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One-for-All Intelligent Material for Triple-Modality Imaging-Guided Cancer Surgery
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One-for-All Intelligent Material for Triple-Modality ImagingGuided Cancer Surgery Di Gu1 and Lefeng Zeng1,2,* In the October issue of Chem, Ben Zhong Tang and co-workers develop a new one-for-all organic agent for triple-modality imaging-guided cancer surgery, in which the fluorescence, photoacoustic (PA), and Raman properties could be precisely tuned and boosted by tuning the molecular structure and intramolecular motions. Complete tumor removal is one of the key treatment for malignant tumors and is sometimes the only potentially curative treatment option.1 Visualizing the full tumor from nearby healthy tissue during the operation, including regional spread and small tumor nodules is decisively important for the therapeutic outcome. Therefore, development of imaging techniques for precise cancer surgery is momentously desirable. Among the versatile optical imaging techniques, fluorescence imaging possesses many desirable properties including real-time, superior specificity and high sensitivity, but suffers from poor penetration capability and spatial resolution.2,3 Photoacoustic (PA) imaging, based on the photoacoustic effect, holds the advantage of deep tissue penetration but lacks high sensitivity.4 Raman spectroscopy has become an emerging tool for cell imaging during surgical procedures. The development of materials possessing a strong Raman signal in the Raman-silent region of cells (1,800–2,800 cm 1) permits precise intraoperative inspection of residual tumors.5 All three imaging techniques have their own strengths and weaknesses, and they have the characteris-
tics of complementary advantages. It is momentously desirable to develop a smart imaging agent with tunable photophysical properties, whose absorbed energy can be controlled for fluorescence, PA, or Raman imaging as needed. Multi-modality imaging agents that combine various components in one system is one of the common approaches. However, sophisticated composition, low reproducibility, and uncertain pharmacokinetics make it less accessible for clinical translation. Alternatively, one-for-all organic agents with intrinsic multifunctions is a more promising strategy.6 In the October issue of Chem, Ben Zhong Tang and co-workers smartly develop a new one-for-all intelligent material for triple-modality imaging-guided cancer surgery in which the fluorescence, photoacoustic (PA), and Raman properties could be precisely tuned and boosted by tuning the molecular structure and intramolecular motions7 (Figure 1A). The authors synthesized a donor-acceptor (D-A) type organic small molecule by using alkoxysubstituted triphenylamine (OTPA) and thiadiazoloquinoxaline (TQ) as the donor and acceptor, respectively. It is beneficial for intramolecular charge transfer (ICT) from OTPA to TQ, there-
2742 Chem 5, 2742–2750, November 14, 2019 ª 2019 Elsevier Inc.
fore leading to a much lower electronic band gap or longer absorption spectrum. A series of analogs with different substituted groups (i.e., phenyl, phenyl-alkyne, and phenyl-alkynephenyl) in TQ core were composed. Among them, compound OTPA-TQ3 with the large phenyl-alkyne-phenyl substitutes exhibit the highest fluorescence, PA, and Raman (in cell-silent region) signals (Figure 1B). The phenylalkyne-phenyl units serves three purposes: (1) the largest intramolecular rotation units has the most twisted molecular geometry and the strongest aggregation-induced emission (AIE) effect, which contributes to the highest near-infrared (NIR) fluorescent brightness; (2) larger molecular rotors leads to stronger intramolecular motions and thus generates stronger PA signal; and (3) it also gains OTPA-TQ3 intense Raman signal at 2215 cm 1 in the cellsilent region. Furthermore, the authors rendered the hydrophobic compounds with good in vivo biocompatibility by encapsulating OTPA-TQ3 into smallnanosized nanoparticles. An amphiphilic lipid-PEG2000 co-polymer was used as the encapsulation matrix (Figure 1C). Then the authors systematically verified the in vivo utilization of OTPATQ3-based nanoagent in imageguided cancer surgery in subcutaneous tumor-bearing mice. NIR fluorescence imaging and PA imaging were performed before surgery. The fluorescence signal and PA signals at the tumor site gradually amplifies and reaches the maximum at 24 h after injection. For in vivo fluorescence
1Department
of Urology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
2Department
of Cardiology, Shanghai Ninth People’s Hospital, Shanghai, China *Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2019.10.017
Figure 1. One-for-all Organic Agent Enables Triple-Modality Imaging-Guided Cancer Surgery (A) Schematic illustration of the one-for-all organic agent for image-guided surgery. (B) Chemical structures and optimized molecular geometries of OTPA-TQ3 in the ground state. (C) Schematic illustration of the nanoprecipitation process. (D) Representative fluorescence image and PA image of tumor-bearing mice at 24 h after injection of OTPA-TQ3 NPs. (E) Survival curves for the tumor-bearing mice after various treatments as indicated.
imaging, the tumor signal-to-background is 9.2, and the average PA signal in the tumor at 24 h is 7.0 times higher than the background (0 h) before nanoagent injection. Both pre-operative NIR fluorescence imaging and PA imaging show that the OTPA-TQ3 nanoparticles (NPs) can detect the tumors in vivo at 24 h after injection, providing the surgeon with comprehensive information about tumor. (Figure 1D) After the injection of OTPA-TQ3 NPs for 24 h, the surgeon
performed the first tumor resection surgery (S1) with their experience followed by NIR fluorescence and Raman imaging simultaneously. The residual small tumors and their boundaries were detected by Raman imaging with microscopic resolution in the suspicious areas with faint fluorescence. About 94% of the tested tiny areas with Raman signal are confirmed as tumors when consulting the H&E staining. Because Raman imaging is quicker than histological analysis, it exhibits good poten-
tial for intraoperative residual tumor inspection. Strikingly, the intraoperative fluorescence-Raman imaging with OTPA-TQ3 NPs can precisely identify tiny residual tumors after S1 with diameters of about 450 mm. After demonstrating the existence of residual tumors, the second surgery (S2) was performed to remove the residual tumors until there were no fluorescence and Raman signals. It was demonstrated that the mice in the S2 group survived much longer than the mice
Chem 5, 2742–2750, November 14, 2019 2743
without surgical treatment and only undergoing S1 (Figure 1E). The low toxicity of OTPA-TQ3 NPs was confirmed by cellular viability assays, hepatic and renal function analyses, and blood routine examination. Moreover, Tang et al. studied the influence of agent dose and found that a concentration of 650 mM could provide the most detailed information about tumors with little side effect. The authors developed a one-for-all molecular agent that can serve as powerful fluorescent probe, PA contrast agent, and Raman probe as needed, which give excellent performance in boosting the cancer surgery outcomes. Such function-transformable NP with controlled photophysical capabilities show unique merits over
other optical agents in terms of simply combining various components into one platform. A few challenges remain for the translation of this method. More in-depth pharmacokinetics and long-term toxicity tests, as well as nonxenograft tumor models for patients with metastases, should be explored to reinforce the authors’ conclusions. Overall, the study is a major step forward in the area of multi-modality organic imaging and is a noteworthy application of smart nanomaterials.
1. Wang, P., Fan, Y., Lu, L., Liu, L., Fan, L., Zhao, M., Xie, Y., Xu, C., and Zhang, F. (2018). NIR-II nanoprobes in-vivo assembly to improve image-guided surgery for metastatic ovarian cancer. Nat. Commun. 9, 2898. 2. Vahrmeijer, A.L., Hutteman, M., van der Vorst, J.R., van de Velde, C.J.H., and Frangioni, J.V. (2013). Image-guided cancer surgery using
near-infrared fluorescence. Nat. Rev. Clin. Oncol. 10, 507–518. 3. Feng, Z., Yu, X., Jiang, M., Zhu, L., Zhang, Y., Yang, W., Xi, W., Li, G., and Qian, J. (2019). Excretable IR-820 for in vivo NIR-II fluorescence cerebrovascular imaging and photothermal therapy of subcutaneous tumor. Theranostics 9, 5706–5719. 4. Steinberg, I., Huland, D.M., Vermesh, O., Frostig, H.E., Tummers, W.S., and Gambhir, S.S. (2019). Photoacoustic clinical imaging. Photoacoustics 14, 77–98. 5. Li, S., Chen, T., Wang, Y., Liu, L., Lv, F., Li, Z., Huang, Y., Schanze, K.S., and Wang, S. (2017). Conjugated polymer with intrinsic alkyne units for synergistically enhanced Raman imaging in living cells. Angew. Chem. Int. Ed. Engl. 56, 13455–13458. 6. Feng, G., and Liu, B. (2016). Multifunctional AIEgens for future theranostics. Small 12, 6528–6535. 7. Qi, J., Li, J., Liu, R., Li, Q., Zhang, H., Lam, J.W.Y., Kwok, R.T.K., Liu, D., Ding, D., and Tang, B.Z. (2019). Boosting fluorescencephotoacoustic-Raman properties in one fluorophore for precise cancer surgery. Chem 5, 2657–2677.
Preview
Dearomative [4 + 2] Cycloaddition of Pyridine via Energy-Transfer Catalysis Liang Chang,1 Yilin Chen,1 and Zhiwei Zuo1,* In this issue of Chem, Glorius and coworkers report the first photocatalytic dearomative cycloaddition of pyridine with alkene. High-value isoquinuclidines could be easily assembled from N-cinamoyl picolinamides under mild and operationally simple conditions. It seemed too good to be true that complex isoquinuclidines could be directly assembled from simple pyridines and alkenes via [4 + 2] cycloaddition. With the ever-increasing demand for the exploration of chemical space, the rapid construction of this type of complex molecule with a well-defined three-dimensional structure from feedstock chemicals has become an urgent need and a major driving force in the
synthetic community. The recent development of visible-light-induced energy-transfer catalysis, as depicted in Scheme 1, has enabled a major breakthrough in the dearomative cyclization of pyridine. As just reported in this issue of Chem by the Glorius group, a photocatalytic [4 + 2] cycloaddition that transfers N-cinnamoyl picolinamides into high-value isoquinuclidines under mild and operation-
2744 Chem 5, 2742–2750, November 14, 2019 ª 2019 Elsevier Inc.
ally simple conditions has been achieved, elegantly demonstrating the synthetic potential of visible-light photocatalysis in the construction of complex structures.1 Nitrogen-containing heterocycles have long been recognized as one of the most privileged structural manifolds in chemical synthesis because of their ubiquitous presence in natural products, approved pharmaceuticals, and preclinical chemical entities.2 Among the available synthetic strategies, catalytic dearomatization of aromatic heterocycles, such as indole and pyridine, has emerged as a rather effective and popular approach.3 Because of their availability in commercial sources and the modularity of the hexagonal
1School
of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China *Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2019.10.020
One-for-All Intelligent Material for Triple-Modality ImagingGuided Cancer Surgery Di Gu1 and Lefeng Zeng1,2,* In the October issue of Chem, Ben Zhong Tang and co-workers develop a new one-for-all organic agent for triple-modality imaging-guided cancer surgery, in which the fluorescence, photoacoustic (PA), and Raman properties could be precisely tuned and boosted by tuning the molecular structure and intramolecular motions. Complete tumor removal is one of the key treatment for malignant tumors and is sometimes the only potentially curative treatment option.1 Visualizing the full tumor from nearby healthy tissue during the operation, including regional spread and small tumor nodules is decisively important for the therapeutic outcome. Therefore, development of imaging techniques for precise cancer surgery is momentously desirable. Among the versatile optical imaging techniques, fluorescence imaging possesses many desirable properties including real-time, superior specificity and high sensitivity, but suffers from poor penetration capability and spatial resolution.2,3 Photoacoustic (PA) imaging, based on the photoacoustic effect, holds the advantage of deep tissue penetration but lacks high sensitivity.4 Raman spectroscopy has become an emerging tool for cell imaging during surgical procedures. The development of materials possessing a strong Raman signal in the Raman-silent region of cells (1,800–2,800 cm 1) permits precise intraoperative inspection of residual tumors.5 All three imaging techniques have their own strengths and weaknesses, and they have the characteris-
tics of complementary advantages. It is momentously desirable to develop a smart imaging agent with tunable photophysical properties, whose absorbed energy can be controlled for fluorescence, PA, or Raman imaging as needed. Multi-modality imaging agents that combine various components in one system is one of the common approaches. However, sophisticated composition, low reproducibility, and uncertain pharmacokinetics make it less accessible for clinical translation. Alternatively, one-for-all organic agents with intrinsic multifunctions is a more promising strategy.6 In the October issue of Chem, Ben Zhong Tang and co-workers smartly develop a new one-for-all intelligent material for triple-modality imaging-guided cancer surgery in which the fluorescence, photoacoustic (PA), and Raman properties could be precisely tuned and boosted by tuning the molecular structure and intramolecular motions7 (Figure 1A). The authors synthesized a donor-acceptor (D-A) type organic small molecule by using alkoxysubstituted triphenylamine (OTPA) and thiadiazoloquinoxaline (TQ) as the donor and acceptor, respectively. It is beneficial for intramolecular charge transfer (ICT) from OTPA to TQ, there-
2742 Chem 5, 2742–2750, November 14, 2019 ª 2019 Elsevier Inc.
fore leading to a much lower electronic band gap or longer absorption spectrum. A series of analogs with different substituted groups (i.e., phenyl, phenyl-alkyne, and phenyl-alkynephenyl) in TQ core were composed. Among them, compound OTPA-TQ3 with the large phenyl-alkyne-phenyl substitutes exhibit the highest fluorescence, PA, and Raman (in cell-silent region) signals (Figure 1B). The phenylalkyne-phenyl units serves three purposes: (1) the largest intramolecular rotation units has the most twisted molecular geometry and the strongest aggregation-induced emission (AIE) effect, which contributes to the highest near-infrared (NIR) fluorescent brightness; (2) larger molecular rotors leads to stronger intramolecular motions and thus generates stronger PA signal; and (3) it also gains OTPA-TQ3 intense Raman signal at 2215 cm 1 in the cellsilent region. Furthermore, the authors rendered the hydrophobic compounds with good in vivo biocompatibility by encapsulating OTPA-TQ3 into smallnanosized nanoparticles. An amphiphilic lipid-PEG2000 co-polymer was used as the encapsulation matrix (Figure 1C). Then the authors systematically verified the in vivo utilization of OTPATQ3-based nanoagent in imageguided cancer surgery in subcutaneous tumor-bearing mice. NIR fluorescence imaging and PA imaging were performed before surgery. The fluorescence signal and PA signals at the tumor site gradually amplifies and reaches the maximum at 24 h after injection. For in vivo fluorescence
1Department
of Urology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
2Department
of Cardiology, Shanghai Ninth People’s Hospital, Shanghai, China *Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2019.10.017
Figure 1. One-for-all Organic Agent Enables Triple-Modality Imaging-Guided Cancer Surgery (A) Schematic illustration of the one-for-all organic agent for image-guided surgery. (B) Chemical structures and optimized molecular geometries of OTPA-TQ3 in the ground state. (C) Schematic illustration of the nanoprecipitation process. (D) Representative fluorescence image and PA image of tumor-bearing mice at 24 h after injection of OTPA-TQ3 NPs. (E) Survival curves for the tumor-bearing mice after various treatments as indicated.
imaging, the tumor signal-to-background is 9.2, and the average PA signal in the tumor at 24 h is 7.0 times higher than the background (0 h) before nanoagent injection. Both pre-operative NIR fluorescence imaging and PA imaging show that the OTPA-TQ3 nanoparticles (NPs) can detect the tumors in vivo at 24 h after injection, providing the surgeon with comprehensive information about tumor. (Figure 1D) After the injection of OTPA-TQ3 NPs for 24 h, the surgeon
performed the first tumor resection surgery (S1) with their experience followed by NIR fluorescence and Raman imaging simultaneously. The residual small tumors and their boundaries were detected by Raman imaging with microscopic resolution in the suspicious areas with faint fluorescence. About 94% of the tested tiny areas with Raman signal are confirmed as tumors when consulting the H&E staining. Because Raman imaging is quicker than histological analysis, it exhibits good poten-
tial for intraoperative residual tumor inspection. Strikingly, the intraoperative fluorescence-Raman imaging with OTPA-TQ3 NPs can precisely identify tiny residual tumors after S1 with diameters of about 450 mm. After demonstrating the existence of residual tumors, the second surgery (S2) was performed to remove the residual tumors until there were no fluorescence and Raman signals. It was demonstrated that the mice in the S2 group survived much longer than the mice
Chem 5, 2742–2750, November 14, 2019 2743
without surgical treatment and only undergoing S1 (Figure 1E). The low toxicity of OTPA-TQ3 NPs was confirmed by cellular viability assays, hepatic and renal function analyses, and blood routine examination. Moreover, Tang et al. studied the influence of agent dose and found that a concentration of 650 mM could provide the most detailed information about tumors with little side effect. The authors developed a one-for-all molecular agent that can serve as powerful fluorescent probe, PA contrast agent, and Raman probe as needed, which give excellent performance in boosting the cancer surgery outcomes. Such function-transformable NP with controlled photophysical capabilities show unique merits over
other optical agents in terms of simply combining various components into one platform. A few challenges remain for the translation of this method. More in-depth pharmacokinetics and long-term toxicity tests, as well as nonxenograft tumor models for patients with metastases, should be explored to reinforce the authors’ conclusions. Overall, the study is a major step forward in the area of multi-modality organic imaging and is a noteworthy application of smart nanomaterials.
1. Wang, P., Fan, Y., Lu, L., Liu, L., Fan, L., Zhao, M., Xie, Y., Xu, C., and Zhang, F. (2018). NIR-II nanoprobes in-vivo assembly to improve image-guided surgery for metastatic ovarian cancer. Nat. Commun. 9, 2898. 2. Vahrmeijer, A.L., Hutteman, M., van der Vorst, J.R., van de Velde, C.J.H., and Frangioni, J.V. (2013). Image-guided cancer surgery using
near-infrared fluorescence. Nat. Rev. Clin. Oncol. 10, 507–518. 3. Feng, Z., Yu, X., Jiang, M., Zhu, L., Zhang, Y., Yang, W., Xi, W., Li, G., and Qian, J. (2019). Excretable IR-820 for in vivo NIR-II fluorescence cerebrovascular imaging and photothermal therapy of subcutaneous tumor. Theranostics 9, 5706–5719. 4. Steinberg, I., Huland, D.M., Vermesh, O., Frostig, H.E., Tummers, W.S., and Gambhir, S.S. (2019). Photoacoustic clinical imaging. Photoacoustics 14, 77–98. 5. Li, S., Chen, T., Wang, Y., Liu, L., Lv, F., Li, Z., Huang, Y., Schanze, K.S., and Wang, S. (2017). Conjugated polymer with intrinsic alkyne units for synergistically enhanced Raman imaging in living cells. Angew. Chem. Int. Ed. Engl. 56, 13455–13458. 6. Feng, G., and Liu, B. (2016). Multifunctional AIEgens for future theranostics. Small 12, 6528–6535. 7. Qi, J., Li, J., Liu, R., Li, Q., Zhang, H., Lam, J.W.Y., Kwok, R.T.K., Liu, D., Ding, D., and Tang, B.Z. (2019). Boosting fluorescencephotoacoustic-Raman properties in one fluorophore for precise cancer surgery. Chem 5, 2657–2677.
Preview
Dearomative [4 + 2] Cycloaddition of Pyridine via Energy-Transfer Catalysis Liang Chang,1 Yilin Chen,1 and Zhiwei Zuo1,* In this issue of Chem, Glorius and coworkers report the first photocatalytic dearomative cycloaddition of pyridine with alkene. High-value isoquinuclidines could be easily assembled from N-cinamoyl picolinamides under mild and operationally simple conditions. It seemed too good to be true that complex isoquinuclidines could be directly assembled from simple pyridines and alkenes via [4 + 2] cycloaddition. With the ever-increasing demand for the exploration of chemical space, the rapid construction of this type of complex molecule with a well-defined three-dimensional structure from feedstock chemicals has become an urgent need and a major driving force in the
synthetic community. The recent development of visible-light-induced energy-transfer catalysis, as depicted in Scheme 1, has enabled a major breakthrough in the dearomative cyclization of pyridine. As just reported in this issue of Chem by the Glorius group, a photocatalytic [4 + 2] cycloaddition that transfers N-cinnamoyl picolinamides into high-value isoquinuclidines under mild and operation-
2744 Chem 5, 2742–2750, November 14, 2019 ª 2019 Elsevier Inc.
ally simple conditions has been achieved, elegantly demonstrating the synthetic potential of visible-light photocatalysis in the construction of complex structures.1 Nitrogen-containing heterocycles have long been recognized as one of the most privileged structural manifolds in chemical synthesis because of their ubiquitous presence in natural products, approved pharmaceuticals, and preclinical chemical entities.2 Among the available synthetic strategies, catalytic dearomatization of aromatic heterocycles, such as indole and pyridine, has emerged as a rather effective and popular approach.3 Because of their availability in commercial sources and the modularity of the hexagonal
1School
of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China *Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2019.10.020