Visualizing Photodynamic Therapy in Transgenic Zebrafish Using Organic Nanoparticles with Aggregation-Induced Emission
Corresponding Author: Bin Liu
Nano-Micro Letters,
Vol. 10 No. 4 (2018), Article Number: 61
Abstract
Photodynamic therapy (PDT) employs accumulation of photosensitizers (PSs) in malignant tumor tissue followed by the light-induced generation of cytotoxic reactive oxygen species to kill the tumor cells. The success of PDT depends on optimal PS dosage that is matched with the ideal power of light. This in turn depends on PS accumulation in target tissue and light administration time and period. As theranostic nanomedicine is driven by multifunctional therapeutics that aim to achieve targeted tissue delivery and image-guided therapy, fluorescent PS nanoparticle (NP) accumulation in target tissues can be ascertained through fluorescence imaging to optimize the light dose and administration parameters. In this regard, zebrafish larvae provide a unique transparent in vivo platform to monitor fluorescent PS bio-distribution and their therapeutic efficiency. Using fluorescent PS NPs with unique aggregation-induced emission characteristics, we demonstrate for the first time the real-time visualization of polymeric NP accumulation in tumor tissue and, more importantly, the best time to conduct PDT using transgenic zebrafish larvae with inducible liver hyperplasia as an example.
Highlights:
1 The key novelty of this work is the creation of an in vivo model that can be used to effectively visualize image-guided photodynamic therapy. This allows fast screening of the performance of photosensitizers and their formulations.
2 Transparent zebrafish larvae provide a visual understanding of bio-distribution of nanoparticles, thereby enabling smarter formulation strategies.
Keywords
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- E. Cerman, O. Çekiç, Clinical use of photodynamic therapy in ocular tumors. Surv. Ophthalmol. 60(6), 557–574 (2015). https://doi.org/10.1016/j.survophthal.2015.05.004
- E. Rodriguez, P. Baas, J.S. Friedberg, Innovative therapies: photodynamic therapy. Thorac. Surg. Clin. 14(4), 557–566 (2004). https://doi.org/10.1016/j.thorsurg.2004.06.004
- N. Zhao, B. Wu, X. Hu, D. Xing, NIR-triggered high-efficient photodynamic and chemo-cascade therapy using caspase-3 responsive functionalized upconversion nanoparticles. Biomaterials 141, 40–49 (2017). https://doi.org/10.1016/j.biomaterials.2017.06.031
- H. Cabral, M. Nakanishi, M. Kumagai, W.-D. Jang, N. Nishiyama, K. Kataoka, A photo-activated targeting chemotherapy using glutathione sensitive camptothecin-loaded polymeric micelles. Pharm. Res. 26(1), 82–92 (2009). https://doi.org/10.1007/s11095-008-9712-2
- M. Diehn, R.W. Cho, N.A. Lobo, T. Kalisky, M.J. Dorie et al., Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458(7239), 780–783 (2009). https://doi.org/10.1038/nature07733
- V. Sosa, T. Moliné, R. Somoza, R. Paciucci, H. Kondoh, M.E. Lleonart, Oxidative stress and cancer: an overview. Ageing Res. Rev. 12(1), 376–390 (2013). https://doi.org/10.1016/j.arr.2012.10.004
- R. Laptev, M. Nisnevitch, G. Siboni, Z. Malik, M.A. Firer, Intracellular chemiluminescence activates targeted photodynamic destruction of leukaemic cells. Br. J. Cancer 95(2), 189–192 (2006). https://doi.org/10.1038/sj.bjc.6603241
- D. Mao, W. Wu, S. Ji, C. Chen, F. Hu, D. Kong, D. Ding, B. Liu, Chemiluminescence-guided cancer therapy using a chemiexcited photosensitizer. Chem 3(6), 991–1007 (2017). https://doi.org/10.1016/j.chempr.2017.10.002
- I. Yoon, J.Z. Li, Y.K. Shim, Advance in photosensitizers and light delivery for photodynamic therapy. Clin. Endosc. 46(1), 7–23 (2013). https://doi.org/10.5946/ce.2013.46.1.7
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- S.S. Dhillon, T.L. Demmy, S. Yendamuri, G. Loewen, C. Nwogu, M. Cooper, B.W. Henderson, A phase I study of light dose for photodynamic therapy (PDT) Using 2-[1-hexyloxyethyl]-2 devinyl pyropheophorbide-a (HPPH) for treatment of non-small cell carcinoma in situ or non-small cell microinvasive bronchogenic carcinoma: a dose ranging study. J. Thorac. Oncol. 11(2), 234–241 (2016). https://doi.org/10.1016/j.jtho.2015.10.020
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- M.D. Glidden, J.P. Celli, I. Massodi, I. Rizvi, B.W. Pogue, T. Hasan, Image-based quantification of benzoporphyrin derivative uptake, localization, and photobleaching in 3D tumor models, for optimization of pdt parameters. Theranostics 2(9), 827–839 (2012). https://doi.org/10.7150/thno.4334
- O.J. Klein, Y.K. Jung, C.L. Evans, Longitudinal, quantitative monitoring of therapeutic response in 3D in vitro tumor models with oct for high-content therapeutic screening. Methods 66(2), 299–311 (2014). https://doi.org/10.1016/j.ymeth.2013.08.028
- D. Braichotte, J.-F. Savary, T. Glanzmann, P. Monnier, G. Wagnières, H. Van Den Bergh, Optimizing light dosimetry in photodynamic therapy of the bronchi by fluorescence spectroscopy. Lasers Med. Sci. 11(4), 247–254 (1996). https://doi.org/10.1007/BF02134915
- I. Salas-García, F. Fanjul-Vélez, J.L. Arce-Diego, Superficial radially resolved fluorescence and 3D photochemical time-dependent model for photodynamic therapy. Opt. Lett. 39(7), 1845–1848 (2014). https://doi.org/10.1364/OL.39.001845
- N. Kosaka, M. Ogawa, P.L. Choyke, H. Kobayashi, Clinical implications of near-infrared fluorescence imaging in cancer. Future Oncol. 5(9), 1501–1511 (2009). https://doi.org/10.2217/fon.09.109
- R.R. Zhang, A.B. Schroeder, J.J. Grudzinski, E.L. Rosenthal, J.M. Warram, A.N. Pinchuk, K.W. Eliceiri, J.S. Kuo, J.P. Weichert, Beyond the margins: real-time detection of cancer using targeted fluorophores. Nat. Rev. Clin. Oncol. 14(6), 347–364 (2017). https://doi.org/10.1038/nrclinonc.2016.212
- J. Fang, H. Nakamura, H. Maeda, 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. 63(3), 136–151 (2011). https://doi.org/10.1016/j.addr.2010.04.009
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- D. Wang, H. Su, R.T.K. Kwok, X. Hu, H. Zou et al., Rational design of a water-soluble NIR AIEgen, and its application in ultrafast wash-free cellular imaging and photodynamic cancer cell ablation. Chem. Sci. 9(15), 3685–3693 (2018). https://doi.org/10.1039/C7SC04963C
- J. Condeelis, R. Weissleder, In vivo imaging in cancer. Cold Spring Harbor Perspect. Biol. 2(12), 3848–3860 (2010). https://doi.org/10.1101/cshperspect.a003848
- F. Campbell, F.L. Bos, S. Sieber, G. Arias-Alpizar, B.E. Koch, J. Huwyler, A. Kros, J. Bussmann, Directing nanoparticle biodistribution through evasion and exploitation of stab 2-dependent nanoparticle uptake. ACS Nano 12(3), 2138–2150 (2018). https://doi.org/10.1021/acsnano.7b06995
- S. Sieber, P. Grossen, P. Detampel, S. Siegfried, D. Witzigmann, J. Huwyler, Zebrafish as an early stage screening tool to study the systemic circulation of nanoparticulate drug delivery systems in vivo. J. Control. Release 264, 180–191 (2017). https://doi.org/10.1016/j.jconrel.2017.08.023
- P. Goldsmith, Zebrafish as a pharmacological tool: the how, why and when. Curr. Opin. Pharmacol. 4(5), 504–512 (2004). https://doi.org/10.1016/j.coph.2004.04.005
- A.T. Nguyen, A. Emelyanov, C.H.V. Koh, J.M. Spitsbergen, S. Parinov, Z. Gong, An inducible kras(V12) transgenic zebrafish model for liver tumorigenesis and chemical drug screening. Dis. Model. Mech. 5(1), 63–72 (2012). https://doi.org/10.1242/dmm.008367
- S. Xu, W. Wu, X. Cai, C.-J. Zhang, Y. Yuan, J. Liang, G. Feng, P. Manghnani, B. Liu, Highly efficient photosensitizers with aggregation-induced emission characteristics obtained through precise molecular design. Chem. Commun. 53(62), 8727–8730 (2017). https://doi.org/10.1039/C7CC04864E
- J. Xiang, X. Cai, X. Lou, G. Feng, X. Min et al., Biocompatible green and red fluorescent organic dots with remarkably large two-photon action cross sections for targeted cellular imaging and real-time intravital blood vascular visualization. ACS Appl. Mater. Interfaces 7(27), 14965–14974 (2015). https://doi.org/10.1021/acsami.5b03766
- S.R. Popielarski, S. Hu-Lieskovan, S.W. French, T.J. Triche, M.E. Davis, A nanoparticle-based model delivery system to guide the rational design of gene delivery to the liver. 2. In vitro and in vivo uptake results. Bioconjugate Chem. 16(5), 1071–1080 (2005). https://doi.org/10.1021/bc0501146
- Y.-N. Zhang, W. Poon, A.J. Tavares, I.D. McGilvray, W.C.W. Chan, Nanoparticle–liver interactions: cellular uptake and hepatobiliary elimination. J. Control. Release 240, 332–348 (2016). https://doi.org/10.1016/j.jconrel.2016.01.020
- J.M. Burns, W.J. Cooper, J.L. Ferry, D.W. King, B.P. DiMento et al., Methods for reactive oxygen species (ROS) detection in aqueous environments. Aquat. Sci. 74(4), 683–734 (2012). https://doi.org/10.1007/s00027-012-0251-x
- J. Ge, M. Lan, B. Zhou, W. Liu, L. Guo et al., A graphene quantum dot photodynamic therapy agent with high singlet oxygen generation. Nat. Commun. 5, 4596 (2014). https://doi.org/10.1038/ncomms5596
- N.D. Lawson, B.M. Weinstein, In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev. Biol. 248(2), 307–318 (2002). https://doi.org/10.1006/dbio.2002.0711
- K.M. Tsoi, S.A. MacParland, X.-Z. Ma, V.N. Spetzler, J. Echeverri et al., Mechanism of hard nanomaterial clearance by the liver. Nat. Mater. 15(11), 1212–1221 (2016). https://doi.org/10.1038/nmat4718
- M.I. Sezan, A.M. Tekalp, R. Schaetzing, Automatic, anatomically selective, artifact-free enhancement of digital chest radiographs, in Proceedings of the SPIE 0914, Medical Imaging II, 27 June 1988. https://doi.org/10.1117/12.968653
- S.Y. Surkova, E.M. Myasnikova, K.N. Kozlov, A.A. Samsonova, J. Reinitz, M.G. Samsonova, Methods for acquisition of quantitative data from confocal images of gene expression in situ. Cell Tissue Biol. 2(2), 200–215 (2008). https://doi.org/10.1134/S1990519X08020156
References
E. Cerman, O. Çekiç, Clinical use of photodynamic therapy in ocular tumors. Surv. Ophthalmol. 60(6), 557–574 (2015). https://doi.org/10.1016/j.survophthal.2015.05.004
E. Rodriguez, P. Baas, J.S. Friedberg, Innovative therapies: photodynamic therapy. Thorac. Surg. Clin. 14(4), 557–566 (2004). https://doi.org/10.1016/j.thorsurg.2004.06.004
N. Zhao, B. Wu, X. Hu, D. Xing, NIR-triggered high-efficient photodynamic and chemo-cascade therapy using caspase-3 responsive functionalized upconversion nanoparticles. Biomaterials 141, 40–49 (2017). https://doi.org/10.1016/j.biomaterials.2017.06.031
H. Cabral, M. Nakanishi, M. Kumagai, W.-D. Jang, N. Nishiyama, K. Kataoka, A photo-activated targeting chemotherapy using glutathione sensitive camptothecin-loaded polymeric micelles. Pharm. Res. 26(1), 82–92 (2009). https://doi.org/10.1007/s11095-008-9712-2
M. Diehn, R.W. Cho, N.A. Lobo, T. Kalisky, M.J. Dorie et al., Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458(7239), 780–783 (2009). https://doi.org/10.1038/nature07733
V. Sosa, T. Moliné, R. Somoza, R. Paciucci, H. Kondoh, M.E. Lleonart, Oxidative stress and cancer: an overview. Ageing Res. Rev. 12(1), 376–390 (2013). https://doi.org/10.1016/j.arr.2012.10.004
R. Laptev, M. Nisnevitch, G. Siboni, Z. Malik, M.A. Firer, Intracellular chemiluminescence activates targeted photodynamic destruction of leukaemic cells. Br. J. Cancer 95(2), 189–192 (2006). https://doi.org/10.1038/sj.bjc.6603241
D. Mao, W. Wu, S. Ji, C. Chen, F. Hu, D. Kong, D. Ding, B. Liu, Chemiluminescence-guided cancer therapy using a chemiexcited photosensitizer. Chem 3(6), 991–1007 (2017). https://doi.org/10.1016/j.chempr.2017.10.002
I. Yoon, J.Z. Li, Y.K. Shim, Advance in photosensitizers and light delivery for photodynamic therapy. Clin. Endosc. 46(1), 7–23 (2013). https://doi.org/10.5946/ce.2013.46.1.7
T.C. Zhu, J.C. Finlay, The role of photodynamic therapy (PDT) physics. Med. Phys. 35(7), 3127–3136 (2008). https://doi.org/10.1118/1.2937440
S.S. Dhillon, T.L. Demmy, S. Yendamuri, G. Loewen, C. Nwogu, M. Cooper, B.W. Henderson, A phase I study of light dose for photodynamic therapy (PDT) Using 2-[1-hexyloxyethyl]-2 devinyl pyropheophorbide-a (HPPH) for treatment of non-small cell carcinoma in situ or non-small cell microinvasive bronchogenic carcinoma: a dose ranging study. J. Thorac. Oncol. 11(2), 234–241 (2016). https://doi.org/10.1016/j.jtho.2015.10.020
M.T. Jarvi, M.S. Patterson, B.C. Wilson, Insights into photodynamic therapy dosimetry: simultaneous singlet oxygen luminescence and photosensitizer photobleaching measurements. Biophys. J. 102(3), 661–671 (2012). https://doi.org/10.1016/j.bpj.2011.12.043
M.D. Glidden, J.P. Celli, I. Massodi, I. Rizvi, B.W. Pogue, T. Hasan, Image-based quantification of benzoporphyrin derivative uptake, localization, and photobleaching in 3D tumor models, for optimization of pdt parameters. Theranostics 2(9), 827–839 (2012). https://doi.org/10.7150/thno.4334
O.J. Klein, Y.K. Jung, C.L. Evans, Longitudinal, quantitative monitoring of therapeutic response in 3D in vitro tumor models with oct for high-content therapeutic screening. Methods 66(2), 299–311 (2014). https://doi.org/10.1016/j.ymeth.2013.08.028
D. Braichotte, J.-F. Savary, T. Glanzmann, P. Monnier, G. Wagnières, H. Van Den Bergh, Optimizing light dosimetry in photodynamic therapy of the bronchi by fluorescence spectroscopy. Lasers Med. Sci. 11(4), 247–254 (1996). https://doi.org/10.1007/BF02134915
I. Salas-García, F. Fanjul-Vélez, J.L. Arce-Diego, Superficial radially resolved fluorescence and 3D photochemical time-dependent model for photodynamic therapy. Opt. Lett. 39(7), 1845–1848 (2014). https://doi.org/10.1364/OL.39.001845
N. Kosaka, M. Ogawa, P.L. Choyke, H. Kobayashi, Clinical implications of near-infrared fluorescence imaging in cancer. Future Oncol. 5(9), 1501–1511 (2009). https://doi.org/10.2217/fon.09.109
R.R. Zhang, A.B. Schroeder, J.J. Grudzinski, E.L. Rosenthal, J.M. Warram, A.N. Pinchuk, K.W. Eliceiri, J.S. Kuo, J.P. Weichert, Beyond the margins: real-time detection of cancer using targeted fluorophores. Nat. Rev. Clin. Oncol. 14(6), 347–364 (2017). https://doi.org/10.1038/nrclinonc.2016.212
J. Fang, H. Nakamura, H. Maeda, 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. 63(3), 136–151 (2011). https://doi.org/10.1016/j.addr.2010.04.009
S. Zhen, S. Wang, S. Li, W. Luo, M. Gao et al., Efficient red/near-infrared fluorophores based on benzo[1,2-b:4,5-b′]dithiophene 1,1,5,5-tetraoxide for targeted photodynamic therapy and in vivo two-photon fluorescence bioimaging. Adv. Funct. Mater. 28(13), 1706945 (2018). https://doi.org/10.1002/adfm.201706945
D. Wang, H. Su, R.T.K. Kwok, X. Hu, H. Zou et al., Rational design of a water-soluble NIR AIEgen, and its application in ultrafast wash-free cellular imaging and photodynamic cancer cell ablation. Chem. Sci. 9(15), 3685–3693 (2018). https://doi.org/10.1039/C7SC04963C
J. Condeelis, R. Weissleder, In vivo imaging in cancer. Cold Spring Harbor Perspect. Biol. 2(12), 3848–3860 (2010). https://doi.org/10.1101/cshperspect.a003848
F. Campbell, F.L. Bos, S. Sieber, G. Arias-Alpizar, B.E. Koch, J. Huwyler, A. Kros, J. Bussmann, Directing nanoparticle biodistribution through evasion and exploitation of stab 2-dependent nanoparticle uptake. ACS Nano 12(3), 2138–2150 (2018). https://doi.org/10.1021/acsnano.7b06995
S. Sieber, P. Grossen, P. Detampel, S. Siegfried, D. Witzigmann, J. Huwyler, Zebrafish as an early stage screening tool to study the systemic circulation of nanoparticulate drug delivery systems in vivo. J. Control. Release 264, 180–191 (2017). https://doi.org/10.1016/j.jconrel.2017.08.023
P. Goldsmith, Zebrafish as a pharmacological tool: the how, why and when. Curr. Opin. Pharmacol. 4(5), 504–512 (2004). https://doi.org/10.1016/j.coph.2004.04.005
A.T. Nguyen, A. Emelyanov, C.H.V. Koh, J.M. Spitsbergen, S. Parinov, Z. Gong, An inducible kras(V12) transgenic zebrafish model for liver tumorigenesis and chemical drug screening. Dis. Model. Mech. 5(1), 63–72 (2012). https://doi.org/10.1242/dmm.008367
S. Xu, W. Wu, X. Cai, C.-J. Zhang, Y. Yuan, J. Liang, G. Feng, P. Manghnani, B. Liu, Highly efficient photosensitizers with aggregation-induced emission characteristics obtained through precise molecular design. Chem. Commun. 53(62), 8727–8730 (2017). https://doi.org/10.1039/C7CC04864E
J. Xiang, X. Cai, X. Lou, G. Feng, X. Min et al., Biocompatible green and red fluorescent organic dots with remarkably large two-photon action cross sections for targeted cellular imaging and real-time intravital blood vascular visualization. ACS Appl. Mater. Interfaces 7(27), 14965–14974 (2015). https://doi.org/10.1021/acsami.5b03766
S.R. Popielarski, S. Hu-Lieskovan, S.W. French, T.J. Triche, M.E. Davis, A nanoparticle-based model delivery system to guide the rational design of gene delivery to the liver. 2. In vitro and in vivo uptake results. Bioconjugate Chem. 16(5), 1071–1080 (2005). https://doi.org/10.1021/bc0501146
Y.-N. Zhang, W. Poon, A.J. Tavares, I.D. McGilvray, W.C.W. Chan, Nanoparticle–liver interactions: cellular uptake and hepatobiliary elimination. J. Control. Release 240, 332–348 (2016). https://doi.org/10.1016/j.jconrel.2016.01.020
J.M. Burns, W.J. Cooper, J.L. Ferry, D.W. King, B.P. DiMento et al., Methods for reactive oxygen species (ROS) detection in aqueous environments. Aquat. Sci. 74(4), 683–734 (2012). https://doi.org/10.1007/s00027-012-0251-x
J. Ge, M. Lan, B. Zhou, W. Liu, L. Guo et al., A graphene quantum dot photodynamic therapy agent with high singlet oxygen generation. Nat. Commun. 5, 4596 (2014). https://doi.org/10.1038/ncomms5596
N.D. Lawson, B.M. Weinstein, In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev. Biol. 248(2), 307–318 (2002). https://doi.org/10.1006/dbio.2002.0711
K.M. Tsoi, S.A. MacParland, X.-Z. Ma, V.N. Spetzler, J. Echeverri et al., Mechanism of hard nanomaterial clearance by the liver. Nat. Mater. 15(11), 1212–1221 (2016). https://doi.org/10.1038/nmat4718
M.I. Sezan, A.M. Tekalp, R. Schaetzing, Automatic, anatomically selective, artifact-free enhancement of digital chest radiographs, in Proceedings of the SPIE 0914, Medical Imaging II, 27 June 1988. https://doi.org/10.1117/12.968653
S.Y. Surkova, E.M. Myasnikova, K.N. Kozlov, A.A. Samsonova, J. Reinitz, M.G. Samsonova, Methods for acquisition of quantitative data from confocal images of gene expression in situ. Cell Tissue Biol. 2(2), 200–215 (2008). https://doi.org/10.1134/S1990519X08020156