Anticancer phototherapy using activation of E -combretastatins by two-photon–induced isomerization

Scherer, Kathrin M.; Bisby, Roger H.; Botchway, Stanley W.; Hadfield, John A.; Parker, Anthony W.

doi:10.1117/1.jbo.20.5.051004

Cited by 21 publications

(16 citation statements)

References 28 publications

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“…The 1 ‐exposed cells within the irradiated square clearly show apoptosis/cell death, whereas the surrounding non‐irradiated cells do not. Little to no killing of cells is seen in the absence of 1 with light power as high as 25 mW which under these conditions relates to a dose of 2720 J cm −2 , this is the lower end of light doses reported to date for two‐photon photosensitizers –. This result therefore demonstrates the potential of 1 as a specific two‐photon‐activated PS at low concentrations and at doses of light that, alone, are not harmful to cells.…”

Section: Figurementioning

confidence: 64%

Metal Complexes for Two‐Photon Photodynamic Therapy: A Cyclometallated Iridium Complex Induces Two‐Photon Photosensitization of Cancer Cells under Near‐IR Light

McKenzie

Sazanovich

Baggaley

et al. 2016

Chemistry A European J

150

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Photodynamic therapy (PDT) uses photosensitizers (PS) which only become cytotoxic upon light‐irradiation. Transition‐metal complexes are highly promising PS due to long excited‐state lifetimes, and high photo‐stabilities. However, these complexes usually absorb higher‐energy UV/Vis light, whereas the optimal tissue transparency is in the lower‐energy NIR region. Two‐photon excitation (TPE) can overcome this dichotomy, with simultaneous absorption of two lower‐energy NIR‐photons populating the same PS‐active excited state as one higher‐energy photon. We introduce two low‐molecular weight, long‐lived and photo‐stable iridium complexes of the [Ir(N^C)2(N^N)]+ family with high TP‐absorption, which localise to mitochondria and lysosomal structures in live cells. The compounds are efficient PS under 1‐photon irradiation (405 nm) resulting in apoptotic cell death in diverse cancer cell lines at low light doses (3.6 J cm−2), low concentrations, and photo‐indexes greater than 555. Remarkably 1 also displays high PS activity killing cancer cells under NIR two‐photon excitation (760 nm), which along with its photo‐stability indicates potential future clinical application.

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Section: Figurementioning

confidence: 64%

Metal Complexes for Two‐Photon Photodynamic Therapy: A Cyclometallated Iridium Complex Induces Two‐Photon Photosensitization of Cancer Cells under Near‐IR Light

McKenzie

Sazanovich

Baggaley

et al. 2016

Chemistry A European J

150

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“…39 Similarly, E-combretastatins are shown here to readily diffuse to the central regions of similar diameter tumor spheroids and since their photoisomerization and activation to the Z-isomer is an oxygen independent process, they should be effective within hypoxic regions of cell models and tumors. We have attempted to study cell killing within small defined regions of tumor spheroids following treatment using the same approach as in our previous successful work 25 with cell monolayers. These experiments involved E-combretastatin uptake into the spheroid, photoirradiation (typically of a 150 × 50 × 10 μm 3 volume at 50 μm height into the spheroid), and incubation for 24 to 48 h followed by apoptotic cell labeling.…”

Section: Discussionmentioning

confidence: 99%

“…1). [23][24][25] While Z-combretastatins are nonfluorescent, the intrinsic fluorescence of E-combretastatins has enabled real-time monitoring of E-combretastatin uptake in monolayers of live mammalian cells by two-photon excitation fluorescence lifetime imaging (2PE-FLIM). 23,24 E-combretastatins have fluorescence lifetimes that are dependent on solvent polarity and viscosity and were shown to be proportional to fluorescence quantum yields.…”

mentioning

confidence: 99%

“…Once within the cell, the E-combretastatin (absorption λ max ∼ 320 nm) may be activated by two-photon absorption at 625-630 nm and the resulting cell death demonstrated using fluorescence assays. 25 Both two-photon irradiation and fluorescent assays using confocal imaging may be performed using a single adapted microscope system. 26 The present report moves our previous work with combretastatins in monolayer cell cultures into 3-D model systems to demonstrate prodrug uptake and activation at depth within a model tissue structure.…”

mentioning

confidence: 99%

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Three-dimensional imaging and uptake of the anticancer drug combretastatin in cell spheroids and photoisomerization in gels with multiphoton excitation

et al. 2015

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Abstract. The uptake of E -combretastatins, potential prodrugs of the anticancer Z -isomers, into multicellular spheroids has been imaged by intrinsic fluorescence in three dimensions using two-photon excited fluorescence lifetime imaging with 625-nm ultrafast femtosecond laser pulses. Uptake is initially observed at the spheroid periphery but extends to the spheroid core within 30 min. Using agarose gels as a three-dimensional model, the conversion of Z ðtransÞ → E ðcisÞ via two-photon photoisomerization is demonstrated and the location of this photochemical process may be precisely selected within the micron scale in all three dimensions at depths up to almost 2 mm. We discuss these results for enhanced tissue penetration at longer near-infrared wavelengths for cancer therapy and up to three-photon excitation and imaging using 930-nm laser pulses with suitable combretastatin analogs. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

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“…Cell killing with micrometre precision was achieved at optimized prodrug concentrations and laser powers (e.g. 2 & 3c or 2d) Figure 7C is adapted from Scherer et al (2015) [122]. its singlet electronic state by one-or two-photon absorption from which it decays by geometric conversion (isomerization) on a sub-nanosecond timescale to its Zisomer.…”

Section: Alternative Strategy For Two-photon Phototherapy (2p-pdt) Wimentioning

confidence: 99%

New Approaches to Photodynamic Therapy from Types I, II and III to Type IV Using One or More Photons

Scherer

Bisby²,

Botchway³

et al. 2017

ACAMC

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Photodynamic therapy (PDT) is an alternative cancer treatment to conventional surgery, radiotherapy and chemotherapy. It is based on activating a drug with light that triggers the generation of cytotoxic species that promote tumour cell killing. At present, PDT is mainly used in the treatment of wet age-related macular degeneration, for precancerous conditions of the skin (e.g. actinic keratosis) and in the palliative care of advanced cancers, for instance of the bladder or the oesophagus. Due to a lack of phase III clinical trials and limitations of light penetration to deeper lying tumours (in excess of 1 cm), PDT is still not used as a first line cancer treatment, which is surprising given the first clinical trials by Dougherty's group dating back to the 1970's. However research continues to demonstrate the potential benefits of PDT and the need to stimulate funding and uptake of clinical studies using next generation photosensitizers offering advanced targeted delivery, improved photodynamic dose combined with modern light delivery technologies. This review surveys the available PDT treatments and emerging novel developments in the field with a particular focus on two-photon techniques that are anticipated to improve the effectiveness of PDT in tissues at depth and on next generation drugs that work without the need of the presence of oxygen for photosensitization making them effective where hypoxia has taken hold.

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Anticancer phototherapy using activation of E -combretastatins by two-photon–induced isomerization

Cited by 21 publications

References 28 publications

Metal Complexes for Two‐Photon Photodynamic Therapy: A Cyclometallated Iridium Complex Induces Two‐Photon Photosensitization of Cancer Cells under Near‐IR Light

Metal Complexes for Two‐Photon Photodynamic Therapy: A Cyclometallated Iridium Complex Induces Two‐Photon Photosensitization of Cancer Cells under Near‐IR Light

Three-dimensional imaging and uptake of the anticancer drug combretastatin in cell spheroids and photoisomerization in gels with multiphoton excitation

New Approaches to Photodynamic Therapy from Types I, II and III to Type IV Using One or More Photons

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