Radiopharmaceutical Chemistry

Bioorthogonal labeling of theranostics and multimodality imaging probes

Labeling of biomolecules is one of the major limitations hampering further deployment of targeted radiation therapy and functional imaging as experimental and clinical tools. Labeling of biovectors (proteins, antibodies, oligonucleotides, etc.) is still too complicated and the development of radiopharmaceuticals has not kept pace with the discoveries in biology. Thus, our group is aiming at the development of a versatile radiolabeling method based on bioorthogonal chemical reactions. To determine if our strategy is unlocking the actual limitations, we will apply it to molecules known to target specific oncogenic proteins (i.e. SSTR2, GRPR, PSMA and CA-IX).

Targeted Alpha/Auger Therapy (TAT)

The therapeutic outcome of peptide receptor radionuclide therapy (PRRT) can be improved by replacing the conventional β- emitter (177Lu) with a highly cytotoxic alpha emitting radionuclide (212Pb, 225Ac) or an Auger emitter (i.e. 195mPt). Somatostatin targeting peptides and prostate-specific membrane antigen (PSMA) ligands will be labeled with an alpha or Auger emitter; and their potential to eradicate tumors will be evaluated.  Considering that damage to healthy organs may also be increased, the tumor targeting abilities of our ligands will be optimized to prevent severe radiotoxicity in healthy tissues and warrant a safe use of targeted alpha/Auger therapy (TAT).

Pretargeting: a safer and more efficient treatment of cancer

The remarkable specificity and affinity of peptides make them extremely attractive vectors for the delivery of diagnostic and therapeutic radionuclides to cancer cells. Over the past two decades, a wide variety of peptide-based radiopharmaceuticals has been successfully developed to target tumor cells. A significant limitation of the use of radiolabeled therapeutic peptides, however, is their relatively high accumulation in non-target tissues, leading to high radiation doses to healthy organs. Our objective is to apply pretargeting strategies based on bioorthogonal chemistry to perform in vivo radiolabeling of the peptide and to yield optimal tumor radiation dose while minimizing adverse effects.

Theranostic small-molecule drug conjugates

Chemotherapy remains at the time being the mainstay of systemic treatment for patients presenting with metastatic cancer. Chemotherapy has however the major drawback of non-cancer specific toxicity. Therefore, more targeted approaches delivering cytotoxic treatment directly to the tumor might decrease systemic toxicity while possibly increasing the dose of cytotoxic agent delivered to the tumor. In this project, we are aiming at the design of small-molecule drug conjugates (SMDCs), containing a targeting vector conjugated to potent antineoplastic drugs, for prostate cancer. Incorporation of a theranostic radionuclide pair will allow in vivo noninvasive identification of the cancerous lesions and improved treatment efficacy.

• Chen K-T, Nguyen K, Ieritano C, Gao F, Seimbille Y. A flexible synthesis of 68Ga-labeled carbonic anhydrase IX (CAIX)- targeted molecules via CBT/1,2-aminothiol click reaction. Molecules, 2019; 24: 23 (accessible here).
• Gao F, Ieritano C, Chen K-T, Dias G, Rousseau J, Bénard F, Seimbille Y. Two bifunctional desferrioxamine chelators for bioorthogonal labeling of biovectors with zirconium-89. Organic and Biomolecular Chemistry. 2018; 16: 5102-5106 (accessible here).
• De Blois E, de Zanger R, Oehlke E, Chan HS, Breeman W. Semi-automated system for concentrating 68Ga-eluate to obtain high molar and volume concentration of 68Ga-radiopharmaca for preclinical applications. Nuclear Medicine and Biology. 2018; 64-65: 16-21 (accessible here).
• Chen K-T, Ieritano C, Seimbille Y. Early-stage incorporation strategy for regioselective labeling of peptides using the 2-cyanobenzothiazole/1,2-aminothiol bioorthogonal click reaction. ChemistryOpen, 2018; 7(3): 256-261 (accessible here).
• Chan HS, de Blois E, Morgenstern A, Bruchertseifer F, de Jong M, Breeman W, Konijnenberg M. In vitro comparison of 213Bi- and 177Lu-radiation for peptide receptor radionuclide therapy. PLoS One. 2017; 12(7): e0181473 (accessible here).
• Chan HS, de Blois E, Konijnenberg MW, Morgenstern A, Bruchertseifer F, Norenberg JP, Verzijlbergen FJ, de Jong M, Breeman WAP. Optimizing labeling conditions of 213Bi-DOTATATE for preclinical applications of peptide receptor targeted alpha therapy. EJNMMI Radiopharm Chem. 2017; 1(1): 9 (accessible here).
• Colin DJ, Inkster JAH, Germain S, Seimbille Y. Preclinical validations of [18F]FPyPEGCBT-c(RGDfK): a 18F-labelled RGD peptide prepared by ligation of 2-cyanobenzothiazole and 1,2-aminothiol to image angiogenesis. EJNMMI Radiopharm Chem. 2016; 1-16 (accessible here).
• Chan HS, Konijnenberg MW, Daniels T, Nysus M, Makvandi M, de Blois E, Breeman WA, Atcher RW, de Jong M, Norenberg JP. Improved safety and efficacy of 213Bi-DOTATATE-targeted alpha therapy of somatostatin receptor-expressing neuroendocrine tumors in mice pre-treated with L-lysine. EJNMMI Res. 2016; 6(1): 83 (accessible here).
• Chan HS, Konijnenberg MW, de Blois E, Koelewijn S, Baum RP, Morgenstern A, Bruchertseifer F, Breeman WA, de Jong M. Influence of tumor size on the efficacy of targeted alpha therapy with (213)Bi-[DOTA(0), Tyr(3)]-octreotate. EJNMMI Res. 2016; 6(1): 6 (accessible here).
• Inkster J, Colin D, Seimbille Y. A novel 2-cyanobenzothiazole-based 18F prosthetic group for conjugation to 1,2-aminothiol-bearing targeting vectors. Organic and Biomolecular Chemistry. 2015; 13: 3667-3676 (accessible here).

Collaboration within Erasmus MC

• Prof. dr. Marion de Jong (Department of Radiology and Nuclear Medicine)
• Prof. dr. Clemens Löwik and Dr. Laura Mezanotte (Department of Radiology and Nuclear Medicine)
• Dr. Julie Nonnekens (Department of Molecular Genetics and Department of Radiology and Nuclear Medicine)
• Dr. Simone Dalm (Department of Radiology and Nuclear Medicine)
• Dr. Tessa Brabander (Department of Radiology and Nuclear Medicine)
• Dr. Astrid van der Veldt (Department of Oncology and Department of Radiology and Nuclear Medicine)
• Dr. Johannes Hofland (Department of Internal Medicine)
• Prof. dr. Frank Grosveld and Dr. Dubravka Drabek, (Department of Cell Biology)

Collaboration outside of Erasmus MC

• Prof. dr. Jason Lewis, Memorial Sloan Kettering Cancer Center (New-York, USA)
• Dr Cécile Perrio, University of Normandy (Caen, France)
• Prof. Paul Schaffer, Life Sciences Division, TRIUMF (Vancouver, Canada)
• Prof. Ferid Haddad, University of Nantes (Nantes, France)
• Dr Elisabeth Oehlke, FH Aachen University of applied Sciences (Aachen, Germany)
• Prof. Jianguo Lin and Dr Feng Gao, Jiangsu Institute of Nuclear Medicine (Wuxi, China)
• Prof. dr. Albert Windhorst and Dr Alex Poot, VUmc

• PI: Yann Seimbille, PhD – Assistant Professor
• Erik de Blois, PhD – Radiochemist
• Kuo-Ting Chen, PhD – Postdoctoral fellow
• Maryana Handula, MSc – Research Technician
• Jason Beaufrez, MSc – PhD student, Erasmus University and University of Normandy
• Erika Murce Silva, MSc – PhD student, Erasmus University
• Marc Stroet, MSc – PhD student, Erasmus University
• Jim Nieuwenhuizen (BSc student/intern)
• Erika Blaauw (BSc student/intern), MLO Techniek College Rotterdam
• Lucas Mues (BSc student/intern), FH Aachen University of applied Sciences