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No UV Irradiation Needed! Chemiexcited AIE Dots for Cancer Theranostics
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No UV Irradiation Needed! Chemiexcited AIE Dots for Cancer Theranostics Xinggui Gu1,2 and Ben Zhong Tang1,3,* In this issue of Chem, Liu and coworkers have developed a novel theranostic system based on nanoparticles with aggregation-induced emission characteristics (AIE dots), which emit long-wavelength chemiluminescence (CL) and generate singlet oxygen upon chemiexcitation by H2O2, offering a new strategy for CL image-guided tumor therapy. Health has been an eternal pursuit of humanity. According to recent statistics, the proportion of tumor-related deaths accounts for the largest yearby-year rise in mortality; cancer has thus become a leading threat to world health.1 Clinical medicine has been exploring rapid, effective, precise modalities for the diagnosis and therapy of cancers. Image-guided therapy is emerging as one of the most promising strategies for precisely curing tumors because it offers the advantages of spatiotemporal imaging and effective therapy.2 However, the necessity of using high-energy rays, often UV light, as an excitation source in photoluminescence (PL) processes and the shallow penetration of UV light have negatively affected the therapeutic efficiency of PL image-guided therapy.3 To achieve a high therapeutic efficiency for imageguided photodynamic therapy (PDT) of deep tumors in vivo, the external light source must preferably excite the deeply localized luminogen and photosensitizer (PS). Although much effort has been made in the area, improving the penetration depth remains an uphill battle. Chemiluminescence (CL) is generated by the energy released from a chemical reaction between a strong oxidant (e.g., H2O2) and a high-energy com-
922
pound without excitation by an external light source.4 CL imaging is superior to its counterpart of traditional PL in terms of deeper penetration and a higher signal-to-noise ratio. CL offers the potential of creating self-illuminating PDT systems for improving therapeutic efficiency in deep tumors if the PS can be chemiexcited to generate singlet oxygen (1O2) inside the cells without irradiation by an external light source.5 Such a chemiexcited PDT system can completely get rid of the problem of light penetration. Conventional luminophores often suffer from aggregation-caused quenching (ACQ) and a decreased photosensitizing ability after being encapsulated into nanoparticles, which hampers their applications in developing efficient theranostic systems. Recently, luminogens with aggregation-induced emissions (AIEgens), particularly those with luminescence in the far-red/near-infrared (FR/ NIR) spectral region, have been developed into AIE nanoparticles (AIE dots) for image-guided PDT in nanomedicine.6,7 If AIE dots could be chemiexcited to generate bright CL and high 1O2 concentration, it would realize CL image-guided chemiexcited PDT in vivo. Bin Liu and coworkers at the National University of Singapore and Nankai
Chem 3, 917–927, December 14, 2017 ª 2017 Elsevier Inc.
University (China) explored this possibility. In this issue of Chem,8 the researchers report their successful development of a CL system based on AIE dots for image-guided chemiexcited PDT (Figure 1). They simply fabricated the AIE dots by co-encapsulating an AIEgen with FR/NIR emission (TBD) and bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate (CPPO) into amphipathic pluronic F-127 in the presence of soybean oil (Figure 1A). The addition of H2O2 led to the decomposition of CPPO by the peroxide to yield a highly energetic 1,2-dioxetanedione intermediate (Figure 1B). This intermediate excited the nearby PS molecules of TBD to emit FR/NIR light via a chemically initiated electron-exchange luminescence process. Meanwhile, the excited TBD underwent intersystem crossing from the excited singlet state to the excited triplet state and subsequently reacted with oxygen to generate 1O2 species. The FR/NIR emission and the reactive oxygen species were generated simultaneously by direct chemiexcitation without any external light source, in sharp contrast to the traditional PL-based PDT systems. In comparison with normal cells, cancer cells usually show an elevated H2O2 level. This creates a tumor microenvironment with a high peroxide concentration,9 which enables the AIE dots to be specifically activated by H2O2 to
1Department
of Chemistry, Hong Kong Branch of Chinese National Engineering Research Centre for Tissue Restoration and Reconstruction, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
2Beijing
Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China
3Center
for Aggregation-Induced Emission, South China University of Technology, Guangzhou 510640, China *Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2017.11.013
Figure 1. AIE Dots for CL Image-Guided Chemiexcited PDT (A) Fabrication of the AIE dots. (B) Working principle for the CL emission and chemiexcited 1 O 2 generation by the AIE dots in the presence of H 2 O 2 . (C) Cancer imaging by the AIE dots in the H 2 O 2 -rich tumor microenvironment. (D) In vivo imaging of abdominal metastatic breast tumors in mice after intravenous injections of the AIE dots by PL (left) and CL (right). The tumor regions are marked by yellow circles. (E) Therapeutic effects on the tumors by the AIE dots in the presence and absence of FEITC. Adapted from Mao et al. 8
generate CL and chemiexcited 1O2 for selective cancer imaging and therapy. Liu and coworkers established a tumor model to evaluate the capability of CL imaging by the AIE dots. After intravenous injection, the AIE dots preferentially accumulated in the tumor region as a result of the enhanced permeability and retention (EPR) and were activated by H2O2 in the microenvironment (Figure 1C). In vivo imaging from the AIE dots of the abdominal metastatic breast tumor indicates that the CL was specifically generated in the cancer region, whereas negligible PL signals were detected under external light
excitation (Figure 1D), clearly manifesting the advantage of CL imaging for diagnosing deep tumors. The CL half-life of the AIE dots plays a crucial role in the CL-guided chemiexcited PDT because the function of the AIE dots in vivo must be ensured before they accumulate in the tumor site. This is determined by the rate of CPPO consumption inside the AIE dots by H2O2. Once the limited amount of CPPO is consumed, the AIE dots will not be able to emit CL any more. The Singaporean and Chinese researchers applied soybean oil as a retarder to
slow down the reaction rate between CPPO and H2O2. This largely increased the half-life from 1 to 2.3 hr, longer than the time for the circulation after intravenous injection of the AIE dots. The tumor-targeting ability of AIE dots for specific CL imaging and chemiexcited PDT stems from the synergistic effects of the higher H2O2 concentration in tumors and the selectivity of the AIE dots toward the peroxide, which circumvents the drawbacks of instability, complications, and high costs of the current tumor-targeting strategies. The researchers utilized a
Chem 3, 917–927, December 14, 2017
923
chemical drug, b-phenylethyl isothiocyanate (FEITC), to enhance preferential H2O2 accumulation in tumor cells by depletion of GSH and inhibition of GPX enzyme activity. The CL emission of the AIE dots and the chemiexcited 1 O2 production were obviously enhanced. The AIE dot system of C-TBD/FEITC has thus realized high image contrast and great selectivity for tumors as an effective cancer therapy in the suppression of tumor growth (Figure 1E). Recent years have witnessed a rapid growth of AIE for biomedicine applications.10 Because of the intrinsic rotor structures of AIEgens, they often absorb in the short-wavelength (e.g., UV) region, which is not ideal for in vivo imaging and therapy. To solve this problem, much work has been devoted to the realization of long-wavelength excitations and emissions in their PL processes, such as the extension of p electron conjugation of AIE skele-
tons, attachment of strong electron donors and acceptors into AIE cores, and development of two-photon excitable AIEgens. The large amount of input has not produced the desired output as a result of the great difficulty in simultaneously realizing deep penetrations of excitation and emission lights. The AIE-dot-based CL strategy reported by Liu and coworkers here opens up a new avenue for easily overcoming this key limitation of the PL process. It will motivate researchers to design more AIE dots with brighter CL emissions and higher chemiexcited 1O2 productions for light-source-free imageguided therapeutic systems in clinical practice. 1. Hanahan, D., and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646–674. 2. Galloway, R.L., Jr. (2001). The process and development of image-guided procedures. Annu. Rev. Biomed. Eng. 3, 83–108. 3. Zhou, Z., Song, J., Nie, L., and Chen, X. (2016). Reactive oxygen species generating systems
meeting challenges of photodynamic cancer therapy. Chem. Soc. Rev. 45, 6597–6626. 4. Hu, L., and Xu, G. (2010). Applications and trends in electrochemiluminescence. Chem. Soc. Rev. 39, 3275–3304. 5. Magalha˜es, C.M., Esteves da Silva, J.C., and Pinto da Silva, L. (2016). Chemiluminescence and bioluminescence as an excitation source in the photodynamic therapy of cancer: a critical review. ChemPhysChem 17, 2286–2294. 6. Qian, J., and Tang, B.Z. (2017). AIE luminogens for bioimaging and theranostics: from organelles to animals. Chem 3, 56–91. 7. Gu, X., Kwok, R.T.K., Lam, J.W.Y., and Tang, B.Z. (2017). AIEgens for biological process monitoring and disease theranostics. Biomaterials 146, 115–135. 8. Mao, D., Wu, W., Ji, S., Chen, C., Hu, F., Kong, D., Ding, D., and Liu, B. (2017). Chemiluminescence-guided cancer therapy using a chemiexcited photosensitizer. Chem 3, this issue, 991–1007. 9. Szatrowski, T.P., and Nathan, C.F. (1991). Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 51, 794–798. 10. Mei, J., Leung, N.L.C., Kwok, R.T.K., Lam, J.W.Y., and Tang, B.Z. (2015). AggregationInduced Emission: Together We Shine, United We Soar! Chem. Rev. 115, 11718–11940.
Preview
How Much Pressure Is Too Much Pressure for a MOF? George K.H. Shimizu1,* Recently in Joule, Zhou and coworkers have reported the pressure dependence of structure and gas sorption of a metal-organic framework (MOF), showing that there are potential pitfalls to MOF densification. Metal-organic frameworks (MOFs) are spanning the gap between academic and applied domains. This is enabled by three inter-related factors: the always-improving performances being demonstrated by MOFs for a range of industrial applications, the increasing chemical stabilities of MOFs, and the subsequent increased levels of engagement with engineering partners to
924
take promising materials to higher technology levels and ultimate implementation. The most often discussed applications of MOFs relate to gas separation or gas storage, and most attention is being paid to post-combustion carbon capture1 or methane storage.2 Two factors germane to the use of solids in sorbent and separation beds are densification3 and structuring.4 A promising
Chem 3, 917–927, December 14, 2017 ª 2017 Published by Elsevier Inc.
sorbent solid will undoubtedly have excellent excess (surface) gas sorption, but in the bulk material, there will be numerous other types of interparticle voids where the gas is possibly simply being stored via compression, reducing any beneficial sorptive effects of the solid surface.5 Densifying the solid reduces the presence of these lower-value voids and the volume of the separation bed. In parallel, a columnar tower cannot simply be filled with a powder to create a separation bed, regardless of the excellent capacity or selectivity of the solid sorbent. For any fluid phase separation, the solid in the bed will
1Department
of Chemistry, University of Calgary, Calgary, AB T2N 1N4, Canada *Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2017.12.001
No UV Irradiation Needed! Chemiexcited AIE Dots for Cancer Theranostics Xinggui Gu1,2 and Ben Zhong Tang1,3,* In this issue of Chem, Liu and coworkers have developed a novel theranostic system based on nanoparticles with aggregation-induced emission characteristics (AIE dots), which emit long-wavelength chemiluminescence (CL) and generate singlet oxygen upon chemiexcitation by H2O2, offering a new strategy for CL image-guided tumor therapy. Health has been an eternal pursuit of humanity. According to recent statistics, the proportion of tumor-related deaths accounts for the largest yearby-year rise in mortality; cancer has thus become a leading threat to world health.1 Clinical medicine has been exploring rapid, effective, precise modalities for the diagnosis and therapy of cancers. Image-guided therapy is emerging as one of the most promising strategies for precisely curing tumors because it offers the advantages of spatiotemporal imaging and effective therapy.2 However, the necessity of using high-energy rays, often UV light, as an excitation source in photoluminescence (PL) processes and the shallow penetration of UV light have negatively affected the therapeutic efficiency of PL image-guided therapy.3 To achieve a high therapeutic efficiency for imageguided photodynamic therapy (PDT) of deep tumors in vivo, the external light source must preferably excite the deeply localized luminogen and photosensitizer (PS). Although much effort has been made in the area, improving the penetration depth remains an uphill battle. Chemiluminescence (CL) is generated by the energy released from a chemical reaction between a strong oxidant (e.g., H2O2) and a high-energy com-
922
pound without excitation by an external light source.4 CL imaging is superior to its counterpart of traditional PL in terms of deeper penetration and a higher signal-to-noise ratio. CL offers the potential of creating self-illuminating PDT systems for improving therapeutic efficiency in deep tumors if the PS can be chemiexcited to generate singlet oxygen (1O2) inside the cells without irradiation by an external light source.5 Such a chemiexcited PDT system can completely get rid of the problem of light penetration. Conventional luminophores often suffer from aggregation-caused quenching (ACQ) and a decreased photosensitizing ability after being encapsulated into nanoparticles, which hampers their applications in developing efficient theranostic systems. Recently, luminogens with aggregation-induced emissions (AIEgens), particularly those with luminescence in the far-red/near-infrared (FR/ NIR) spectral region, have been developed into AIE nanoparticles (AIE dots) for image-guided PDT in nanomedicine.6,7 If AIE dots could be chemiexcited to generate bright CL and high 1O2 concentration, it would realize CL image-guided chemiexcited PDT in vivo. Bin Liu and coworkers at the National University of Singapore and Nankai
Chem 3, 917–927, December 14, 2017 ª 2017 Elsevier Inc.
University (China) explored this possibility. In this issue of Chem,8 the researchers report their successful development of a CL system based on AIE dots for image-guided chemiexcited PDT (Figure 1). They simply fabricated the AIE dots by co-encapsulating an AIEgen with FR/NIR emission (TBD) and bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate (CPPO) into amphipathic pluronic F-127 in the presence of soybean oil (Figure 1A). The addition of H2O2 led to the decomposition of CPPO by the peroxide to yield a highly energetic 1,2-dioxetanedione intermediate (Figure 1B). This intermediate excited the nearby PS molecules of TBD to emit FR/NIR light via a chemically initiated electron-exchange luminescence process. Meanwhile, the excited TBD underwent intersystem crossing from the excited singlet state to the excited triplet state and subsequently reacted with oxygen to generate 1O2 species. The FR/NIR emission and the reactive oxygen species were generated simultaneously by direct chemiexcitation without any external light source, in sharp contrast to the traditional PL-based PDT systems. In comparison with normal cells, cancer cells usually show an elevated H2O2 level. This creates a tumor microenvironment with a high peroxide concentration,9 which enables the AIE dots to be specifically activated by H2O2 to
1Department
of Chemistry, Hong Kong Branch of Chinese National Engineering Research Centre for Tissue Restoration and Reconstruction, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
2Beijing
Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China
3Center
for Aggregation-Induced Emission, South China University of Technology, Guangzhou 510640, China *Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2017.11.013
Figure 1. AIE Dots for CL Image-Guided Chemiexcited PDT (A) Fabrication of the AIE dots. (B) Working principle for the CL emission and chemiexcited 1 O 2 generation by the AIE dots in the presence of H 2 O 2 . (C) Cancer imaging by the AIE dots in the H 2 O 2 -rich tumor microenvironment. (D) In vivo imaging of abdominal metastatic breast tumors in mice after intravenous injections of the AIE dots by PL (left) and CL (right). The tumor regions are marked by yellow circles. (E) Therapeutic effects on the tumors by the AIE dots in the presence and absence of FEITC. Adapted from Mao et al. 8
generate CL and chemiexcited 1O2 for selective cancer imaging and therapy. Liu and coworkers established a tumor model to evaluate the capability of CL imaging by the AIE dots. After intravenous injection, the AIE dots preferentially accumulated in the tumor region as a result of the enhanced permeability and retention (EPR) and were activated by H2O2 in the microenvironment (Figure 1C). In vivo imaging from the AIE dots of the abdominal metastatic breast tumor indicates that the CL was specifically generated in the cancer region, whereas negligible PL signals were detected under external light
excitation (Figure 1D), clearly manifesting the advantage of CL imaging for diagnosing deep tumors. The CL half-life of the AIE dots plays a crucial role in the CL-guided chemiexcited PDT because the function of the AIE dots in vivo must be ensured before they accumulate in the tumor site. This is determined by the rate of CPPO consumption inside the AIE dots by H2O2. Once the limited amount of CPPO is consumed, the AIE dots will not be able to emit CL any more. The Singaporean and Chinese researchers applied soybean oil as a retarder to
slow down the reaction rate between CPPO and H2O2. This largely increased the half-life from 1 to 2.3 hr, longer than the time for the circulation after intravenous injection of the AIE dots. The tumor-targeting ability of AIE dots for specific CL imaging and chemiexcited PDT stems from the synergistic effects of the higher H2O2 concentration in tumors and the selectivity of the AIE dots toward the peroxide, which circumvents the drawbacks of instability, complications, and high costs of the current tumor-targeting strategies. The researchers utilized a
Chem 3, 917–927, December 14, 2017
923
chemical drug, b-phenylethyl isothiocyanate (FEITC), to enhance preferential H2O2 accumulation in tumor cells by depletion of GSH and inhibition of GPX enzyme activity. The CL emission of the AIE dots and the chemiexcited 1 O2 production were obviously enhanced. The AIE dot system of C-TBD/FEITC has thus realized high image contrast and great selectivity for tumors as an effective cancer therapy in the suppression of tumor growth (Figure 1E). Recent years have witnessed a rapid growth of AIE for biomedicine applications.10 Because of the intrinsic rotor structures of AIEgens, they often absorb in the short-wavelength (e.g., UV) region, which is not ideal for in vivo imaging and therapy. To solve this problem, much work has been devoted to the realization of long-wavelength excitations and emissions in their PL processes, such as the extension of p electron conjugation of AIE skele-
tons, attachment of strong electron donors and acceptors into AIE cores, and development of two-photon excitable AIEgens. The large amount of input has not produced the desired output as a result of the great difficulty in simultaneously realizing deep penetrations of excitation and emission lights. The AIE-dot-based CL strategy reported by Liu and coworkers here opens up a new avenue for easily overcoming this key limitation of the PL process. It will motivate researchers to design more AIE dots with brighter CL emissions and higher chemiexcited 1O2 productions for light-source-free imageguided therapeutic systems in clinical practice. 1. Hanahan, D., and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646–674. 2. Galloway, R.L., Jr. (2001). The process and development of image-guided procedures. Annu. Rev. Biomed. Eng. 3, 83–108. 3. Zhou, Z., Song, J., Nie, L., and Chen, X. (2016). Reactive oxygen species generating systems
meeting challenges of photodynamic cancer therapy. Chem. Soc. Rev. 45, 6597–6626. 4. Hu, L., and Xu, G. (2010). Applications and trends in electrochemiluminescence. Chem. Soc. Rev. 39, 3275–3304. 5. Magalha˜es, C.M., Esteves da Silva, J.C., and Pinto da Silva, L. (2016). Chemiluminescence and bioluminescence as an excitation source in the photodynamic therapy of cancer: a critical review. ChemPhysChem 17, 2286–2294. 6. Qian, J., and Tang, B.Z. (2017). AIE luminogens for bioimaging and theranostics: from organelles to animals. Chem 3, 56–91. 7. Gu, X., Kwok, R.T.K., Lam, J.W.Y., and Tang, B.Z. (2017). AIEgens for biological process monitoring and disease theranostics. Biomaterials 146, 115–135. 8. Mao, D., Wu, W., Ji, S., Chen, C., Hu, F., Kong, D., Ding, D., and Liu, B. (2017). Chemiluminescence-guided cancer therapy using a chemiexcited photosensitizer. Chem 3, this issue, 991–1007. 9. Szatrowski, T.P., and Nathan, C.F. (1991). Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 51, 794–798. 10. Mei, J., Leung, N.L.C., Kwok, R.T.K., Lam, J.W.Y., and Tang, B.Z. (2015). AggregationInduced Emission: Together We Shine, United We Soar! Chem. Rev. 115, 11718–11940.
Preview
How Much Pressure Is Too Much Pressure for a MOF? George K.H. Shimizu1,* Recently in Joule, Zhou and coworkers have reported the pressure dependence of structure and gas sorption of a metal-organic framework (MOF), showing that there are potential pitfalls to MOF densification. Metal-organic frameworks (MOFs) are spanning the gap between academic and applied domains. This is enabled by three inter-related factors: the always-improving performances being demonstrated by MOFs for a range of industrial applications, the increasing chemical stabilities of MOFs, and the subsequent increased levels of engagement with engineering partners to
924
take promising materials to higher technology levels and ultimate implementation. The most often discussed applications of MOFs relate to gas separation or gas storage, and most attention is being paid to post-combustion carbon capture1 or methane storage.2 Two factors germane to the use of solids in sorbent and separation beds are densification3 and structuring.4 A promising
Chem 3, 917–927, December 14, 2017 ª 2017 Published by Elsevier Inc.
sorbent solid will undoubtedly have excellent excess (surface) gas sorption, but in the bulk material, there will be numerous other types of interparticle voids where the gas is possibly simply being stored via compression, reducing any beneficial sorptive effects of the solid surface.5 Densifying the solid reduces the presence of these lower-value voids and the volume of the separation bed. In parallel, a columnar tower cannot simply be filled with a powder to create a separation bed, regardless of the excellent capacity or selectivity of the solid sorbent. For any fluid phase separation, the solid in the bed will
1Department
of Chemistry, University of Calgary, Calgary, AB T2N 1N4, Canada *Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2017.12.001