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Gold nanorod-photosensitizer conjugate with extracellular pH-driven tumor targeting ability for photothermal/photodynamic therapy

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Abstract

Chlorin e6-pHLIPss-AuNRs, a gold nanorod-photosensitizer conjugate containing a pH (low) insertion peptide (pHLIP) with a disulfide bond which imparts extracellular pH (pHe)-driven tumor targeting ability, has been successfully developed for bimodal photodynamic and photothermal therapy. In this bimodal therapy, chlorin e6 (Ce6), a second-generation photosensitizer (PS), is used for photodynamic therapy (PDT). Gold nanorods (AuNRs) are used as a hyperthermia agent for photothermal therapy (PTT) and also as a nanocarrier and quencher of Ce6. pHLIPss is designed as a pHe-driven targeting probe to enhance accumulation of Ce6 and AuNRs in cancer cells at low pH. In Ce6-pHLIPss-AuNRs, Ce6 is close to and quenched by AuNRs, causing little PDT effect. When exposed to normal physiological pH 7.4, Ce6-pHLIPss-AuNRs loosely associate with the cell membrane. However, once exposed to acidic pH 6.2, pHLIP actively inserts into the cell membrane, and the conjugates are translocated into cells. When this occurs, Ce6 separates from the AuNRs as a result of disulfide bond cleavage caused by intracellular glutathione (GSH), and singlet oxygen is produced for PDT upon light irradiation. In addition, as individual PTT agent, AuNRs can enhance the accumulation of PSs in the tumor by the enhanced permeation and retention (EPR) effect. Therefore, as indicated by our data, when exposed to acidic pH, Ce6-pHLIPss-AuNRs can achieve synergistic PTT/PDT bimodality for cancer treatment.

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References

  1. Lovell, J. F.; Liu, T.; Chen, J.; Zheng, G. Activatable photosensitizers for imaging and therapy. Chem. Rev. 2010, 110, 2839–2857.

    Article  Google Scholar 

  2. Celli, J. P.; Spring, B. Q.; Rizvi, I.; Evans, C. L.; Samkoe, K. S.; Verma, S.; Pogue, B. W.; Hasan, T. Imaging and photodynamic therapy: Mechanisms, monitoring and optimization. Chem. Rev. 2010, 110, 2795–2838.

    Article  Google Scholar 

  3. Dolmans, D. E. J. G. J.; Fukumura, D.; Jain, R. K. Photodynamic therapy for cancer. Nat. Rev. Cancer 2003, 3, 380–387.

    Article  Google Scholar 

  4. Agostinis, P.; Berg, K.; Cengel, K. A.; Foster, T. H.; Girotti, A. W.; Gollnick, S. O.; Hahn, S. M.; Hamblin, M. R.; Juzeniene, A.; Kessel, D. et al. Photodynamic therapy of cancer: An update. CA Cancer J. Clin. 2011, 61, 250–281.

    Article  Google Scholar 

  5. Dougherty, T. J.; Gomer, C. J.; Henderson, B. W.; Jori, G.; Kessel, D.; Korbelik, M.; Moan, J.; Peng, Q. Photodynamic therapy. J. Natl. Cancer Inst. 1998, 90, 889–905.

    Article  Google Scholar 

  6. Bugaj, A. M. Targeted photodynamic therapy-a promising strategy of tumor treatment. Photochem. Photobiol. Sci. 2011, 10, 1097–1109.

    Article  Google Scholar 

  7. Allison, R. R.; Downie, G. H.; Cuenca, R.; Hu, X. H.; Childs, C. J.; Sibata, C. H. Photosensitizers in clinical PDT. Photodiagn. Photodyn. Ther. 2004, 1, 27–42.

    Article  Google Scholar 

  8. Yang, H. Y.; Wang, F. Y.; Zhang, Z. Y. Photobleaching of chlorins in homogeneous and heterogeneous media. Dyes Pigm. 1999, 43, 109–117.

    Article  Google Scholar 

  9. Lovell, J. F.; Jin, C. S.; Huynh, E.; Jin, H.; Kim, C.; Rubinstein, J. L.; Chan, W. C. W.; Cao, W. G.; Wang, L. H. V.; Zheng, G. Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents. Nat. Mater. 2011, 10, 324–332.

    Article  Google Scholar 

  10. Lin, J.; Wang, S. J.; Huang, P.; Wang, Z.; Chen, S. H.; Niu, G.; Li, W. W.; He, J.; Cui, D. X.; Lu, G. M. et al. Photosensitizer-loaded gold vesicles with strong plasmonic coupling effect for imaging-guided photothermal/photodynamic therapy. ACS Nano 2013, 7, 5320–5329.

    Article  Google Scholar 

  11. Jang, B.; Park, J. Y.; Tung, C. H.; Kim, I. H.; Choi, Y. Gold nanorod-photosensitizer complex for near-infrared fluorescence imaging and photodynamic/photothermal therapy in vivo. ACS Nano 2011, 5, 1086–1094.

    Article  Google Scholar 

  12. Wang, J.; Zhu, G. Z.; You, M. X.; Song, E. Q.; Shukoor, M. I.; Zhang, K. J.; Altman, M. B.; Chen, Y.; Zhu, Z.; Huang, C. Z. et al. Assembly of aptamer switch probes and photosensitizer on gold nanorods for targeted photothermal and photodynamic cancer therapy. ACS Nano 2012, 6, 5070–5077.

    Article  Google Scholar 

  13. Wang, J.; You, M. X.; Zhu, G. Z.; Shukoor, M. I.; Chen, Z.; Zhao, Z. L.; Altman, M. B.; Yuan, Q.; Zhu, Z.; Chen, Y. et al. Photosensitizer-gold nanorod composite for targeted multimodal therapy. Small 2013, 9, 3678–3684.

    Article  Google Scholar 

  14. Gao, L.; Fei, J. B.; Zhao, J.; Li, H.; Cui, Y.; Li, J. B. Hypocrellin loaded gold nanocages with high two-photon efficiency for the photothermal/photodynamic cancer therapy in vitro. ACS Nano 2012, 6, 8030–8040.

    Article  Google Scholar 

  15. Kuo, W. S.; Chang, C. N.; Chang, Y. T.; Yang, M. H.; Chien, Y. H.; Chen, S. J.; Yeh, C. S. Gold nanorods in photodynamic therapy, as hyperthermia agents, and in near-infrared optical imaging. Angew. Chem. Int. Ed. 2010, 49, 2711–2715.

    Article  Google Scholar 

  16. Huang, X. H.; El-Sayed, I. H.; Qian, W.; El-Sayed, M. A. Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. J. Am. Chem. Soc. 2006, 128, 2115–2120.

    Article  Google Scholar 

  17. Young, J. K.; Figueroa, E. R.; Drezek, R. A. Tunable nanostructures as photothermal theranostic agents. Ann. Biomed. Eng. 2012, 40, 438–459.

    Article  Google Scholar 

  18. Zhang, M. F.; Murakami, T.; Ajima, K.; Tsuchida, K.; Sandanayaka, A. S. D.; Ito, O.; Iijima, S.; Yudasaka, M. Fabrication of ZnPc/protein nanohorns for double photodynamic and hyperthermic cancer phototherapy. Proc. Natl. Acad. Sci. USA 2008, 105, 14773–14778.

    Article  Google Scholar 

  19. Tian, B.; Wang, C.; Zhang, S.; Feng, L. Z.; Liu, Z. Photothermally ehanced photodynamic therapy delivered by nano-graphene oxide. ACS nano 2011, 5, 7000–7009.

    Article  Google Scholar 

  20. Maeda, H.; Bharate, G. Y.; Daruwalla, J. Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect. Eur. J. Pharm. Biopharm. 2009, 71, 409–419.

    Article  Google Scholar 

  21. Allen, T. M.; Cullis, P. R. Drug delivery systems: Entering the mainstream. Science 2004, 303, 1818–1822.

    Article  Google Scholar 

  22. Bae, Y. H.; Park, K. Targeted drug delivery to tumors: Myths, reality and possibility. J. Controlled Release 2011, 153, 198–205.

    Article  Google Scholar 

  23. Li, C. W.; Heidt, D. G.; Dalerba, P.; Burant, C. F.; Zhang, L. J.; Adsay, V.; Wicha, M.; Clarke, M. F.; Simeone, M. Identification of pancreatic cancer stem cells. Cancer Res. 2007, 67, 1030–1037.

    Article  Google Scholar 

  24. Fox, E. J.; Salk, J. J.; Loeb, L. A. Cancer genome sequencing-an interim analysis. Cancer Res. 2009, 69, 4948–4950.

    Article  Google Scholar 

  25. Krebs, H. A. The Pasteur effect and the relations between respiration and fermentation. Essays Biochem. 1972, 8, 1–34.

    Google Scholar 

  26. Swietach, P.; Hulikova, A.; Vaughan-Jones, R. D.; Harris, A. L. New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation. Oncogene 2010, 29, 6509–6521.

    Article  Google Scholar 

  27. Warburg, O.; Wind, F.; Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 1927, 8, 519–530.

    Article  Google Scholar 

  28. Gao, W. W.; Chan, J. M.; Farokhzad O. C. pH-responsive nanoparticles for drug delivery. Mol. Pharm. 2010, 7, 1913–1920.

    Article  Google Scholar 

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

    Article  Google Scholar 

  30. Andreev, O. A.; Karabadzhak, A. G.; Weerakkody, D.; Andreev, G. O.; Engelman, D. M.; Reshetnyak, Y. K. pH (low) insertion peptide (pHLIP) inserts across a lipid bilayer as a helix and exits by a different path. Proc. Natl. Acad. Sci. USA 2010, 107, 4081–4086.

    Article  Google Scholar 

  31. Reshetnyak, Y. K.; Andreev, O. A.; Segala, M.; Markin, V. S.; Engelman, D. M. Energetics of peptide (pHLIP) binding to and folding across a lipid bilayer membrane. Proc. Natl. Acad. Sci. USA 2008, 105, 15340–15345.

    Article  Google Scholar 

  32. Reshetnyak, Y. K.; Andreev, O. A.; Lehnert, U.; Engelman, D. M. Translocation of molecules into cells by pH-dependent insertion of a transmembrane helix. Proc. Natl. Acad. Sci. USA 2006, 103, 6460–6465.

    Article  Google Scholar 

  33. Weerakkody, D.; Moshnikova, A.; Thakur, M. S.; Moshnikova, V.; Daniels, J.; Engelman, D. M.; Andreev, O. A.; Reshetnyak, Y. K. Family of pH (low) insertion peptides for tumor targeting. Proc. Natl. Acad. Sci. USA 2013, 110, 5834–5839.

    Article  Google Scholar 

  34. Macholl, S.; Morrison, M. S.; Iveson, P.; Arbo, B. E.; Andreev, O. A.; Reshetnyak, Y. K.; Engelman, D. M; Johannesen, E. In vivo pH imaging with 99mTc-pHLIP. Mol. Imaging Biol. 2012, 14, 725–734.

    Article  Google Scholar 

  35. An, M.; Wijesinghe, D.; Andreev, O. A.; Reshetnyak, Y. K.; Engelman, D. M. pH-(low)-insertion-peptide (pHLIP) translocation of membrane impermeable phalloidin toxin inhibits cancer cell proliferation. Proc. Natl. Acad. Sci. USA 2010, 107, 20246–20250.

    Article  Google Scholar 

  36. Davies, A.; Lewis, D. J.; Watson, S. P.; Thomas, S. G.; Pikramenou, Z. pH-controlled delivery of luminescent europium coated nanoparticles into platelets. Proc. Natl. Acad. Sci. USA 2012, 109, 1862–1867.

    Article  Google Scholar 

  37. Yao, L.; Daniels, J.; Moshnikova, A.; Kuznetsov, S.; Ahmed, A.; Engelman, D. M.; Reshetnyak, Y. K; Andreev, O. A. pHLIP peptide targets nanogold particles to tumors. Proc. Natl. Acad. Sci. USA 2013, 110, 465–470.

    Article  Google Scholar 

  38. Zhao, Z. L.; Meng, H. M.; Wang, N. N.; Donovan, M. J.; Fu, T.; You, M. X.; Chen, Z.; Zhang, X. B.; Tan, W. H. A controlled-release nanocarrier with extracellular pH value driven tumor targeting and translocation for drug delivery. Angew. Chem. Int. Ed. 2013, 52, 7487–7491.

    Article  Google Scholar 

  39. Gratton S. E.; Ropp P. A.; Pohlhaus P. D.; Luft J. C.; Madden V. J.; Napier M. E.; DeSimone, J. M. The effect of particle design on cellular internalization pathways. Proc. Natl. Acad. Sci. USA 2008, 105, 11613–11618.

    Article  Google Scholar 

  40. Cho, E. C.; Xie, J. W.; Wurm, P. A.; Xia, Y. N. Understanding the role of surface charges in cellular adsorption versus internalization by selectively removing gold nanoparticles on the cell surface with a I2/KI etchant. Nano Lett. 2009, 9, 1080–1094.

    Article  Google Scholar 

  41. Oupicky, D.; Ogris, M.; Howard, K. A.; Dash, P. R.; Ulbrich, K.; Seymour, L. W. Importance of lateral and steric stabilization of polyelectrolyte gene delivery vectors for extended systemic circulation. Mol. Ther. 2002, 5, 463–472.

    Article  Google Scholar 

  42. Zhou, R.; Zhou, H. Y.; Xiong, B.; He, Y.; Yeung, E. S. Pericellular matrix enhances retention and cellular uptake of nanoparticles, J. Am. Chem. Soc. 2012, 134, 13404–13409.

    Article  Google Scholar 

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Authors and Affiliations

  1. Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, and Collaborative Research Center of Molecular Engineering for Theranostics, Hunan University, Changsha, 410082, China

    Nannan Wang, Zilong Zhao, Yifan Lv, Huanhuan Fan, Huarong Bai, Hongmin Meng, Yuqian Long, Ting Fu, Xiaobing Zhang & Weihong Tan

  2. Department of Chemistry and Department of Physiology and Functional Genomics, Center for Research at Bio/nano Interface, Shands Cancer Center, UF Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, Florida, 32611-7200, USA

    Weihong Tan

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  1. Nannan Wang
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Correspondence to Weihong Tan.

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Wang, N., Zhao, Z., Lv, Y. et al. Gold nanorod-photosensitizer conjugate with extracellular pH-driven tumor targeting ability for photothermal/photodynamic therapy. Nano Res. 7, 1291–1301 (2014). https://doi.org/10.1007/s12274-014-0493-0

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  • DOI: https://doi.org/10.1007/s12274-014-0493-0

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