Fucoidan-Based Theranostic Nanogel for Enhancing Imaging and Photodynamic Therapy of Cancer
Corresponding Author: Yongdoo Choi
Nano-Micro Letters,
Vol. 12 (2020), Article Number: 47
Abstract
In this study, a fucoidan-based theranostic nanogel (CFN-gel) consisting of a fucoidan backbone, redox-responsive cleavable linker and photosensitizer is developed to achieve activatable near-infrared fluorescence imaging of tumor sites and an enhanced photodynamic therapy (PDT) to induce the complete death of cancer cells. A CFN-gel has nanomolar affinity for P-selectin, which is overexpressed on the surface of tumor neovascular endothelial cells as well as many other cancer cells. Therefore, a CFN-gel can enhance tumor accumulation through P-selectin targeting and the enhanced permeation and retention effect. Moreover, a CFN-gel is non-fluorescent and non-phototoxic upon its systemic administration due to the aggregation-induced self-quenching in its fluorescence and singlet oxygen generation. After internalization into cancer cells and tumor neovascular endothelial cells, its photoactivity is recovered in response to the intracellular redox potential, thereby enabling selective near-infrared fluorescence imaging and an enhanced PDT of tumors. Since a CFN-gel also shows nanomolar affinity for the vascular endothelial growth factor, it also provides a significant anti-tumor effect in the absence of light treatment in vivo. Our study indicates that a fucoidan-based theranostic nanogel is a new theranostic material for imaging and treating cancer with high efficacy and specificity.
Highlights:
1 A fucoidan-based theranostic nanogel consisting of a fucoidan backbone, redox-responsive cleavable linker and photosensitizer enables activatable fluorescence imaging of tumor sites and an enhanced photodynamic therapy to induce complete death of cancer.
2 To use fucoidan as a polymeric backbone in the nanogel platform enables cancer targeting by P-selectin binding and enhances anti-tumor effect by inhibiting the binding of the vascular endothelial growth factor.
Keywords
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- D.E. Dolmans, D. Fukumura, R.K. Jain, Photodynamic therapy for cancer. Nat. Rev. Cancer 3, 380–387 (2003). https://doi.org/10.1038/nrc1071
- J.P. Celli, B.Q. Spring, I. Rizvi, C.L. Evans, K.S. Samkoe, S. Verma, B.W. Poque, T. Hasan, Imaging and photodynamic therapy: mechanisms, monitoring, and optimization. Chem. Rev. 110, 2795–2838 (2010). https://doi.org/10.1021/cr900300p
- A. Juzeniene, Chlorin e6-based photosensitizers for photodynamic therapy and photodiagnosis. Photodiagn. Photodyn. Ther. 6, 94–96 (2009). https://doi.org/10.1016/j.pdpdt.2009.06.001
- J.M. Fernandez, M.D. Bilgin, L.I. Grossweiner, Singlet oxygen generation by photodynamic agents. J. Photochem. Photobiol. B 33, 131–140 (1997). https://doi.org/10.1016/S1011-1344(96)07349-6
- R. Bonnett, Photosensitizers of the porphyrin and phthalocyanine series for photodynamic therapy. Chem. Soc. Rev. 24, 19–33 (1995). https://doi.org/10.1039/CS9952400019
- D.K. Chatterjee, L.S. Fong, Y. Zhang, Nanoparticles in photodynamic therapy: an emerging paradigm. Adv. Drug Deliv. Rev. 60, 1627–1637 (2008). https://doi.org/10.1016/j.addr.2008.08.003
- L. Cheng, A. Kamkaew, H. Sun, D. Jiang, H.F. Valdovinos et al., Dual-modality positron emission tomography/optical image-guided photodynamic cancer therapy with chlorin e6-containing nanomicelles. ACS Nano 10, 7721–7730 (2016). https://doi.org/10.1021/acsnano.6b03074
- K.Y. Choi, G. Saravanakumar, J.H. Park, K. Park, Hyaluronic acid-based nanocarriers for intracellular targeting: interfacial interactions with proteins in cancer. Colloids Surf. B 99, 82–94 (2012). https://doi.org/10.1016/j.colsurfb.2011.10.029
- K. Senthilkumar, P. Manivasagan, J. Venkatesan, S.K. Kim, Brown seaweed fucoidan: biological activity and apoptosis, growth signaling mechanism in cancer. Int. J. Biol. Macromol. 60, 366–374 (2013). https://doi.org/10.1016/j.ijbiomac.2013.06.030
- F. Atashrazm, R.M. Lowenthal, G.M. Woods, A.F. Holloway, J.L. Dickinson, Fucoidan and cancer: a multifunctional molecule with anti-tumor potential. Mar. Drugs 13, 2327–2346 (2015). https://doi.org/10.3390/md13042327
- C.S. Chiang, Y.J. Lin, R. Lee, Y.H. Lai, H.W. Cheng, C.H. Hsieh, W.C. Shyu, S.Y. Chen, Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhanced tumor-localized immunotherapy. Nat. Nanotechnol. 13, 746–754 (2018). https://doi.org/10.1038/s41565-018-0146-7
- Y. Shamay, M. Elkabets, H. Li, H. Shah, S. Brook et al., P-selectin is a nanotherapeutic delivery target in the tumor microenvironment. Sci. Transl. Med. 8, 345ra87 (2016). https://doi.org/10.1126/scitranslmed.aaf7374
- F. Rouzet, L. Bachelet-Violette, J.M. Alsac, M. Suzuki, A. Meulemans et al., Radiolabeled fucoidan as a P-selectin targeting agent for in vivo imaging of platelet-rich thrombus and endothelial activation. J. Nucl. Med. 52, 1433–1440 (2011). https://doi.org/10.2967/jnumed.110.085852
- X. Li, W. Bauer, I. Israel, M.C. Kreissl, J. Weirather et al., Targeting P-selectin by gallium-68–labeled fucoidan positron emission tomography for noninvasive characterization of vulnerable plaques: correlation with in vivo 17.6T MRI. Arterioscler. Thromb. Vasc. Biol. 34, 1661–1667 (2014). https://doi.org/10.1161/ATVBAHA.114.303485
- H. Maeda, H. Nakamura, J. Fang, The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv. Drug Deliv. Rev. 65, 71–79 (2013). https://doi.org/10.1016/j.addr.2012.10.002
- F. Liu, J. Wang, A.K. Chang, B. Liu, L. Yang, Q. Li, P. Wang, X. Zou, Fucoidan extract derived from Undaria pinnatifida inhibits angiogenesis by human umbilical vein endothelial cells. Phytomedicine 19, 797–803 (2012). https://doi.org/10.1016/j.phymed.2012.03.015
- S. Koyanagi, N. Tanigawa, H. Nakagawa, S. Soeda, H. Shimeno, Oversulfation of fucoidan enhances its anti-angiogenic and antitumor activities. Biochem. Pharmacol. 65, 173–179 (2003). https://doi.org/10.1016/s0006-2952(02)01478-8
- M.C. Chen, W.L. Hsu, P.A. Hwang, T.C. Chou, Low molecular weight fucoidan inhibits tumor angiogenesis through downregulation of HIF-1/VEGF signaling under hypoxia. Mar. Drugs 13, 4436–4451 (2015). https://doi.org/10.3390/md13074436
- M.R. Hamblin, J.L. Miller, I. Rizvi, B. Ortel, E.V. Maytin, T. Hasan, Pegylation of a chlorin(e6) polymer conjugate increases tumor targeting of photosensitizer. Cancer Res. 61, 7155–7162 (2001)
- Y. Choi, R. Weissleder, C.H. Tung, Protease-mediated phototoxicity of a polylysine–chlorin(E6) conjugate. ChemMedChem 1, 698–701 (2006). https://doi.org/10.1002/cmdc.200600053
- Y. Zhao, M.J. Tu, W.P. Wang, J.X. Qiu, A.X. Yu, A.M. Yu, Genetically engineered premicroRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest. Sci. Rep. 6, 26611 (2016). https://doi.org/10.1038/srep26611
- X. Yang, X. Shi, J. Ji, G. Zhai, Development of redox-responsive theranostic nanoparticles for near-infrared fluorescence imaging-guided photodynamic/chemotherapy of tumor. Drug Deliv. 25, 780 (2018). https://doi.org/10.1080/10717544.2018.1451571
References
D.E. Dolmans, D. Fukumura, R.K. Jain, Photodynamic therapy for cancer. Nat. Rev. Cancer 3, 380–387 (2003). https://doi.org/10.1038/nrc1071
J.P. Celli, B.Q. Spring, I. Rizvi, C.L. Evans, K.S. Samkoe, S. Verma, B.W. Poque, T. Hasan, Imaging and photodynamic therapy: mechanisms, monitoring, and optimization. Chem. Rev. 110, 2795–2838 (2010). https://doi.org/10.1021/cr900300p
A. Juzeniene, Chlorin e6-based photosensitizers for photodynamic therapy and photodiagnosis. Photodiagn. Photodyn. Ther. 6, 94–96 (2009). https://doi.org/10.1016/j.pdpdt.2009.06.001
J.M. Fernandez, M.D. Bilgin, L.I. Grossweiner, Singlet oxygen generation by photodynamic agents. J. Photochem. Photobiol. B 33, 131–140 (1997). https://doi.org/10.1016/S1011-1344(96)07349-6
R. Bonnett, Photosensitizers of the porphyrin and phthalocyanine series for photodynamic therapy. Chem. Soc. Rev. 24, 19–33 (1995). https://doi.org/10.1039/CS9952400019
D.K. Chatterjee, L.S. Fong, Y. Zhang, Nanoparticles in photodynamic therapy: an emerging paradigm. Adv. Drug Deliv. Rev. 60, 1627–1637 (2008). https://doi.org/10.1016/j.addr.2008.08.003
L. Cheng, A. Kamkaew, H. Sun, D. Jiang, H.F. Valdovinos et al., Dual-modality positron emission tomography/optical image-guided photodynamic cancer therapy with chlorin e6-containing nanomicelles. ACS Nano 10, 7721–7730 (2016). https://doi.org/10.1021/acsnano.6b03074
K.Y. Choi, G. Saravanakumar, J.H. Park, K. Park, Hyaluronic acid-based nanocarriers for intracellular targeting: interfacial interactions with proteins in cancer. Colloids Surf. B 99, 82–94 (2012). https://doi.org/10.1016/j.colsurfb.2011.10.029
K. Senthilkumar, P. Manivasagan, J. Venkatesan, S.K. Kim, Brown seaweed fucoidan: biological activity and apoptosis, growth signaling mechanism in cancer. Int. J. Biol. Macromol. 60, 366–374 (2013). https://doi.org/10.1016/j.ijbiomac.2013.06.030
F. Atashrazm, R.M. Lowenthal, G.M. Woods, A.F. Holloway, J.L. Dickinson, Fucoidan and cancer: a multifunctional molecule with anti-tumor potential. Mar. Drugs 13, 2327–2346 (2015). https://doi.org/10.3390/md13042327
C.S. Chiang, Y.J. Lin, R. Lee, Y.H. Lai, H.W. Cheng, C.H. Hsieh, W.C. Shyu, S.Y. Chen, Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhanced tumor-localized immunotherapy. Nat. Nanotechnol. 13, 746–754 (2018). https://doi.org/10.1038/s41565-018-0146-7
Y. Shamay, M. Elkabets, H. Li, H. Shah, S. Brook et al., P-selectin is a nanotherapeutic delivery target in the tumor microenvironment. Sci. Transl. Med. 8, 345ra87 (2016). https://doi.org/10.1126/scitranslmed.aaf7374
F. Rouzet, L. Bachelet-Violette, J.M. Alsac, M. Suzuki, A. Meulemans et al., Radiolabeled fucoidan as a P-selectin targeting agent for in vivo imaging of platelet-rich thrombus and endothelial activation. J. Nucl. Med. 52, 1433–1440 (2011). https://doi.org/10.2967/jnumed.110.085852
X. Li, W. Bauer, I. Israel, M.C. Kreissl, J. Weirather et al., Targeting P-selectin by gallium-68–labeled fucoidan positron emission tomography for noninvasive characterization of vulnerable plaques: correlation with in vivo 17.6T MRI. Arterioscler. Thromb. Vasc. Biol. 34, 1661–1667 (2014). https://doi.org/10.1161/ATVBAHA.114.303485
H. Maeda, H. Nakamura, J. Fang, The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv. Drug Deliv. Rev. 65, 71–79 (2013). https://doi.org/10.1016/j.addr.2012.10.002
F. Liu, J. Wang, A.K. Chang, B. Liu, L. Yang, Q. Li, P. Wang, X. Zou, Fucoidan extract derived from Undaria pinnatifida inhibits angiogenesis by human umbilical vein endothelial cells. Phytomedicine 19, 797–803 (2012). https://doi.org/10.1016/j.phymed.2012.03.015
S. Koyanagi, N. Tanigawa, H. Nakagawa, S. Soeda, H. Shimeno, Oversulfation of fucoidan enhances its anti-angiogenic and antitumor activities. Biochem. Pharmacol. 65, 173–179 (2003). https://doi.org/10.1016/s0006-2952(02)01478-8
M.C. Chen, W.L. Hsu, P.A. Hwang, T.C. Chou, Low molecular weight fucoidan inhibits tumor angiogenesis through downregulation of HIF-1/VEGF signaling under hypoxia. Mar. Drugs 13, 4436–4451 (2015). https://doi.org/10.3390/md13074436
M.R. Hamblin, J.L. Miller, I. Rizvi, B. Ortel, E.V. Maytin, T. Hasan, Pegylation of a chlorin(e6) polymer conjugate increases tumor targeting of photosensitizer. Cancer Res. 61, 7155–7162 (2001)
Y. Choi, R. Weissleder, C.H. Tung, Protease-mediated phototoxicity of a polylysine–chlorin(E6) conjugate. ChemMedChem 1, 698–701 (2006). https://doi.org/10.1002/cmdc.200600053
Y. Zhao, M.J. Tu, W.P. Wang, J.X. Qiu, A.X. Yu, A.M. Yu, Genetically engineered premicroRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest. Sci. Rep. 6, 26611 (2016). https://doi.org/10.1038/srep26611
X. Yang, X. Shi, J. Ji, G. Zhai, Development of redox-responsive theranostic nanoparticles for near-infrared fluorescence imaging-guided photodynamic/chemotherapy of tumor. Drug Deliv. 25, 780 (2018). https://doi.org/10.1080/10717544.2018.1451571