Nuclide Chemistry

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 tum…
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).
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).

Research Goals

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.

Research Activities

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.

2018

  • Visualisation of interstitial lung disease by molecular imaging of integrin αvβ3 and somatostatin receptor 2 Schniering J, Benešová M, Brunner M, Haller S, Cohrs S, Frauenfelder T, Vrugt B, Feghali-Bostwick CA, Schibli R, Distler O, Mueller C, Maurer B
    ANNALS OF THE RHEUMATIC DISEASES , (2018).
    DOI: annrheumdis-2018-214322
  • Design and Preclinical Evaluation of an Albumin-Binding PSMA Ligand for 64Cu-Based PET Imaging Umbricht CA, Benešová M, Hasler R, Schibli R, van der Meulen NP, Müller C
    MOLECULAR PHARMACEUTICS , (2018).
    DOI: acs.molpharmaceut.8b00712
  • In Vivo Labeling of Plasma Proteins for Imaging of Enhanced Vascular Permeability in the Lungs Schniering J, Borgna F, Siwowska K, Benešová M, Cohrs S, Hasler R, van der Meulen NP, Maurer B, Schibli R, Müller C
    MOLECULAR PHARMACEUTICS 15, 4995 (2018).
    DOI: acs.molpharmaceut.8b00606
  • Diastereomerically Pure 6R- and 6S-3'-aza-2'-18F-Fluoro-5-Methyltetrahydrofolates Show Unprecedented High Uptake in Folate Receptor-positive KB Tumors Boss SD, Müller C, Siwowska K, Schmid RM, Groehn V, Schibli R, Ametamey SM
    JOURNAL OF NUCLEAR MEDICINE , (2018).
    DOI: jnumed.118.213314
  • Pharmacological upregulation of prostate-specific membrane antigen (PSMA) expression in prostate cancer cells Kranzbühler B, Salemi S, Umbricht CA, Müller C, Burger IA, Sulser T, Eberli D
    PROSTATE 78, 758 (2018).
    DOI: pros.23522
  • Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates Müller C, Guzik P, Siwowska K, Cohrs S, Schmid RM, Schibli R
    MOLECULES 23, E1465 (2018).
    DOI: molecules23061465
  • Scandium and terbium radionuclides for radiotheranostics: current state of development towards clinical application Müller C, Domnanich KA, Umbricht CA, van der Meulen NP
    BRITISH JOURNAL OF RADIOLOGY , (2018).
    DOI: bjr.20180074
  • Preclinical Development of Novel PSMA-Targeting Radioligands: Modulation of Albumin-Binding Properties To Improve Prostate Cancer Therapy Umbricht CA, Benešová M, Schibli R, Müller C
    MOLECULAR PHARMACEUTICALS , (2018).
    DOI: acs.molpharmaceut.8b00152
  • Imaging of Folate Receptor Expressing Macrophages in the Rat Groove Model of Osteoarthritis: Using a New DOTA-Folate Conjugate de Visser HM, Korthagen NM, Müller C, Ramakers RM, Krijger GC, Lafeber FPJG, Beekman FJ, Mastbergen SC, Weinans H
    CARTILAGE 9, 183 (2018).
    DOI: 1947603517738073
  • Albumin-Binding PSMA Ligands: Optimization of the Tissue Distribution Profile Benešová M, Umbricht CA, Schibli R, Müller C
    MOLECULAR PHARMACEUTICS 15, 934 (2018).
    DOI: acs.molpharmaceut.7b00877
  • Reduced 18F-Folate Conjugates as a New Class of PET Tracers for Folate Receptor Imaging Boss SD, Müller C, Siwowska K, Büchel JI, Schmid RM, Groehn V, Schibli R, Ametamey SM
    BIOCONJUGATE CHEMISTRY 29, 1119 (2018).
    DOI: acs.bioconjchem.7b00775

2017

  • 47Sc as useful β–-emitter for the radiotheragnostic paradigm: a comparative study of feasible production routes Domnanich KA, Müller C, Benešová M, Dressler R, Haller S, Köster U, Ponsard B, Schibli R, Türler A, van der Meulen NP
    EJNMMI RADIOPHARMACY AND CHEMISTRY 2, 5 (2017).
    DOI:
  • Production and separation of 43Sc for radiopharmaceutical purposes Domnanich KA, Eichler R, Müller C, Jordi S, Yakusheva V, Braccini S, Behe M, Schibli R, Türler A, van der Meulen NP
    EJNMMI RADIOPHARMACY AND CHEMISTRY 2, 14 (2017).
    DOI:
  • Synthesis, Radiolabeling, and Characterization of Plasma Protein-Binding Ligands: Potential Tools for Modulation of the Pharmacokinetic Properties of (Radio)Pharmaceuticals Müller C, Farkas R, Borgna F, Schmid RM, Benešová M, Schibli R
    BIOCONJUGATE CHEMISTRY 28, 2372 (2017).
    DOI: acs.bioconjchem.7b00378
  • Therapeutic Radiometals Beyond 177Lu and 90Y: Production and Application of Promising α-Particle, β--Particle, and Auger Electron Emitters Müller C, van der Meulen NP, Benešová M, Schibli R
    JOURNAL OF NUCLEAR MEDICINE 58 (Suppl 2), 91S (2017).
    DOI: jnumed.116.186825
  • Clinical evaluation of the radiolanthanide terbium-152: first-in-human PET/CT with 152Tb-DOTATOC Baum 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
    DALTON TRANSACTION 46, 14638 (2017).
    DOI: c7dt01936j
  • Folate Receptor-Positive Gynecological Cancer Cells: In Vitro and In Vivo Characterization Siwowska K, Schmid RM, Cohrs S, Schibli R, Müller C
    PHARMACEUTICALS (BASEL) 10, E72 (2017).
    DOI: ph10030072
  • A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice Pellegrini G, Siwowska K, Haller S, Antoine DJ, Schibli R, Kipar A, Müller C
    PHARMACEUTICALS (BASEL) 10, E57 (2017).
    DOI: ph10020057
  • First-in-Human PET/CT Imaging of Metastatic Neuroendocrine Neoplasms with Cyclotron-Produced 44Sc-DOTATOC: A Proof-of-Concept Study Singh A,van der Meulen NP, Müller C, Klette I, Kulkarni HR, Türler A, Schibli R, Baum RP
    CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS 32, 124 (2017).
    DOI: cbr.2016.2173
  • 44Sc-PSMA-617 for radiotheragnostics in tandem with 177Lu-PSMA-617-preclinical investigations in comparison with 68Ga-PSMA-11 and 68Ga-PSMA-617 Umbricht CA, Benešová M, Schmid RM, Türler A, Schibli R, van der Meulen NP, Müller C
    EJNMMI RESEARCH 7, 9 (2017).
    DOI: s13550-017-0257-4
  • Preclinical Comparison of Albumin-Binding Radiofolates: Impact of Linker Entities on the in Vitro and in Vivo Properties Siwowska K, Haller S, Bortoli F, Benešová M, Groehn V, Bernhardt P, Schibli R, Müller C
    MOLECULAR PHARMACEUTICS 14, 523 (2017).
    DOI: acs.molpharmaceut.6b01010

2016

  • 44Sc for labeling of DOTA- and NODAGA functionalized peptides: preclinical in vitro and in vivo investigations Domnanich KA, Müller C, Farkas R, Schmid RM, Ponsard B, Schibli S, Türler A, van der Meulen NP
    EJNMMI RADIOPHARMACY AND CHEMISTRY 1, 5 (2016).
    DOI: s41181-016-0013-5
  • Alpha-PET with terbium-149: evidence and perspectives for radiotheragnostics Müller C, Vermeulen C, Köster U, Johnston K, Türler A, Schibli R, van der Meulen NP
    EJNMMI RADIOPHARMACY AND CHEMISTRY 1, 5 (2016).
    DOI: s41181-016-0008-2
  • Preclinical in vivo application of (152)Tb-DOTANOC: a radiolanthanide for PET imaging Müller C, Vermeulen C, Johnston K, Köster U, Schmid R, Türler A, van der Meulen NP
    EJNMMI RESEARCH 6, 35 (2016).
    DOI: s13550-016-0189-4
  • Evaluation of the first 44Sc-labeled Affibody molecule for imaging of HER2-expressing tumors Honarvar H, Müller C, Cohrs S, Haller S, Westerlund K, Karlström AE, van der Meulen NP, Schibli R, Tolmachev V
    NUCLEAR MEDICINE AND BIOLOGY 45, 15 (2016).
    DOI: j.nucmedbio.2016.10.004
  • (64)Cu- and (68)Ga-Based PET Imaging of Folate Receptor-Positive Tumors: Development and Evaluation of an Albumin-Binding NODAGA-Folate Farkas R, Siwowska K, Ametamey SM, Schibli R, van der Meulen NP, Müller C
    MOLECULAR PHARMACEUTICS 13, 1979 (2016).
    DOI: acs.molpharmaceut.6b00143
  • Contribution of Auger/conversion electrons to renal side effects after radionuclide therapy: preclinical comparison of (161)Tb-folate and (177)Lu-folate Haller S, Pellegrini G, Vermeulen C, van der Meulen NP, Köster U, Bernhardt P, Schibli R, Müller C
    EJNMMI RESEARCH 1, 13 (2016).
    DOI: s13550-016-0171-1
  • Imaging quality of (44)Sc in comparison with five other PET radionuclides using Derenzo phantoms and preclinical PET Bunka M, Müller C, Vermeulen C, Haller S, Türler A, Schibli R, van der Meulen NP
    APPLIED RADIATION AND ISOTOPES 110, 129 (2016).
    DOI: j.apradiso.2016.01.006
  • Comparative Studies of Three Pairs of α- and γ-Conjugated Folic Acid Derivatives Labeled with Fluorine-18 Boss SD, Betzel T, Müller C, Fischer CR, Haller S, Reber J, Groehn V, Schibli R, Ametamey SM
    BIOCONJUGATE CHEMISTRY 27, 74 (2016).
    DOI: acs.bioconjchem.5b00644

2015

  • Folate receptor-targeted radionuclide therapy: preclinical investigation of anti-tumor effects and potential radionephropathy Haller S, Reber J, Brandt S, Bernhardt P, Groehn V, Schibli R, Müller C
    NUCLEAR MEDICINE AND BIOLOGY 42, 770 (2015).
    DOI: j.nucmedbio.2015.06.006
  • Cyclotron production of (44)Sc: From bench to bedside van der Meulen NP, Bunka M, Domnanich KA, Müller C, Haller S, Vermeulen C, Türler A, Schibli R
    NUCLEAR MEDICINE AND BIOLOGY 42, 745 (2015).
    DOI: j.nucmedbio.2015.05.00
  • Triamcinolone acetonide activates an anti-inflammatory and folate receptor-positive macrophage that prevents osteophytosis in vivo Siebelt M, Korthagen N, Wei W, Groen H6, Bastiaansen-Jenniskens Y, Müller C, Waarsing JH, de Jong M, Weinans H
    ARTHRITIS RESEARCH & THERAPY 17, 352 (2015).
    DOI: s13075-015-0865-1
  • Investigation of the chick embryo as a potential alternative to the mouse for evaluation of radiopharmaceuticals Haller S, Ametamey SM, Schibli R, Müller C
    NUCLEAR MEDICINE AND BIOLOGY 42, 226 (2015).
    DOI: j.nucmedbio.2014.10.010
  • Folate Receptor-Targeted Multimodality Imaging of Ovarian Cancer in a Novel Syngeneic Mouse Model Ocak M, Gillman AG, Bresee J, Zhang L, Vlad AM, Müller C, Schibli R, Edwards WB, Anderson CJ, Gach HM
    MOLECULAR PHARMACEUTICS 12, 542 (2015).
    DOI: mp500628g

2014

  • Inhibited osteoclastic bone resorption through alendronate treatment in rats reduces severe osteoarthritis progression Siebelt M, Waarsing JH, Groen HC, Müller C, Koelewijn SJ, de Blois E, Verhaar JA, de Jong M, Weinans H
    BONE 66, 163 (2014).
    DOI: j.bone.2014.06.009
  • Investigation of the chick embryo as a potential alternative to the mouse for evaluation of radiopharmaceuticals Haller S, Ametamey SM, Schibli R, Müller C
    NUCLEAR MEDICINE AND BIOLOGY , (2014).
    DOI: j.nucmedbio.2014.10.010
  • Direct in vitro and in vivo comparison of (161)Tb and (177)Lu using a tumour-targeting folate conjugate Müller C, Reber J, Haller S, Dorrer H, Bernhardt P, Zhernosekov K, Türler A, Schibli R
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 41, 476 (2014).
    DOI: s00259-013-2563-z
  • Promising Prospects for 44Sc-/47Sc-Based Theragnostics: Application of 47Sc for Radionuclide Tumor Therapy in Mice Müller C, Bunka M, Haller S, Köster U, Groehn V, Bernhardt P, van der Meulen N, Türler A, Schibli R
    JOURNAL OF NUCLEAR MEDICINE 55, 1658 (2014).
    DOI: jnumed.114.141614
  • Folate receptor targeted alpha-therapy using terbium-149 Müller C, Reber J, Haller S, Dorrer H, Köster U, Johnston K, Zhernosekov K, Türler A, Schibli R
    PHARMACEUTICALS (BASEL) 7, 353 (2014).
    DOI: ph7030353
  • Future prospects for SPECT imaging using the radiolanthanide terbium-155 - production and preclinical evaluation in tumor-bearing mice Müller 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
    NUCLEAR MEDICINE AND BIOLOGY 41, Suppl:e58 (2014).
    DOI: j.nucmedbio.2013.11.002

Contact

Cristina Müller
Group leader
OIPA/101
5232 Villigen PSI
Switzerland

 

Telephone:
+41 56 310 4454
Fax:
+41 56 310 2849
E-mail:
cristina.mueller@psi.ch
 

Group members:

Francesca Borgna
Susan Cohrs
Luisa Deberle
Hsin-Yu Fang
Patrycja Guzik
Fan Sozzi-Guo
Viviane Tschan

Directions to PSI

How to get to the Paul Scherrer Institute (description and map)