folic acid; tumor targeting; folate receptor; Vitamin; SPECT; Imaging; Therapy; Radiopharmaceutical; Cancer; Inflammation
Groehn V, Moser R, Ross TL, Betzel T, Muller C, Schibli R, Ametamey S (2011), Synthesis of Precursors for F-18-Labeling of Folic Acid for PET Application, in SYNTHESIS-STUTTGART
, (22), 3639-3648.
Piscaer TM, Muller C, Mindt TL, Lubberts E, Verhaar JAN, Krenning EP, Schibli R, De Jong M, Weinans H (2011), Imaging of Activated Macrophages in Experimental Osteoarthritis Using Folate-Targeted Animal Single-Photon-Emission Computed Tomography/Computed Tomography, in ARTHRITIS AND RHEUMATISM
, 63(7), 1898-1907.
Muller C, Vlahov IR, Santhapuram HKR, Leamon CP, Schibli R (2011), Tumor targeting using Ga-67-DOTA-Bz-folate - investigations of methods to improve the tissue distribution of radiofolates, in NUCLEAR MEDICINE AND BIOLOGY
, 38(5), 715-723.
Muller C, Schibli R (2010), Folic Acid Conjugates for Nuclear Imaging of Folate Receptor-Positive Cancer, in JOURNAL OF NUCLEAR MEDICINE
, 52(1), 1-4.
Ross TL, Honer M, Muller C, Groehn V, Schibli R, Ametamey SM (2010), A New F-18-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor Positive Tumors, in JOURNAL OF NUCLEAR MEDICINE
, 51(11), 1756-1762.
Muller C, Reddy JA, Leamon CP, Schibli R (2010), Effects of the Antifolates Pemetrexed and CB3717 on the Tissue Distribution of Tc-99m-EC20 in Xenografted and Syngeneic Tumor-Bearing Mice, in MOLECULAR PHARMACEUTICS
, 7(2), 597-604.
Müller C, Schibli R, Folate Receptor Targeted Radionuclide Imaging Agents, in Jackman and Leamon (ed.), Springer Science & Business Media, LLC, 65-92.
Background: The vitamin folic acid has emerged as promising targeting ligand for selective delivery of attached imaging and therapeutic probes to cancer tissues and sites of inflammation. The utility of folic acid as a “Trojan Horse” has arisen from its favorable characteristics. It is small in size and stable under various conditions and therefore relatively easy accessible for chemical modification. As a vitamin it is essential for the organism and consequently non-immunogenic. Importantly, folic acid features high affinity for the folate receptor (FR), even after conjugation to its diagnostic/therapeutic cargo. In normal tissues and organs the FR is highly restricted despite its upregulation on both, cancer cells (FR-alpha) and activated macrophages (FR-beta), frequently involved in inflammatory diseases. Numerous publications report the usefulness of folic acid as a molecular “Trojan Horse” for both diagnostic and therapeutic purposes.In radiopharmaceutical science the FR has been explored for targeting with folate radiopharmaceuticals for SPECT and PET. In (pre)clinical trials radiofolates have shown a promising potential as imaging agents of FR-positive pathologic cells. A problematic issue of the FR-targeting strategy is, however, the expression of FRs in the kidneys, resulting in a high and specific renal accumulation of radioactivity. Therefore, the development and application of radiofolate-based therapy has not yet been envisaged since particle-emitting radiation could cause severe nephrotoxicity. During the last six years, folate derivatives for radiolabeling with 99mTc/188Re or 111In/177Lu have been synthesized and biologically evaluated in our group. Biodistribution and imaging studies with mice showed specific accumulation of the radiofolates in FR-positive tumor xenografts but also in FR-positive kidneys. The result thereof is unfavorably low tumor-to-kidney ratios of radioactivity. However, in recent studies we found a significant kidney blockade without affecting the tumor uptake when radiofolates were applied in combination with an antifolate (e.g. pemetrexed). With this findings we reached the edge towards the development of folate-based radionuclide therapy. Goals: Based on our previous work and experience and a detailed study in the literature, we identified the following goals that we wish to tackle. The therapeutic approach using radiofolates of particle-emitting radiation should be addressed as our primary aim. First, we want to apply the therapeutic approach on FR-positive cancer cells in vitro in order to investigate the antitumor effect of radiofolates alone and in combination with antifolates. In a second step we plan to translate our experience from in vitro studies to the in vivo situation and apply folate-based radionuclide therapy in combination with antifolate preinjection/treatment. Parallel to this, the effects of antifolates on radiofolate uptake in tumor and normal cells will be investigated in vitro and in vivo. Understanding the “antifolate-effect” is in particular important with regard to a potential translation of the approach into a clinical setting. Another goal is the design of novel folate conjugates. By chemical modifications we wish to improve the overall pharmacokinetic profile of radiofolates and, more specifically, we aim for a more selective targeting of pathologic cells while minimizing toxicity to healthy tissues. Since FR-targeting is also useful for imaging/therapy of the FR-? on activated macrophages in inflammatory diseases, we plan to investigate this additional field. In this context we have started collaborations with groups experienced in the field of inflammatory diseases.Expected Value of the Proposal: Implementation of our project will enable the understanding of several yet unexplored, but interesting and unanswered questions. To answer the questions of how FRs and other (anti)folate transport mechanisms are functioning in pathologic and healthy cells and how they can be modulated or blocked is important for all FR-targeting strategies. Application of folate-based radionuclide therapy would represent a mile-stone in the field of nuclear medicine. Ovarian cancer is one example of a tumor type that frequently (> 90 % of the cases) expresses the FR. This cancer type is the fifth leading cause of cancer deaths in women. One out of 40-60 women have a lifetime chance to develop this malignancy. Surgery is the preferred treatment, however, it is only sufficient for malignant tumors that are well-differentiated and confined to the ovary. The development of FR-targeted diagnosis and therapy is not only restricted to cancer but could be employed also for inflammatory diseases that involve activated macrophages such as e.g. rheumatoid arthritis. Rheumatoid arthritis is the most frequent chronic inflammatory autoimmune disorder. A disabling and painful inflammatory condition is the consequence that could possibly end in substantial loss of mobility due to pain and joint destruction. The incidence of rheumatoid arthritis is about 3 cases per 10`000 people per year and the prevalence 1 % of the population.Taken these issues into account, the development of folate-based radiopharmaceuticals for diagnostic and in particular therapeutic purposes is of critical value. Only early and reliable diagnosis and effective treatment modalities can help to face this set of healthy problems that is rapidly growing in the western population.