Abstract
Targeted radionuclide therapy is based on systemic application of particle-emitting radiopharmaceuticals which are directed toward a specific tumor-associated target. Accumulation of the radiopharmaceutical in targeted cancer cells results in high doses of absorbed radiation energy whereas toxicity to non-targeted healthy tissue is limited. This strategy has found widespread application in the palliative treatment of neuroendocrine tumors using somatostatin-based radiopeptides. The folate receptor (FR) has been identified as a target associated with a variety of frequent tumor types (e.g., ovarian, lung, brain, renal, and colorectal cancer). In healthy organs and tissue FR-expression is restricted to only a few sites such as for instance the kidneys. This demonstrates why FR-targeting is an attractive strategy for the development of new therapy concepts. Due to its high FR-binding affinity (KD < 10−9 M) the vitamin folic acid has emerged as an almost ideal targeting agent. Therefore, a variety of folic acid radioconjugates for nuclear imaging have been developed. However, in spite of the large number of cancer patients who could benefit of a folate-based radionuclide therapy, a therapeutic concept with folate radioconjugates has not yet been envisaged for clinical application. The reason is the generally high accumulation of folate radioconjugates in the kidneys where emission of particle-radiation may result in damage to the renal tissue. Therefore, the design of more sophisticated folate radioconjugates providing improved tissue distribution profiles are needed. This review article summarizes recent developments with regard to a therapeutic application of folate radioconjugates. A new construct of a folate radioconjugate and an application protocol which makes use of a pharmacological interaction allowed the first preclinical therapy experiments with radiofolates. These results raise hope for future application of such new concepts also in the clinic.
Highlights
FOLATE RECEPTOR AND FOLIC ACIDFolate receptors (FRs) are glycoproteins with molecular weights of 38–44 kDa which exist in several isoforms [1, 2]
The drawback of a high renal accumulation of conventional radiofolates can largely be overcome by co-application of the antifolate pemetrexed or by a chemical modification of the folate radioconjugate with an albumin-binding entity
Both strategies resulted in significantly increased tumor-to-kidney ratios and allowed the performance of preclinical therapy studies using particle-emitting isotopes
Summary
Folate receptors (FRs) are glycoproteins with molecular weights of 38–44 kDa which exist in several isoforms [1, 2]. Evaluation of a large number of non-small cell lung cancers revealed that high FR-expression levels correlated with a better survival [14]. Folic acid is small in size (441 Da) and accessible for chemical modification. It is relatively stable in solution of a wide range of pH-values and at elevated temperatures [22]. Since binding to the FR results in an endocytotic uptake of folic acid cellular delivery of even larger payloads which are conjugated to folic acid is accessible [23, 24] All of these features together make folic acid an excellent candidate for tumor targeting allowing selective delivery of attached probes to FR-expressing (cancer) cells
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