Therapeutic use of radiopharmaceuticals

Therapeutic use of radiopharmaceuticals

Radiopharmaceuticals that are used therapeutically are molecules with radiolabelling. This means that certain atoms in this molecule have been exchanged by their radioactive isotopes. These radiolabelled molecules are designed to deliver therapeutic doses of ionising radiation (mostly β-radiation) to specific disease sites around the body. The more specific the targeting is, the fewer the side effects expected. For any design of a treatment regime including radiopharmaceuticals, it is important to consider what the decay properties of the radionuclide are and what the clearance route and rate from nontarget radiosensitive tissue is.

1. ¹³¹Iodine: therapy for hyperthyroidism

Iodine has the chemical symbol I and atomic number 53. It is a member of the halogens (group 17 of the periodic table of elements) (Figure 10.13).

Elemental iodine is characterised by the purple colour of its vapour. Free iodine typically exists (like the other halogens) as the diatomic molecule I₂. Iodide (I⁻) is the highly water-soluble anion, which is mainly found in the oceans. Iodine and its compounds are mainly used in nutrition. It has relatively low toxicity and is easy to include into organic compounds, which has led to its application as part of many X-ray contrast agents. Iodine is required by humans to synthesise the thyroid hormones, and therefore iodine will accumulate in the thyroid gland. Iodine has only one stable isotope (¹²⁷₅₃I), but it has several radioactive isotopes. Some of these are used for medicinal purposes including diagnostic tests and treatment. Radioisotopes of iodine will accumulate in the thyroid gland and therefore can be used clinically. The radioactive isotope ¹²⁹I has a half-life of 15.7 million years, ¹²⁵I has 59 days and ¹²³I has 13 h. The last one is used in nuclear medicine as an imaging agent because of its gamma radiation and its short half-life. Using a gamma camera, images of the human body can be made showing areas of accumulation of the radioisotope.

 ¹³¹I is the product of nuclear fission (as experienced during the Chernobyl disaster) and is a β-emitting radioisotope which will be transported to the thyroid gland if inhaled. Fortunately, it can be replaced by treatment with potassium iodide (nonradioactive), which will replace the radioisotope. Nevertheless, ¹³¹I can be used as a therapeutic agent against thyroid cancer when applied in high doses. Paradoxically, the β-emitting radioisotope causes cancer when it is applied in low doses, but it will destroy its surrounding tissue if the dose is high enough. Therefore, preparations containing ¹³¹I⁻ are often used to treat hyperthyroidism. These preparations are normally administered orally either as capsules or solution.

2. ⁸⁹Strontium

Strontium is an alkaline-earth element with the atomic number 38, is a member of group 2 in the periodic table of elements and has the chemical symbol Sr (Figure 10.14).

Strontium is a soft grey metal and is more reactive with water than calcium. On contact with water, it pro-duces strontium hydroxide and hydrogen gas. In order to protect the element, strontium metal is usually kept under mineral oil to prevent oxidation. Natural strontium is formed of a mixture of four stable isotopes – ⁸⁴Sr, ⁸⁶Sr, ⁸⁷Sr and ⁸⁸Sr, with the last one being the predominant one.

 ⁸⁹Sr is an artificial radioisotope and is a β-emitter with a half-life of 50.5 days. It is a product of the neutron activation of ⁸⁸Sr and decays to the stable ⁸⁹yttrium. Metastron is a product containing ⁸⁹Sr and is licensed by the FDA. It comes in a ready-to-use vial and expires within 28 days. It is supplied with a calibration vial, so that the pharmacist will be able to ensure that the patients get the accurate dose prescribed .

Because of the similarity of strontium and calcium (neighbouring elements in the periodic table of ele-ments), strontium is believed to be metabolised in the human body in a similar way and accumulates, for example, in the bones. This has led to its application as a treatment option for pain caused by bone metastasis. It is known that >50% of patients with prostate, breast or lung cancer will develop painful bone metastasis. The exact mechanism of relief from bone pain is not known. ⁸⁹SrCl₂ is administered intravenously and, as its distribution in the human body is similar to that of calcium, it is quickly cleared from the blood and deposited in the bone mineral. Strontium can be found in the hydroxyapatite cells of the bones rather in bone marrow cells. The radioisotope ⁸⁹Sr delivers localised β-radiation, inducing a pain relieving effect. A majority of the administered SrCl₂ is actively distributed to the metastases. Any free SrCl₂ is excreted renally or along with the faeces .

Low platelet count is the most likely side effect occurring in patients being treated with ⁸⁹SrCl₂. Platelet counts should return to preadministration levels after 6 months once treatment is finished. Treatment with ⁸⁹SrCl₂ is not recommended in patients with an already low platelet or white blood cell count, and for patients receiving this treatment the blood parameters have to be regularly checked even after the treatment is completed.

3. Boron neutron capture therapy (BNCT)

Boron has two stable isotopes, ¹⁰B and ¹¹B, and 14 radioisotopes with very short half-lives. ¹¹B is the most abundant isotope and represents 80% of natural boron, whilst ¹⁰B (∼20%) finds a significant clinical appli-cation in the so-called boron neutron capture therapy (BNCT).

BNCT is a noninvasive treatment option for malignant tumours, especially brain tumours and head and neck cancers, and is currently under clinical trials. The patient is injected with a nonradioactive ¹⁰B-containing compound that acts as a neutron-capturing agent and shows high selectivity to cancer tissues. Once the compound has reached the tumour, the patient is exposed to a beam of low-energy neutrons, the so-called epithermal neutrons. These neutrons lose their energy once they penetrate the skin, but they can still interact with the neutron-capturing agent and initiate a nuclear reaction. This reaction of ¹⁰B with a neutron results in the conversion to the nonradioactive isotope ⁷Li and low-energy gamma radiation together with the emission of α-radiation (⁴₂He²⁺ particles). α-Radiation is a radiation with a short range and bombards the local tumour tissue from within the tumour cells. The linear energy transfer (LET) of these α-particles ranges approximately one cell diameter, which means there is minimum exposure to healthy tissue (Figure 10.15).

 ¹⁰B + n_th → [¹¹B]→⁴He+⁷Li + 2.31 MeV

A variety of carrier molecules for ¹⁰B have been investigated, including carbohydrates, antibodies, liposomes and amino acids. There are currently only two boron compounds as BNCT delivery agents used in clinical trials. Sodium mercaptoundecahydro-closo-dodecaborate (Na₂B₁₂H₁₁SH), known as borocaptate (BSH), was mainly used in clinical trials in Japan, whereas the boron-based amino acid (L)-4-dihydroxy-borylphenylalanine (BPA, boronophenylalanine) is used in clinical trials in Europe and the United states (Figure 10.16) [3, 4].