Research ArticleBasic Science Investigation
Open Access

[123I]CC1: A PARP-Targeting, Auger Electron–Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer

Chung Ying Chan, Zijun Chen, Florian Guibbal, Gemma Dias, Gianluca Destro, Edward O’Neill, Mathew Veal, Doreen Lau, Michael Mosley, Thomas C. Wilson, Véronique Gouverneur and Bart Cornelissen
Journal of Nuclear Medicine September 2023, jnumed.123.265429; DOI: https://doi.org/10.2967/jnumed.123.265429

Article Figures & Data

Figures

  • Figure
  • FIGURE 1.
    FIGURE 1.

    (A) Chemical structures of olaparib and CC1. (B) Molecular docking of olaparib (brown backbone) and CC1 (green) to PARP1 shows excellent overlap. (C) Cell-free enzymatic inhibition of PARP1, PARP2, and PARP3 by CC1 or olaparib. IC50 = inhibitory concentration of 50%.

  • FIGURE 2.
    FIGURE 2.

    (A) Radiosynthesis of [123I]CC1 by copper-assisted iododeboronation. (B) Uptake of [123I]CC1 in AsPC1, PSN1, and U87MG cells after 1 h of exposure. (C) Blocking of [123I]CC1 uptake in U87MG cells by panel of unlabeled CC1 or other PARP inhibitors. (D) Uptake of [123I]CC1 in PSN1, AsPC1, or Capan1 cells. ****P < 0.0001. RCY = Radiochemical yield.

  • FIGURE 3.
    FIGURE 3.

    (A) Flow cytometry measurements of PARP1, PARP2, and γH2AX expression at 1 or 24 h after 1 h of exposure to [123I]CC1 (50 kBq, 138.8 GBq/μmol, in 2 mL of growth medium) in PSN1 and U87MG cells, relative to 0 h. (B and C) Clonogenic survival of PSN1 or U87MG cells, comparing exposure of cells for 1 h to [123I]CC1 (0–10 kBq in 0.2 mL of growth medium), nonlabeled CC1, or olaparib. ns, P > 0.05. *P < 0.05. **P < 0.01. ***P < 0.001. ****P < 0.0001. ns = not significant.

  • FIGURE 4.
    FIGURE 4.

    (A) SPECT image, 45 min after intravenous administration of [123I]CC1 (3 MBq; coronal maximum intensity projection). (B) Volume-of-interest analysis of dynamic SPECT images in selected tissues of mice bearing PSN1 xenografts. (C) Biodistribution of [123I]CC1 in selected tissues of mice bearing PSN1 xenografts at 1, 2, or 24 h after intravenous administration of [123I]CC1 (3 MBq). (D) Biodistribution in selected tissues of mice bearing PSN1 xenografts at 2 h after intravenous injection of [123I]CC1 (3 MBq) with or without excess unlabeled rucaparib (0.5 mg). (E) Autoradiography of tumor sections harvested 2 h after intravenous injection of [123I]CC1 (3 MBq) in mice bearing PSN1, U87MG, or MDA-MB-231 xenografts. (F) Tumor uptake 1 h after intravenous injection of [123I]CC1 (3 MBq) in mice bearing PSN1, U87MG, or MDA-MB-231 xenografts. ns, P > 0.05. *P < 0.05. %ID = percentage injected dose; ns = not significant.

  • FIGURE 5.
    FIGURE 5.

    (A) Tumor growth after single intravenous administration of [123I]CC1 (3 MBq, 124.2–341.9 GBq/μmol) or equivalent amount of nonlabeled CC1 in mice bearing PSN1 xenografts. (B) Kaplan–Meier survival plots of A (survival event, V = 600 mm3). (C) Representative photographs of mice bearing PSN1 xenografts, 15 d after [123I]CC1 or CC1 administration. (D) Animal weights after administration of [123I]CC1 or CC1 (mixed tumor models). (E and F) Tumor growth curves after single intravenous administration of [123I]CC1 (3 MBq) or equivalent amount of nonlabeled CC1 in mice bearing U87MG or MDA-MB-231 xenografts. (G) Representative hematoxylin and eosin staining in selected normal tissues at 28 d after administration of [123I]CC1 (3 MBq) or untreated C57BL/6 mice. IV = intravenous.

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