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A rotaxane-based platform for tailoring the pharmacokinetics of cancer-targeted radiotracers


d'Orchymont, Faustine; Holland, Jason P (2022). A rotaxane-based platform for tailoring the pharmacokinetics of cancer-targeted radiotracers. Chemical Science, 13(43):12713-12725.

Abstract

Radiolabelled monoclonal antibodies (mAbs) are a cornerstone of molecular diagnostic imaging and targeted radioimmunotherapy in nuclear medicine, but one of the major challenges in the field is to identify ways of reducing the radiation burden to patients. We reasoned that a rotaxane-based platform featuring a non-covalent mechanical bond between the radionuclide complex and the biologically active mAb could offer new ways of controlling the biophysical properties of cancer-specific radiotracers for positron emission tomography (PET). Herein, we present the photoradiosynthesis and characterisation of [89Zr]ZrFe-[4]rotaxane-azepin-onartuzumab ([89Zr]ZrFe-2), a unique rotaxane-antibody conjugate for PET imaging and quantification of the human hepatocyte growth factor receptor (c-MET). Multiple component self-assembly reactions were combined with simultaneous 89Zr-radiolabelling and light-induced bioconjugation methods to give [89Zr]ZrFe-2 in 15 ± 1% (n = 3) decay-corrected radiochemical yield, with >90% radiochemical purity, and molar activities suitable for PET imaging studies (>6.1 MBq mg−1 of protein). Cellular assays confirmed the specificity of [89Zr]ZrFe-2 binding to the c-MET receptor. Temporal PET imaging in athymic nude mice bearing subcutaneous MKN-45 gastric adenocarcinoma xenografts demonstrated specific binding of [89Zr]ZrFe-2 toward c-MET in vivo, where tumour uptake reached 9.8 ± 1.3 %ID g−1 (72 h, n = 5) in a normal group and was reduced by ∼56% in a control (blocking) group. Head-to-head comparison of the biodistribution and excretion profile of [89Zr]ZrFe-2versus two control compounds, alongside characterisation of two potential metabolites, showed that the rotaxane-radiotracer has an improved clearance profile with higher tumour-to-tissue contrast ratios and reduced radiation exposure to critical (dose-limiting) organs including liver, spleen, and kidneys. Collectively, the experimental results suggested that non-covalent mechanical bonds between the radionuclide and mAb can be used to fine-tune the pharmacokinetic profile of supramolecular radiopharmaceuticals in ways that are simply not accessible when using traditional covalent design.

Abstract

Radiolabelled monoclonal antibodies (mAbs) are a cornerstone of molecular diagnostic imaging and targeted radioimmunotherapy in nuclear medicine, but one of the major challenges in the field is to identify ways of reducing the radiation burden to patients. We reasoned that a rotaxane-based platform featuring a non-covalent mechanical bond between the radionuclide complex and the biologically active mAb could offer new ways of controlling the biophysical properties of cancer-specific radiotracers for positron emission tomography (PET). Herein, we present the photoradiosynthesis and characterisation of [89Zr]ZrFe-[4]rotaxane-azepin-onartuzumab ([89Zr]ZrFe-2), a unique rotaxane-antibody conjugate for PET imaging and quantification of the human hepatocyte growth factor receptor (c-MET). Multiple component self-assembly reactions were combined with simultaneous 89Zr-radiolabelling and light-induced bioconjugation methods to give [89Zr]ZrFe-2 in 15 ± 1% (n = 3) decay-corrected radiochemical yield, with >90% radiochemical purity, and molar activities suitable for PET imaging studies (>6.1 MBq mg−1 of protein). Cellular assays confirmed the specificity of [89Zr]ZrFe-2 binding to the c-MET receptor. Temporal PET imaging in athymic nude mice bearing subcutaneous MKN-45 gastric adenocarcinoma xenografts demonstrated specific binding of [89Zr]ZrFe-2 toward c-MET in vivo, where tumour uptake reached 9.8 ± 1.3 %ID g−1 (72 h, n = 5) in a normal group and was reduced by ∼56% in a control (blocking) group. Head-to-head comparison of the biodistribution and excretion profile of [89Zr]ZrFe-2versus two control compounds, alongside characterisation of two potential metabolites, showed that the rotaxane-radiotracer has an improved clearance profile with higher tumour-to-tissue contrast ratios and reduced radiation exposure to critical (dose-limiting) organs including liver, spleen, and kidneys. Collectively, the experimental results suggested that non-covalent mechanical bonds between the radionuclide and mAb can be used to fine-tune the pharmacokinetic profile of supramolecular radiopharmaceuticals in ways that are simply not accessible when using traditional covalent design.

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Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Physical Sciences > General Chemistry
Uncontrolled Keywords:General Chemistry
Language:English
Date:1 January 2022
Deposited On:05 Jan 2023 09:47
Last Modified:29 Mar 2024 02:37
Publisher:Royal Society of Chemistry
ISSN:2041-6520
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1039/d2sc03928a
Project Information:
  • : FunderSwiss National Science Foundation
  • : Grant IDPP00P2_163683
  • : Project Title
  • : FunderSwiss National Science Foundation
  • : Grant IDPP00P2_190093
  • : Project Title
  • : Funderwiss Government Excellence Scholarship
  • : Grant ID2017.0043
  • : Project Title
  • : FunderH2020
  • : Grant ID101001734
  • : Project TitleLight-induced synthesis of protein-drug conjugates for imaging and therapy
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
  • Content: Accepted Version