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Radiopharmazeutische Chemie

Prinzipien der Radiopharmazie

Therapies based on radionuclides

Molecular imaging plays a pivotal role in todays individualized therapy strategies. Beyond this, the tracers used in nuclear medicine procedures provide the possibility to achieve tumor selective therapeutics. The efficiency of systemic tumor treatments is limited by the side effects. As a result, the value of any treatment modality is defined by specificity of the effect on the tumor versus the dose limiting organs. The ratios achieved with the standard chemotherapeutics are not sufficient for an effective treatment of most solid tumors. Radionuclides can be used for treatment purposes in analogy to radiation therapies combined with radiological imaging methods such as CT (Figure 1). 

Figure 1: PET imaging and endoradiotherapy, the main pillars of nuclear medicine, are applied in analogy to the matched pair CT/radiation therapy.

This can be exploited to improve the limits of the current treatment of solid tumors. As shown in Figure 2, surgery and radiation therapy, still the main treatment modalities can only be applied to tumors above the limit of detection (typically 1 cm in diameter). These tumors are generally a very aggressive phenotype, disseminated disease is not amenable to both modalities. Once metastasized, the treatment of choice is drug therapy. However, the standard chemotherapeutics do not achieve selective tumor uptake.

Figure 2: The progression of solid tumors and the corresponding means of therapy. Most tumors exist in a silent phenotype. After an angiogenic switch the tumor acquires blood supply and thus turns into the aggressive form observed clinically. Radiation therapy and surgery, the treatment modalities of choice, can only be applied for tumors above the limit of detection – the aggressive phenotype – this limits their potential resulting in the poor outcome of today’s tumor treatment. Tumors below the limit of detection and very importantly disseminated disease are only amenable to drug therapy. While the standard chemotherapeutic drugs do not provide tumor specificity, most endoradiotherapeutic drugs specifically target tumor tissue.

The application of targeted therapies using cytotoxic radioisotopes (alpha or beta emitting isotopes) has been shown to provide the ratios required to treat patients with different tumors that were resistant to all other therapies and to demonstrate the possibility to go beyond the potential of all known systemic treatment modalities. Prime examples for this efficacy are 90Y-DOTATOC (neuroendocrine tumors), 90Y-Zevalin (non-Hodgkin lymphoma), 131I-Benzamides (melanoma), 131I-Iodide (cancers of the thyroid), 223Ra-Xofigo (prostate tumor metastases) and 131I-MIP1466 (prostate tumors). As visualized in Figure 3 this presents a groundbreaking option for the therapy of oncological diseases. Generally, two strategies can be followed to enhance the efficacy of tumor therapies. As the efficacy of any tumor treatment is defined by the quotient of the effect on tumor versus the dose limiting organs, these strategies are a) specific action of the cytotoxic agent on tumor cells and b) specific uptake of the cytotoxic agent.

Figure 3: A) The dose-effect-correlation observed for therapeutic approaches. The width of the therapeutic window can be increased by either compounds with specific action on tumor cells (i.e. kinase inhibitors such as Glivec) or by compounds that specifically accumulate in the diseased tissue. B) shows the specific uptake of 124I-MIP1466, a theranostic compound for the diagnosis and treatment of prostate tumor patients. C) Specific uptake of 68Ga-DOTATOC in a patient with a massive liver infiltration by metastases of a neuroendocrine tumor.