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A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy

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Abstract

In many cancers early intervention involves surgical resection of small localised tumour masses. Inadequate resection leads to recurrence whereas overzealous treatment can lead to organ damage. This work describes production of a HER2 targeting antibody Fab fragment dual conjugated to achieve both real time near-infrared fluorescent imaging and photodynamic therapy. The use of fluorescence emission from a NIR-dye could be used to guide resection of tumour bulk, for example during endoscopic diagnosis for oesophago-gastric adenocarcinoma, this would then be followed by activation of the photodynamic therapeutic agent to destroy untreated localised areas of cancer infiltration and tumour infiltrated lymph nodes. This theranostic agent was prepared from the Fab fragment of trastuzumab initially by functional disulfide re-bridging and site-specific click reaction of a NIR-dye. This was followed by further reaction with a novel pre-activated form of the photosensitiser chlorin e6 with the exposed fragments’ lysine residues. Specific binding of the theranostic agent was observed in vitro with a HER2 positive cell line and cellular near-infrared fluorescence was observed with flow cytometry. Specific photo-activity of the conjugates when exposed to laser light was observed with HER2 positive but not HER2 negative cell lines in vitro, this selectivity was not seen with the unconjugated drug. This theranostic agent demonstrates that two different photo-active functions can be coupled to the same antibody fragment with little interference to their independent activities.

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Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Department for Tissue & Energy, Division of Surgery & Interventional Science, Cruciform Building, Gower Street, London, WC1E 6AE, UK

    H. Pye, M. A. Butt, H. W. Reinert, M. Qurashi, L. Funnell, A. May, R. Hamoudi, M. P. Deonarain & L. B. Lovat

  2. Upper Gastrointestinal Service, University College London Hospitals NHS Foundation Trust, 250 Euston Road, London, NW1 2PG, UK

    M. A. Butt & L. B. Lovat

  3. Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK

    A. Maruani, J. P. M. Nunes, J. R. Baker, M. E. B. Smith, S. Caddick & V. Chudasama

  4. Antikor BioPharma, Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage, Herts, SG1 2FX, UK

    J. S. Marklew, I. Stamati, M. P. Deonarain & G. Yahioglu

  5. Department of Chemistry, Imperial College London, Exhibition Road, London SW7 2AZ, UK

    M. Qurashi, M. P. Deonarain & G. Yahioglu

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  1. H. Pye
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  2. M. A. Butt
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  3. H. W. Reinert
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  18. L. B. Lovat
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Corresponding authors

Correspondence to G. Yahioglu, V. Chudasama or L. B. Lovat.

Additional information

Electronic supplementary information (ESI) available: Contains more detail on the production of high purity trastuzumab Fab alkyne. Analysis showing Fab-alkyne binding positively to other relevant human gastrointestinal tract adenocarcinomas. The methods for the chemical synthesis of the bridging agent (N-propargyl-3,4-dibromomaleimide) and the anhydride-Ce6 and the chemical structure and fluorescence spectra of the two dyes in their free forms; NIR dye and Ce6. See DOI: 10.1039/c6pp00139d

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Pye, H., Butt, M.A., Reinert, H.W. et al. A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy. Photochem Photobiol Sci 15, 1227–1238 (2016). https://doi.org/10.1039/c6pp00139d

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