumarin phototriggers specifically switch on fluorescence and photocleavage upon bonding to thiol-bearing protein. J. Am. Chem. Soc. 2012, 134, 5052–5055.

    CAS  Article  Google Scholar 

  25. [25]

    Lu, Z. K.; Weber, R.; Twieg, R. J. Improved synthesis of DCDHF fluorophores with maleimide functional groups. Tetrahedron Lett. 2006, 47, 7213–7217.

    CAS  Article  Google Scholar 

  26. [26]

    Babin, J.; Pelletier, M.; Lepage, M.; Allard, J. F.; Morris, D.; Zhao, Y. A new two-photon-sensitive block copolymer nanocarrier. Angew. Chem., Int. Ed. 2009, 48, 3329–3332.

    CAS  Article  Google Scholar 

  27. [27]

    Zhao, L. Z.; Peng, J. J.; Huang, Q.; Li, C. Y.; Chen, M.; Sun, Y.; Lin, Q. N.; Zhu, L. Y.; Li, F. Y. Near-infrared photoregulated drug release in living tumor tissue via yolk-shell upconversion nanocages. Adv. Funct. Mater. 2014, 24, 363–371.

    CAS  Article  Google Scholar 

  28. [28]

    Lin, Q. N.; Bao, C. Y.; Yang, Y. L.; Liang, Q. N.; Zhang, D. S.; Cheng, S. Y.; Zhu, L. Y. Highly discriminating photorelease of anticancer drugs based on hypoxia activatable phototrigger conjugated chitosan nanoparticles. Adv. Mater. 2013, 25, 1981–1986.

    CAS  Article  Google Scholar 

  29. [29]

    Liu, Q.; Wang, W. P.; Zhan, C. Y.; Yang, T. S.; Kohane, D. S. Enhanced precision of nanoparticle phototargeting in vivo at a safe irradiance. Nano Lett. 2016, 16, 4516–4520.

    CAS  Article  Google Scholar 

  30. [30]

    Wang, Y. F.; Liu, C. H.; Ji, T. J.; Mehta, M.; Wang, W. P.; Marino, E.; Chen, J.; Kohane, D. S. Intravenous treatment of choroidal neovascularization by photo-targeted nanoparticles. Nat. Commun. 2019, 10, 804.

    CAS  Article  Google Scholar 

  31. [31]

    Wang, W. P.; Liu, Q.; Zhan, C. Y.; Barhoumi, A.; Yang, T. S.; Wylie, R. G.; Armstrong, P. A.; Kohane, D. S. Efficient triplet-triplet annihilation-based upconversion for nanoparticle phototargeting. Nano Lett. 2015, 15, 6332–6338.

    CAS  Article  Google Scholar 

  32. [32]

    Lv, W.; Li, Y. F.; Li, F. Y.; Lan, X.; Zhang, Y. M.; Du, L. L.; Zhao, Q.; Phillips, D. L.; Wang, W. P. Upconversion-like photolysis of BODIPY-based prodrugs via a one-photon process. J. Am. Chem. Soc. 2019, 141, 17482–17486.

    CAS  Article  Google Scholar 

  33. [33]

    Bosanquet, A. G.; Clarke, H. E. Chlorambucil: Stability of solutions during preparation and storage. Cancer Chemother. Pharmacol 1986, 18, 176–179.

    CAS  Article  Google Scholar 

  34. [34]

    Ou, K. Y.; Xu, X. J.; Guan, S. Y.; Zhang, R. H.; Zhang, X. Y.; Kang, Y.; Wu, J. Nanodrug carrier based on poly(ursolic acid) with self-anticancer activity against colorectal cancer. Adv. Funct. Mater. 2019, 30, 1907857.

    Article  Google Scholar 

  35. [35]

    Cao, Z. Y.; Ma, Y. C.; Sun, C. Y.; Lu, Z. D.; Yao, Z. Y.; Wang, J. X.; Li, D. D.; Yuan, Y. Y.; Yang, X. Z. Ros-sensitive polymeric nanocarriers with red light-activated size shrinkage for remotely controlled drug release. Chem. Mater. 2018, 30, 517–525.

    Article  Google Scholar 

  36. [36]

    Sun, R.; Shen, S.; Zhang, Y. J.; Xu, C. F.; Cao, Z. T.; Wen, L. P.; Wang, J. Nanoparticle-facilitated autophagy inhibition promotes the efficacy of chemotherapeutics against breast cancer stem cells. Biomaterials 2016, 103, 44–55.

    CAS  Article  Google Scholar 

  37. [37]

    Lv, W.; Long, K. Q.; Yang, Y.; Chen, S. J.; Zhan, C. Y.; Wang, W. P. A red light-triggered drug release system based on one-photon upconversion-like photolysis. Adv. Healthc. Mater. 2020, 9, 2001118.

    CAS  Article  Google Scholar 

  38. [38]

    Sarfati, G.; Dvir, T.; Elkabets, M.; Apte, R. N.; Cohen, S. Targeting of polymeric nanoparticles to lung metastases by surface-attachment of YIGSR peptide from laminin. Biomaterials 2011, 32, 152–161.

    CAS  Article  Google Scholar 

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This work was supported by the Research Grants Council of Hong Kong (Early Career Scheme, No. 27115220), Ming Wai Lau Centre for Reparative Medicine Associate Member Program, and Young Scientists Fund of the National Natural Science Foundation of China (No. 81803469). We thank Dr. Jenny Lam at The University of Hong Kong for providing the A549 cell line. We acknowledge the assistance of The University of Hong Kong Li Ka Shing Faculty of Medicine Faculty Core Facility.

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Correspondence to Weiping Wang.

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Li, Y., Lv, W., Wang, L. et al. Photo-triggered nucleus targeting for cancer drug delivery. Nano Res. (2021).

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  • phototargeting
  • dePEGylation
  • nucleus targeting
  • coumarin
  • photoresponsive prodrugs