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RGD Conjugated Cell Uptake Off to On Responsive NIR-AZA Fluorophores: Applications toward Intraoperative Fluorescence Guided Surgery
Wu, Dan; Daly, Harrison C; Grossi, Marco; Conroy, Emer; Li, Bo; Gallagher, William M; Elmes, Robert; O'Shea, Donal F
<p>This is an accepted manuscript from the Royal Society of Chemistry, available at <a href=""></a></p> <p>The use of NIR-fluorescence imaging to demarcate tumour boundaries for real-time guidance of their surgical resection has a huge untapped potential. However, fluorescence imaging using molecular fluorophores, even with a targeting biomolecule attached, has a major shortcoming of signal interference from non-specific background fluorescence outside the region of interest. This poor selectivity necessitates prolonged time delays to allow clearance of background fluorophore and retention within the tumour prior to image acquisition. In this report, an innovative approach to overcome this issue is described in which cancer targeted off to on bio-responsive NIRfluorophores are utilised to switch-on first within the tumour. Bio-responsive cRGD, iRGD and PEG conjugates have been synthesised using activated ester/amine or maleimide/thiol couplings to link targeting and fluorophore components. Their off to on emission responses were measured and compared with an always-on non-responsive control with each bio-responsive derivative showing large fluorescence enhancement values. Live cell imaging experiments using metastatic breast cancer cells confirmed in vitro bio-responsive capabilities. An in vivo assessment of MDAMB 231 tumour imaging performance for bio-responsive and always-on fluorophores was conducted with monitoring of fluorescence distributions over 96 h. As anticipated, the always-on fluorophore gave an immediate, non-specific and very strong emission throughout whereas the bio-responsive derivatives initially displayed very low fluorescence. All three bio-responsive derivatives switched on within tumours at time points consistent with their conjugated targeting groups. cRGD and iRGD conjugates both had effective tumour turn-on in the first hour, though the cRGD derivative had superior specificity for tumour over the iRGD conjugate. The PEGylated derivative had similar switch-on characteristics but over a much longer period, taking 9 h before a significant emission was observable from the tumour. Evidence for in vivo active tumour targeting was obtained for the best performing cRGD bio-responsive NIR-AZA derivative from competitive binding studies. Overall, this cRGD-conjugate has the potential to overcome the inherent drawback of targeted always-on fluorophores requiring prolonged clearance times and shows excellent potential for clinical translation for intraoperative use in fluorescence guided tumour resections.</p>
Keyword(s): Fluorescence imaging; Cancer targeted off to on bio-responsive NIRfluorophores; Chemistry; Medicinal-Pharmaceutical Chemistry; Medicine and Health Sciences
Publication Date:
Type: Journal article
Peer-Reviewed: Yes
Institution: Royal College of Surgeons in Ireland
Citation(s): Wu D, Daly HC, Grossi M, Conroy E, Li B, Gallagher W, Elmes R, O'Shea DF. RGD Conjugated Cell Uptake Off to On Responsive NIR-AZA Fluorophores: Applications toward Intraoperative Fluorescence Guided Surgery. Chemical Science. 2019
Publisher(s): Royal Society of Chemistry
File Format(s): application/pdf
Related Link(s):
First Indexed: 2019-06-28 07:16:09 Last Updated: 2019-06-28 07:16:09