The folate receptor (FR) is a glycosylphophatidylinositol-anchored protein which is up-regulated in a wide variety of cancer types (FR-alpha) and on activated macrophages (FR-beta) involved in inflammatory diseases. In normal tissues and organs, the FR is highly restricted to only a few sites such as the kidneys. The vitamin folic acid (pteroylglutamic acid) has emerged as a promising FR-targeting ligand for selective delivery of conjugated imaging or therapeutic probes to FR-positive cancer and inflammatory cells. Application of folic acid as a molecular "Trojan Horse" is based on its high affinity for the FR, and receptor-mediated internalization via endocytosis. In Radiopharmaceutical Science the FR has been explored for targeting with folate-based radiopharmaceuticals useful for SPECT and PET imaging. The promising potential of these radiofolates has been shown in (pre)clinical imaging studies with mice bearing FR-positive tumor xenografts.
Figure 1: Derivatization of folic acid allows stable conjugation of a radioisotope. A variety of radiohalogens and radiometals emitting gamma-rays or positrons are useful for SPECT and PET imaging. Radioisotopes emitting alpha- or beta-particles of suitable energies are useful for targeted radionuclide tumor therapy. Upon binding of folate radioconjugates to the folate receptor (FR) the receptor/ligand complex is internalized via endocytosis resulting in specific radioactivity deposition in FR-positive tumor cells.
Figure 2: Nude mouse with FR-positive KB tumors 48 hours after injection of a 177Lu-radiolabeled folate conjugate. Accumulation of radioactivity is visible in tumor xenografts (green arrows) and in the kidneys (yellow arrows).
Our research goal is the development and application of novel folate conjugates for radiolabeling with diagnostic radioisotopes for SPECT (99mTc, 111In, 67Ga) and PET (18F, 68Ga, 44Sc) and with radioisotopes emitting beta-particles (177Lu, 161Tb) or alpha-particles (149Tb) for therapeutic application. By chemical modification of the folate conjugates and/or a combined application with chemotherapeutics or other substances, we aim to improve the pharmacokinetic profile of the radiofolates in order to obtain selective retention at sites of malignancies or inflammation. Minimizing undesired accumulation of radioactivity in the kidneys is of particular interest for targeted radionuclide anticancer therapy because of the risk to damage radiosensitive renal tissue by particle-emitting radiation.
Our research activities comprise the chemical preparation of folate conjugates and subsequent labeling with various radionuclides. Evaluation of the compounds is performed by means of in vitro experiments (e.g. tumor cells) and in biodistribution studies in mice bearing FR-positive tumor xenografts. Imaging studies are performed with designated small-animal SPECT/CT or PET/CT cameras. In order to assess the anticancer activity of a particular radiofolate we employ different methods of in vitro and in vivo tests. These procedures allow development of folate-based radiopharmaceuticals from bench to bed-side.
Diastereomerically Pure 6R- and 6S-3'-aza-2'-18F-Fluoro-5-Methyltetrahydrofolates Show Unprecedented High Uptake in Folate Receptor-positive KB TumorsBoss SD, Müller C, Siwowska K, Schmid RM, Groehn V, Schibli R, Ametamey SM
Imaging of Folate Receptor Expressing Macrophages in the Rat Groove Model of Osteoarthritis: Using a New DOTA-Folate Conjugatede Visser HM, Korthagen NM, Müller C, Ramakers RM, Krijger GC, Lafeber FPJG, Beekman FJ, Mastbergen SC, Weinans H
47Sc as useful β–-emitter for the radiotheragnostic paradigm: a comparative study of feasible production routesDomnanich KA, Müller C, Benešová M, Dressler R, Haller S, Köster U, Ponsard B, Schibli R, Türler A, van der Meulen NP
EJNMMI RADIOPHARMACY AND CHEMISTRY2,
Production and separation of 43Sc for radiopharmaceutical purposesDomnanich KA, Eichler R, Müller C, Jordi S, Yakusheva V, Braccini S, Behe M, Schibli R, Türler A, van der Meulen NP
EJNMMI RADIOPHARMACY AND CHEMISTRY2,
Synthesis, Radiolabeling, and Characterization of Plasma Protein-Binding Ligands: Potential Tools for Modulation of the Pharmacokinetic Properties of (Radio)PharmaceuticalsMüller C, Farkas R, Borgna F, Schmid RM, Benešová M, Schibli R
Clinical evaluation of the radiolanthanide terbium-152: first-in-human PET/CT with 152Tb-DOTATOCBaum RP, Singh A, Benešová M, Vermeulen C, Gnesin S, Köster U, Johnston K, Müller D, Senftleben S, Kulkarni HR, Türler A, Schibli R, Prior JO, van der Meulen NP, Müller C
First-in-Human PET/CT Imaging of Metastatic Neuroendocrine Neoplasms with Cyclotron-Produced 44Sc-DOTATOC: A Proof-of-Concept StudySingh A,van der Meulen NP, Müller C, Klette I, Kulkarni HR, Türler A, Schibli R, Baum RP
CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS32,
44Sc-PSMA-617 for radiotheragnostics in tandem with 177Lu-PSMA-617-preclinical investigations in comparison with 68Ga-PSMA-11 and 68Ga-PSMA-617Umbricht CA, Benešová M, Schmid RM, Türler A, Schibli R, van der Meulen NP, Müller C
Preclinical Comparison of Albumin-Binding Radiofolates: Impact of Linker Entities on the in Vitro and in Vivo PropertiesSiwowska K, Haller S, Bortoli F, Benešová M, Groehn V, Bernhardt P, Schibli R, Müller C
44Sc for labeling of DOTA- and NODAGA functionalized peptides: preclinical in vitro and in vivo investigationsDomnanich KA, Müller C, Farkas R, Schmid RM, Ponsard B, Schibli S, Türler A, van der Meulen NP
Evaluation of the first 44Sc-labeled Affibody molecule for imaging of HER2-expressing tumorsHonarvar H, Müller C, Cohrs S, Haller S, Westerlund K, Karlström AE, van der Meulen NP, Schibli R, Tolmachev V
(64)Cu- and (68)Ga-Based PET Imaging of Folate Receptor-Positive Tumors: Development and Evaluation of an Albumin-Binding NODAGA-FolateFarkas R, Siwowska K, Ametamey SM, Schibli R, van der Meulen NP, Müller C
Contribution of Auger/conversion electrons to renal side effects after radionuclide therapy: preclinical comparison of (161)Tb-folate and (177)Lu-folateHaller S, Pellegrini G, Vermeulen C, van der Meulen NP, Köster U, Bernhardt P, Schibli R, Müller C
Triamcinolone acetonide activates an anti-inflammatory and folate receptor-positive macrophage that prevents osteophytosis in vivoSiebelt M, Korthagen N, Wei W, Groen H6, Bastiaansen-Jenniskens Y, Müller C, Waarsing JH, de Jong M, Weinans H
Inhibited osteoclastic bone resorption through alendronate treatment in rats reduces severe osteoarthritis progressionSiebelt M, Waarsing JH, Groen HC, Müller C, Koelewijn SJ, de Blois E, Verhaar JA, de Jong M, Weinans H
Promising Prospects for 44Sc-/47Sc-Based Theragnostics: Application of 47Sc for Radionuclide Tumor Therapy in MiceMüller C, Bunka M, Haller S, Köster U, Groehn V, Bernhardt P, van der Meulen N, Türler A, Schibli R
Future prospects for SPECT imaging using the radiolanthanide terbium-155 - production and preclinical evaluation in tumor-bearing miceMüller C, Fischer E, Behe M, Köster U, Dorrer H, Reber J, Haller S, Cohrs S, Blanc A, Grünberg J, Bunka M, Zhernosekov K, van der Meulen N, Johnston K, Türler A, Schibli R