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.