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Cited by 350Nanoplatforms for cancer theranosticsLuminescence and Fluorescent MaterialsPhotoacoustic and Ultrasonic Imaging

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Light-driven transformable optical agent with adaptive functions for boosting cancer surgery outcomes

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Qi, Ji, Chen, Chao, Zhang, Xiaoyan, Hu, Xianglong, Ji, Shenglu, Kwok, Ryan T. K., Lam, Jacky W. Y., Ding, Dan, Tang, Ben Zhong·2018·Nature Communications
DOI 10.1038/s41467-018-04222-8PMC PMC5945617
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Abstract

Fluorescence and photoacoustic imaging have different advantages in cancer diagnosis; however, combining effects in one agent normally requires a trade-off as the mechanisms interfere. Here, based on rational molecular design, we introduce a smart organic nanoparticle whose absorbed excitation energy can be photo-switched to the pathway of thermal deactivation for photoacoustic imaging, or to allow opposed routes for fluorescence imaging and photodynamic therapy. The molecule is made of a dithienylethene (DTE) core with two surrounding 2-(1-(4-(1,2,2-triphenylvinyl)phenyl)ethylidene)malononitrile (TPECM) units (DTE-TPECM). The photosensitive molecule changes from a ring-closed, for photoacoustic imaging, to a ring-opened state for fluorescence and photodynamic effects upon an external light trigger. The nanoparticles’ photoacoustic and fluorescence imaging properties demonstrate the advantage of the switch. The use of the nanoparticles improves the outcomes of in vivo cancer surgery using preoperative photoacoustic imaging and intraoperative fluorescent visualization/photodynamic therapy of residual tumours to ensure total tumour removal.

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Figures

Fig. 1 Synthesis, structure and property of photo-controllable DTE-TPECM molecules. a Key synthesis steps, photo-controlled reversibility and optimized geometric structures of DTE-TPECM molecules. Photographs of ROpen-DTE-TPECM and RClosed-DTE-TPECM powders in daylight and under UV light (365 nm). FL: fluorescence. b PL spectra of ROpen-DTE-TPECM in THF/water mixture with various water fractions. c Plot of I/I0 versus water fraction. I0 and I are the peak PL intensities of ROpen-DTE-TPECM (10 μM) in pure THF and THF/water mixtures, respectively. Inset shows the photographs of ROpen-DTE-TPECM in THF/water mixtures with different water fractions taken under UV illumination. d XRD diagrams of ROpen-DTE-TPECM and RClosed-DTE-TPECM
Fig. 1 Synthesis, structure and property of photo-controllable DTE-TPECM molecules. a Key synthesis steps, photo-controlled reversibility and optimized geometric structures of DTE-TPECM molecules. Photographs of ROpen-DTE-TPECM and RClosed-DTE-TPECM powders in daylight and under UV light (365 nm). FL: fluorescence. b PL spectra of ROpen-DTE-TPECM in THF/water mixture with various water fractions. c Plot of I/I0 versus water fraction. I0 and I are the peak PL intensities of ROpen-DTE-TPECM (10 μM) in pure THF and THF/water mixtures, respectively. Inset shows the photographs of ROpen-DTE-TPECM in THF/water mixtures with different water fractions taken under UV illumination. d XRD diagrams of ROpen-DTE-TPECM and RClosed-DTE-TPECMCC BY · PubMed Central
Fig. 2 Illustration of the controllable photophysical processes. The energy balance of photophysics profoundly tilts to either side controlled by external UV/visible light exposure. A: absorption, FL: fluorescence, NR: non-radiation, ISC: intersystem crossing
Fig. 2 Illustration of the controllable photophysical processes. The energy balance of photophysics profoundly tilts to either side controlled by external UV/visible light exposure. A: absorption, FL: fluorescence, NR: non-radiation, ISC: intersystem crossingCC BY · PubMed Central
Fig. 3 Preparation and characterization of the photo-controllable NPs. a Schematic of RClosed NPs and ROpen NPs. b, c DLS profiles and TEM images of b RClosed NPs and c ROpen NPs. Scale bars, 100 nm for TEM images. d Absorption and e PL spectra of RClosed NPs under visible light (610 nm, 0.3 W cm−2) irradiation for different time as indicated. Photographs in d indicate the aqueous solutions of RClosed NPs before and after 610 nm light exposure for 600 s. f The absorption intensity at 650 nm of the NPs during ten circles of visible (610 nm, 0.3 W cm−2)/UV light (365 nm, 0.1 W cm−2) irradiation processes
Fig. 3 Preparation and characterization of the photo-controllable NPs. a Schematic of RClosed NPs and ROpen NPs. b, c DLS profiles and TEM images of b RClosed NPs and c ROpen NPs. Scale bars, 100 nm for TEM images. d Absorption and e PL spectra of RClosed NPs under visible light (610 nm, 0.3 W cm−2) irradiation for different time as indicated. Photographs in d indicate the aqueous solutions of RClosed NPs before and after 610 nm light exposure for 600 s. f The absorption intensity at 650 nm of the NPs during ten circles of visible (610 nm, 0.3 W cm−2)/UV light (365 nm, 0.1 W cm−2) irradiation processesCC BY · PubMed Central
Fig. 4 In vitro PA, fluorescence and ROS generation of the NPs. a PA spectra of RClosed and ROpen NPs. b PA intensities of RClosed and ROpen NPs at 700 nm as a function of molar concentration based on DTE-TPECM molecules. Error bars, mean ± s.d. (n = 3) for a, b. c PA amplitudes of RClosed NPs as a function of number of laser pulses (1.8 × 104 pulses; 1.5 W cm−2 laser and 20 Hz pulse repetition rate). d PA intensities excited with 680 nm pulsed laser of various agents at the same molar concentration (100 μM) based on MB, ICG, DTE-TPECM molecules and the repeat unit of SP. e Plot of A/A0 versus different RONS. A and A0 are the absorption intensity at 680 nm of RClosed NPs, SPNs, MB and ICG in the presence and absence of RONS (400 μM), respectively. Error bars, mean ± s.d. (n = 3) for (d, e). f PL excitation mapping and g fluorescence decay curve of ROpen NPs. h Plot of I/I0 versus light irradiation time. The aqueous solution of RClosed NPs or ROpen NPs (10 μM based on DTE-TPECM) was exposed to 610 nm red light (0.3 W cm−2) and/or 365 nm UV light (0.1 W cm−2). i Plot of I/I0 versus white light (0.25 W cm−2) irradiation time of ROpen NPs (10 μM based on ROpen-DTE-TPECM) in aqueous solution. I0 and I are the PL intensity of DCF at 525 nm before and after light irradiation at designated time intervals in both h, i
Fig. 4 In vitro PA, fluorescence and ROS generation of the NPs. a PA spectra of RClosed and ROpen NPs. b PA intensities of RClosed and ROpen NPs at 700 nm as a function of molar concentration based on DTE-TPECM molecules. Error bars, mean ± s.d. (n = 3) for a, b. c PA amplitudes of RClosed NPs as a function of number of laser pulses (1.8 × 104 pulses; 1.5 W cm−2 laser and 20 Hz pulse repetition rate). d PA intensities excited with 680 nm pulsed laser of various agents at the same molar concentration (100 μM) based on MB, ICG, DTE-TPECM molecules and the repeat unit of SP. e Plot of A/A0 versus different RONS. A and A0 are the absorption intensity at 680 nm of RClosed NPs, SPNs, MB and ICG in the presence and absence of RONS (400 μM), respectively. Error bars, mean ± s.d. (n = 3) for (d, e). f PL excitation mapping and g fluorescence decay curve of ROpen NPs. h Plot of I/I0 versus light irradiation time. The aqueous solution of RClosed NPs or ROpen NPs (10 μM based on DTE-TPECM) was exposed to 610 nm red light (0.3 W cm−2) and/or 365 nm UV light (0.1 W cm−2). i Plot of I/I0 versus white light (0.25 W cm−2) irradiation time of ROpen NPs (10 μM based on ROpen-DTE-TPECM) in aqueous solution. I0 and I are the PL intensity of DCF at 525 nm before and after light irradiation at designated time intervals in both h, iCC BY · PubMed Central
Fig. 5 Targeting modification, cytotoxicity and in vivo pharmacokinetics. a Chemical structure of CYSAYPDSVPMMS peptide. SPPS solid-phase peptide synthesis. b Schematic of the preparation of a RClosed-YSA NP. c Western blot analyses of EphA2 in L02 cells and 4T1 cancer cells. d Cell viability of RClosed-YSA NP-incubated 4T1 cancer cells after 610 nm red light (0.3 W cm−2) irradiation for 5 min. Error bars, mean ± s.d. (n = 4). e Cell viabilities of the converted ROpen-YSA NP-loaded and converted ROpen NP-loaded 4T1 cancer cells under white light irradiation (0.25 W cm−2, 4 min). Error bars, mean ± s.d. (n = 4). *P < 0.05, unpaired Student's t-test (two-tailed). The cells were incubated with RClosed-YSA and RClosed NPs, respectively, followed by exposure to 610 nm red light (0.3 W cm−2) for 5 min, to obtain the converted ring-opening NP-loaded cells. In d and e, the concentration is based on DTE-TPECM. f Pharmacokinetics study of 125I-labelled RClosed-YSA NPs analysed by scintillation count of 125I radioactivity in blood. Error bars, mean ± s.d. (n = 6 rats). Inset displays the schematic of an 125I-labelled RClosed-YSA NP. g Biodistribution of 125I-labelled RClosed-YSA NPs in various tissues of 4T1 tumour-bearing mice at different time points post-intravenous injection. Error bars, mean ± s.d. (n = 6 mice for each time point)
Fig. 5 Targeting modification, cytotoxicity and in vivo pharmacokinetics. a Chemical structure of CYSAYPDSVPMMS peptide. SPPS solid-phase peptide synthesis. b Schematic of the preparation of a RClosed-YSA NP. c Western blot analyses of EphA2 in L02 cells and 4T1 cancer cells. d Cell viability of RClosed-YSA NP-incubated 4T1 cancer cells after 610 nm red light (0.3 W cm−2) irradiation for 5 min. Error bars, mean ± s.d. (n = 4). e Cell viabilities of the converted ROpen-YSA NP-loaded and converted ROpen NP-loaded 4T1 cancer cells under white light irradiation (0.25 W cm−2, 4 min). Error bars, mean ± s.d. (n = 4). *P < 0.05, unpaired Student's t-test (two-tailed). The cells were incubated with RClosed-YSA and RClosed NPs, respectively, followed by exposure to 610 nm red light (0.3 W cm−2) for 5 min, to obtain the converted ring-opening NP-loaded cells. In d and e, the concentration is based on DTE-TPECM. f Pharmacokinetics study of 125I-labelled RClosed-YSA NPs analysed by scintillation count of 125I radioactivity in blood. Error bars, mean ± s.d. (n = 6 rats). Inset displays the schematic of an 125I-labelled RClosed-YSA NP. g Biodistribution of 125I-labelled RClosed-YSA NPs in various tissues of 4T1 tumour-bearing mice at different time points post-intravenous injection. Error bars, mean ± s.d. (n = 6 mice for each time point)CC BY · PubMed Central
Fig. 6 In vivo preoperative PA imaging and intraoperative fluorescence imaging. a Representative time-dependent PA images of subcutaneous tumours from mice intravenously injected with RClosed-YSA and RClosed NPs (800 μM based on RClosed-DTE-TPECM, 100 μL), respectively. Scale bars, 2 mm. b Plot of PA intensity at 700 nm in tumour versus time post injection of RClosed-YSA or RClosed NPs. Error bars, mean ± s.d. (n = 3 mice per group). *P < 0.05, in comparison between RClosed-YSA and RClosed NPs using unpaired Student's t-test (two-tailed). c Representative brightfield images of RClosed-YSA NP-treated tumour-bearing mice before and after surgery as well as representative fluorescence images of mice with complete surgical resection of tumours, followed by 610 nm red light (0.3 W cm−2) irradiation at the operative incision site for 5 min. Scale bars, 3 mm. FL fluorescence, IT irradiation time. d H&E stained tissues at the operative incision site in c indicate no residual tumours left behind. Scale bar, 1 mm. e Representative fluorescence images of RClosed-YSA NP-treated mice with residual tumours post surgery. The operative incision site was irradiated by 610 nm red light (0.3 W cm−2) for 5 min. The red dashed circles in c and e indicate the tumour/operative incision site. The red arrow shows the residual tumours with a diameter below 1 mm. Scale bars, 3 mm. f, H&E stained tissues at the operative incision site in e confirm the existence of residual tumours. Scale bar, 0.5 mm
Fig. 6 In vivo preoperative PA imaging and intraoperative fluorescence imaging. a Representative time-dependent PA images of subcutaneous tumours from mice intravenously injected with RClosed-YSA and RClosed NPs (800 μM based on RClosed-DTE-TPECM, 100 μL), respectively. Scale bars, 2 mm. b Plot of PA intensity at 700 nm in tumour versus time post injection of RClosed-YSA or RClosed NPs. Error bars, mean ± s.d. (n = 3 mice per group). *P < 0.05, in comparison between RClosed-YSA and RClosed NPs using unpaired Student's t-test (two-tailed). c Representative brightfield images of RClosed-YSA NP-treated tumour-bearing mice before and after surgery as well as representative fluorescence images of mice with complete surgical resection of tumours, followed by 610 nm red light (0.3 W cm−2) irradiation at the operative incision site for 5 min. Scale bars, 3 mm. FL fluorescence, IT irradiation time. d H&E stained tissues at the operative incision site in c indicate no residual tumours left behind. Scale bar, 1 mm. e Representative fluorescence images of RClosed-YSA NP-treated mice with residual tumours post surgery. The operative incision site was irradiated by 610 nm red light (0.3 W cm−2) for 5 min. The red dashed circles in c and e indicate the tumour/operative incision site. The red arrow shows the residual tumours with a diameter below 1 mm. Scale bars, 3 mm. f, H&E stained tissues at the operative incision site in e confirm the existence of residual tumours. Scale bar, 0.5 mmCC BY · PubMed Central
Fig. 7 In vivo PDT of residual tumours after debulking surgery (DS). a Time-dependent bioluminescence imaging of residual tumours from mice in different groups. The tumours were debulked on day 0. The 4T1 cancer cells express luciferase, permitting bioluminescence imaging. The black arrows indicate the residual tumours. b Quantitative analysis of bioluminescence intensities of residual tumours from mice with various treatments as indicated. Error bars, mean ± s.d. (n = 10 mice per group). **P < 0.01, one-way ANOVA. c Survival curves for different groups (n = 10 mice per group)
Fig. 7 In vivo PDT of residual tumours after debulking surgery (DS). a Time-dependent bioluminescence imaging of residual tumours from mice in different groups. The tumours were debulked on day 0. The 4T1 cancer cells express luciferase, permitting bioluminescence imaging. The black arrows indicate the residual tumours. b Quantitative analysis of bioluminescence intensities of residual tumours from mice with various treatments as indicated. Error bars, mean ± s.d. (n = 10 mice per group). **P < 0.01, one-way ANOVA. c Survival curves for different groups (n = 10 mice per group)CC BY · PubMed Central

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Metadata

Authors
Qi, J., Chen, C., Zhang, X., Hu, X., Ji, S., Kwok, R. T. K., Lam, J. W. Y., Ding, D., & Tang, B. Z.
Affiliations
  • Hong Kong University of Science and Technology (HK)
  • Nankai University (CN)
Corresponding author
  • Ding, Dan
  • Tang, Ben Zhong
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-05-10
Volume
9
Issue
1
Pages
1848-1848
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-04222-8
PMC
PMC5945617
OpenAlex
W2802852094
Cited by
350
References
56
Citations by year
2026: 10 · 2025: 19 · 2024: 38 · 2023: 29 · 2022: 58 · 2021: 41 · 2020: 58 · 2019: 75 · 2018: 22
FWCI
19.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • National Natural Science Foundation of China (ITCPD/17-9, N_HKUST604/14, AoE/P-03/08, 16301614, ITC-CNERC14SC01, IRT13023, 21 788 102, 16305015, 51622305)
  • Innovation and Technology Commission (ITC PD/17-9, RE:ITCPD/17‐9, CNERC14SC01, ITC- CNERC-14SC01)
  • Guangdong Province Introduction of Innovative R&D Team (201101C0105067115)
  • National Key Research and Development Program of China (2015CB856503, IRT13023, 21788102)
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
  • Physical Sciences › Materials Science › Materials Chemistry › Luminescence and Fluorescent Materials
  • Physical Sciences › Engineering › Biomedical Engineering › Photoacoustic and Ultrasonic Imaging
Keywords
dithienylethene, photoacoustic imaging, fluorescence imaging, photodynamic therapy, organic nanoparticles, photoisomerization, cancer surgery
MeSH terms
Animals, Antineoplastic Agents, Female, Humans, Intraoperative Period, Male, Mice, Inbred BALB C, Neoplasms, Photochemotherapy, Temperature, Survival Rate, Treatment Outcome, Chemotherapy, Adjuvant, Rats, Sprague-Dawley, Photosensitizing Agents, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Rats, Nanoparticles, Preoperative Period, Photoacoustic Techniques, Optical Imaging

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