Luminescent iridium(iii) 2-cyanobenzothiazole complexes as site-specific labels to afford peptide-based phosphorogenic probes and hydrogels for enzyme activity sensing, cancer imaging and photodynamic therapy

Jun-Wen Xu; Lawrence Cho-Cheung Lee; Alex Man-Hei Yip; Guang-Xi Xu; Peter Kam-Keung Leung; Kenneth Kam-Wing Lo

doi:10.1039/d4qi03276d

Luminescent iridium(iii) 2-cyanobenzothiazole complexes as site-specific labels to afford peptide-based phosphorogenic probes and hydrogels for enzyme activity sensing, cancer imaging and photodynamic therapy

Jun-Wen Xu, Lawrence Cho-Cheung Lee, Alex Man-Hei Yip, Guang-Xi Xu, Peter Kam-Keung Leung, Kenneth Kam-Wing Lo^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

2 Citations (Scopus)

24 Downloads (CityUHK Scholars)

Abstract

Site-specific modification of biomolecules is crucial to the development of functional constructs for biomedical applications, offering precise control over the number and location of the functional handles incorporated. In this work, we designed, synthesised and characterised three luminescent cyclometallated iridium(iii) complexes bearing a 2-cyanobenzothiazole (CBT) moiety [Ir(N^C)₂(bpy-CBT)](PF₆) (HN^C = 2-(2,4-difluorophenyl)pyridine (Hdfppy) (1), 2-phenylpyridine (Hppy) (2), methyl 2-phenyl-4-quinolinecarboxylate (Hpqe) (3); bpy-CBT = 4-(2-cyanobenzo[d]thiazol-6-yl)oxymethyl-4′-methyl-2,2′-bipyridine) as site-specific labels for N-terminal cysteine (NCys). These complexes displayed high reactivity and selectivity towards NCys, enabling facile peptide conjugation via the CBT-NCys condensation reaction. Complex 2 was used to prepare a peptide-based phosphorogenic probe 2-MMP-QSY7 for matrix metalloproteinase-2/9 (MMP-2/9) activity sensing and photocytotoxic applications. The conjugate showed substantial emission enhancement (I/I_o = 9.8) in the presence of MMP-2/9, which allowed for the sensitive detection of MMP-2/9 activity in live cells and the facile differentiation of cancer and normal cells. The conjugate also exhibited controllable singlet oxygen generation and thereby photocytotoxicity in these cell lines. Additionally, complex 2 was utilised to fabricate two types of hydrogels: a non-biodegradable hydrogel Gel-1 as a cell culture scaffold integrated with MMP-2/9 sensing capability for examining the enzyme activity in 3D cell culture; and a biodegradable hydrogel Gel-2 as an MMP-2/9-sensitive carrier for selective delivery of luminescent iridium(iii) complexes into cancer cells for imaging and photocytotoxic applications. The results of this work will contribute to the development of site-specific bioconjugation reagents with interesting photophysical properties, facilitating the construction of photofunctional peptide conjugates and biomaterials for biosensing, bioimaging, phototherapy and drug delivery applications. © 2025 The Royal Society of Chemistry.

Original language	English
Pages (from-to)	2266-2279
Journal	Inorganic Chemistry Frontiers
Volume	12
Issue number	6
Online published	28 Jan 2025
DOIs	https://doi.org/10.1039/d4qi03276d
Publication status	Published - 21 Mar 2025

Funding

We thank the Hong Kong Research Grants Council (Project No. CityU 11301121, CityU 11317022, CityU 11309423 and C7075-21GF) and the Hong Kong Research Grants Council and National Natural Science Foundation of China (Project No. N_CityU104/21). We also thank the funding support from “Laboratory for Synthetic Chemistry and Chemical Biology” under the Health@InnoHK Programme launched by Innovation and Technology Commission, The Government of Hong Kong SAR, P. R. China. We thank Mr Michael Wai-Lun Chiang of Department of Chemistry, City University of Hong Kong, for his support with the TEM and SEM measurements. J.-W. X. acknowledges the receipt of a Postgraduate Studentship administered by City University of Hong Kong.

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GRF: Strategic Design of Photofunctional Transition Metal Complexes as Photoinducers to Trigger Cancer-Selective Immunogenic Cell Death
LO, K. W. K. (Principal Investigator / Project Coordinator)
1/01/24 → …
Project: Research
GRF: Targeting N-terminal Cysteine Residues with Photofunctional Transition Metal Complexes for Site-specific Bioconjugation, Live-cell Imaging, and Phototherapeutic Applications
LO, K. W. K. (Principal Investigator / Project Coordinator)
1/01/23 → …
Project: Research
GRF: Modulation of the Luminescence Properties and Photocytotoxic Activity of Transition Metal Complexes through Dissociative Bioorthogonal Reactions for Diagnostic and Therapeutic Applications
LO, K. W. K. (Principal Investigator / Project Coordinator)
1/01/22 → …
Project: Research

Cite this

Xu, J.-W., Lee, L. C.-C., Yip, A. M.-H., Xu, G.-X., Leung, P. K.-K., & Lo, K. K.-W. (2025). Luminescent iridium(iii) 2-cyanobenzothiazole complexes as site-specific labels to afford peptide-based phosphorogenic probes and hydrogels for enzyme activity sensing, cancer imaging and photodynamic therapy. Inorganic Chemistry Frontiers, 12(6), 2266-2279. https://doi.org/10.1039/d4qi03276d

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title = "Luminescent iridium(iii) 2-cyanobenzothiazole complexes as site-specific labels to afford peptide-based phosphorogenic probes and hydrogels for enzyme activity sensing, cancer imaging and photodynamic therapy",

abstract = "Site-specific modification of biomolecules is crucial to the development of functional constructs for biomedical applications, offering precise control over the number and location of the functional handles incorporated. In this work, we designed, synthesised and characterised three luminescent cyclometallated iridium(iii) complexes bearing a 2-cyanobenzothiazole (CBT) moiety [Ir(N^C)2(bpy-CBT)](PF6) (HN^C = 2-(2,4-difluorophenyl)pyridine (Hdfppy) (1), 2-phenylpyridine (Hppy) (2), methyl 2-phenyl-4-quinolinecarboxylate (Hpqe) (3); bpy-CBT = 4-(2-cyanobenzo[d]thiazol-6-yl)oxymethyl-4′-methyl-2,2′-bipyridine) as site-specific labels for N-terminal cysteine (NCys). These complexes displayed high reactivity and selectivity towards NCys, enabling facile peptide conjugation via the CBT-NCys condensation reaction. Complex 2 was used to prepare a peptide-based phosphorogenic probe 2-MMP-QSY7 for matrix metalloproteinase-2/9 (MMP-2/9) activity sensing and photocytotoxic applications. The conjugate showed substantial emission enhancement (I/Io = 9.8) in the presence of MMP-2/9, which allowed for the sensitive detection of MMP-2/9 activity in live cells and the facile differentiation of cancer and normal cells. The conjugate also exhibited controllable singlet oxygen generation and thereby photocytotoxicity in these cell lines. Additionally, complex 2 was utilised to fabricate two types of hydrogels: a non-biodegradable hydrogel Gel-1 as a cell culture scaffold integrated with MMP-2/9 sensing capability for examining the enzyme activity in 3D cell culture; and a biodegradable hydrogel Gel-2 as an MMP-2/9-sensitive carrier for selective delivery of luminescent iridium(iii) complexes into cancer cells for imaging and photocytotoxic applications. The results of this work will contribute to the development of site-specific bioconjugation reagents with interesting photophysical properties, facilitating the construction of photofunctional peptide conjugates and biomaterials for biosensing, bioimaging, phototherapy and drug delivery applications. {\textcopyright} 2025 The Royal Society of Chemistry.",

author = "Jun-Wen Xu and Lee, {Lawrence Cho-Cheung} and Yip, {Alex Man-Hei} and Guang-Xi Xu and Leung, {Peter Kam-Keung} and Lo, {Kenneth Kam-Wing}",

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doi = "10.1039/d4qi03276d",

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Xu, J-W , Lee, LC-C , Yip, AM-H , Xu, G-X , Leung, PK-K & Lo, KK-W 2025, 'Luminescent iridium(iii) 2-cyanobenzothiazole complexes as site-specific labels to afford peptide-based phosphorogenic probes and hydrogels for enzyme activity sensing, cancer imaging and photodynamic therapy', Inorganic Chemistry Frontiers, vol. 12, no. 6, pp. 2266-2279. https://doi.org/10.1039/d4qi03276d

Luminescent iridium(iii) 2-cyanobenzothiazole complexes as site-specific labels to afford peptide-based phosphorogenic probes and hydrogels for enzyme activity sensing, cancer imaging and photodynamic therapy. / Xu, Jun-Wen ; Lee, Lawrence Cho-Cheung ; Yip, Alex Man-Hei et al.
In: Inorganic Chemistry Frontiers, Vol. 12, No. 6, 21.03.2025, p. 2266-2279.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Luminescent iridium(iii) 2-cyanobenzothiazole complexes as site-specific labels to afford peptide-based phosphorogenic probes and hydrogels for enzyme activity sensing, cancer imaging and photodynamic therapy

AU - Xu, Jun-Wen

AU - Lee, Lawrence Cho-Cheung

AU - Yip, Alex Man-Hei

AU - Xu, Guang-Xi

AU - Leung, Peter Kam-Keung

AU - Lo, Kenneth Kam-Wing

PY - 2025/3/21

Y1 - 2025/3/21

N2 - Site-specific modification of biomolecules is crucial to the development of functional constructs for biomedical applications, offering precise control over the number and location of the functional handles incorporated. In this work, we designed, synthesised and characterised three luminescent cyclometallated iridium(iii) complexes bearing a 2-cyanobenzothiazole (CBT) moiety [Ir(N^C)2(bpy-CBT)](PF6) (HN^C = 2-(2,4-difluorophenyl)pyridine (Hdfppy) (1), 2-phenylpyridine (Hppy) (2), methyl 2-phenyl-4-quinolinecarboxylate (Hpqe) (3); bpy-CBT = 4-(2-cyanobenzo[d]thiazol-6-yl)oxymethyl-4′-methyl-2,2′-bipyridine) as site-specific labels for N-terminal cysteine (NCys). These complexes displayed high reactivity and selectivity towards NCys, enabling facile peptide conjugation via the CBT-NCys condensation reaction. Complex 2 was used to prepare a peptide-based phosphorogenic probe 2-MMP-QSY7 for matrix metalloproteinase-2/9 (MMP-2/9) activity sensing and photocytotoxic applications. The conjugate showed substantial emission enhancement (I/Io = 9.8) in the presence of MMP-2/9, which allowed for the sensitive detection of MMP-2/9 activity in live cells and the facile differentiation of cancer and normal cells. The conjugate also exhibited controllable singlet oxygen generation and thereby photocytotoxicity in these cell lines. Additionally, complex 2 was utilised to fabricate two types of hydrogels: a non-biodegradable hydrogel Gel-1 as a cell culture scaffold integrated with MMP-2/9 sensing capability for examining the enzyme activity in 3D cell culture; and a biodegradable hydrogel Gel-2 as an MMP-2/9-sensitive carrier for selective delivery of luminescent iridium(iii) complexes into cancer cells for imaging and photocytotoxic applications. The results of this work will contribute to the development of site-specific bioconjugation reagents with interesting photophysical properties, facilitating the construction of photofunctional peptide conjugates and biomaterials for biosensing, bioimaging, phototherapy and drug delivery applications. © 2025 The Royal Society of Chemistry.

AB - Site-specific modification of biomolecules is crucial to the development of functional constructs for biomedical applications, offering precise control over the number and location of the functional handles incorporated. In this work, we designed, synthesised and characterised three luminescent cyclometallated iridium(iii) complexes bearing a 2-cyanobenzothiazole (CBT) moiety [Ir(N^C)2(bpy-CBT)](PF6) (HN^C = 2-(2,4-difluorophenyl)pyridine (Hdfppy) (1), 2-phenylpyridine (Hppy) (2), methyl 2-phenyl-4-quinolinecarboxylate (Hpqe) (3); bpy-CBT = 4-(2-cyanobenzo[d]thiazol-6-yl)oxymethyl-4′-methyl-2,2′-bipyridine) as site-specific labels for N-terminal cysteine (NCys). These complexes displayed high reactivity and selectivity towards NCys, enabling facile peptide conjugation via the CBT-NCys condensation reaction. Complex 2 was used to prepare a peptide-based phosphorogenic probe 2-MMP-QSY7 for matrix metalloproteinase-2/9 (MMP-2/9) activity sensing and photocytotoxic applications. The conjugate showed substantial emission enhancement (I/Io = 9.8) in the presence of MMP-2/9, which allowed for the sensitive detection of MMP-2/9 activity in live cells and the facile differentiation of cancer and normal cells. The conjugate also exhibited controllable singlet oxygen generation and thereby photocytotoxicity in these cell lines. Additionally, complex 2 was utilised to fabricate two types of hydrogels: a non-biodegradable hydrogel Gel-1 as a cell culture scaffold integrated with MMP-2/9 sensing capability for examining the enzyme activity in 3D cell culture; and a biodegradable hydrogel Gel-2 as an MMP-2/9-sensitive carrier for selective delivery of luminescent iridium(iii) complexes into cancer cells for imaging and photocytotoxic applications. The results of this work will contribute to the development of site-specific bioconjugation reagents with interesting photophysical properties, facilitating the construction of photofunctional peptide conjugates and biomaterials for biosensing, bioimaging, phototherapy and drug delivery applications. © 2025 The Royal Society of Chemistry.

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U2 - 10.1039/d4qi03276d

DO - 10.1039/d4qi03276d

M3 - RGC 21 - Publication in refereed journal

SN - 2052-1553

VL - 12

SP - 2266

EP - 2279

JO - Inorganic Chemistry Frontiers

JF - Inorganic Chemistry Frontiers

IS - 6

ER -

Luminescent iridium(iii) 2-cyanobenzothiazole complexes as site-specific labels to afford peptide-based phosphorogenic probes and hydrogels for enzyme activity sensing, cancer imaging and photodynamic therapy

Abstract

Funding

Publisher's Copyright Statement

RGC Funding Information

UN SDGs

Access Output

Other Access Options

Permanent Link

Other Files and Links

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Projects

GRF: Strategic Design of Photofunctional Transition Metal Complexes as Photoinducers to Trigger Cancer-Selective Immunogenic Cell Death

GRF: Targeting N-terminal Cysteine Residues with Photofunctional Transition Metal Complexes for Site-specific Bioconjugation, Live-cell Imaging, and Phototherapeutic Applications

GRF: Modulation of the Luminescence Properties and Photocytotoxic Activity of Transition Metal Complexes through Dissociative Bioorthogonal Reactions for Diagnostic and Therapeutic Applications

Cite this