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Shielding Unit Engineering of NIR-II Molecular Fluorophores for Improved Fluorescence Performance and Renal Excretion Ability.

ABSTRACT: Molecular fluorophores emitting in the second near-infrared (NIR-II) window with good renal excretion ability are favorable for in vivo bio-imaging and clinical applications. So far, renally excretable fluorophores are still less studied. Understanding the influences of molecular structure on optical properties and renal excretion abilities are vital for fluorophore optimization. Herein, a series of shielding unit-donor-acceptor-donor-shielding unit (S-D-A-D-S) NIR-II molecular fluorophores are designed and synthesized with dialkoxy chains substituted benzene as the S unit. The anchoring positions of dialkoxy chains on benzene are tuned as meso-2,6, para-2,5, or ortho-3,4 to afford three fluorophores: BGM6P, BGP6P and BGO6P, respectively. Experimental and calculation results reveal that alkoxy side chains anchored closer to the conjugated backbone can provide better protection from water molecules and PEG chains, affording higher fluorescence quantum yield (QY) in aqueous solutions. Further, these side chains can enable good encapsulation of backbone, resulting in decreased binding with albumin and improved renal excretion. Thus, fluorophore BGM6P with meso-2,6-dialkoxy chains exhibits the highest quantum yield and fastest renal excretion. This work emphasizes the important roles of side chain patterns on optimizing NIR-II fluorophores with high brightness and renal excretion ability.

SUBMITTER: Liu C

PROVIDER: S-EPMC8443785 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 NIR-fluorophores 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 MDA-MB 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.

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Shielding Unit Engineering of NIR-II Molecular Fluorophores for Improved Fluorescence Performance and Renal Excretion Ability.

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