Biomedical applications of radiopharmaceuticals

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Chapter: Pharmaceutical Drugs and Dosage: Radiopharmaceuticals

There are about 200 radioisotopes that are in current medical use. Radioisotopes can be employed as either radiation sources, for radiotherapy applications, or as radioactive tracers, which are commonly used as diagnostic agents.


Biomedical applications of radiopharmaceuticals

There are about 200 radioisotopes that are in current medical use. Radioisotopes can be employed as either radiation sources, for radiotherapy applications, or as radioactive tracers, which are commonly used as diag-nostic agents. They are also used to determine the biodistribution of particu-lar compounds (in which those radioisotopes are incorporated).


Radioactive tracers and diagnosis

Use of radioisotopes as tracers and diagnostic agents depends on the ease of detection of the radiation emitted by the isotope and the ability of the isotopic element to be incorporated into the molecule that is being traced (such as during the biodistribution studies of new drug candi-dates). As diagnostic agents, radioactive elements are typically adsorbed or incorporated on a carrier. Thus, chemical identity, ability to use dur-ing synthesis, and the form of the radioisotopes are important for their applications as tracers and diagnostic agents. Diagnostic uses of radio-isotopes can be exemplified by thyroid function studies using low dose 131I, erythrocyte tagging for identification of type of anemia using 51Cr, and metabolic studies using 14C. The 14C radioisotope detection in breath can be used to detect the presence of ulcer-causing bacteria Helicobacter pylori. There is an increasing preference for the use of nonradioactive methods of analyses, wherever possible, due to the handling risks associated with radioactive isotopes.

For the use of radioisotopes as diagnostic agents and tracers, the dose of radiation administered to the patients or normal healthy volunteers should be as low as possible, while maintaining accuracy and sensitivity of analytical detection. Thus, the radioisotopes for diagnostic use should ideally be compounds with low half-life that exhibit rapid elimination kinetics and are administered in low doses. Typically, radioisotopes that emit gamma rays are used for diagnostic use, since gamma rays are the most penetrating; the radiation does not stay in the body and is quickly received by the detector. Specialized analytical methods are often devel-oped to analyze low concentration of radioisotopes in plasma and tissue samples.

Technetium-99m (99mTc)—a metastable nuclear isomer of technetium-99 (99Tc), with a half-life of about 6 hours and biological elimination half-life of about 1 day, is the most common radioisotope used in medicine. 99Tc is sourced at the hospitals from its more stable and easily transportable parent isotope, molybdenum-99 (99Mo), with a half-life of about 66 hours, in lead containers. The hospital extracts and uses the needed quantities of 99mTc, as 99Mo degrades to 99mTc.


Radiotherapy

Use of radioisotopes as radiation sources for radiotherapy aims to utilize the tissue damage that results from radiation to, for example, reduce the amount of cancerous tissue. Selection of radioisotopes as radiotherapy agents depends mainly on the type and energy of radiation emitted by the isotope and its depth of tissue penetration. Chemical identity and reactivity are of relatively less importance for radiotherapy applications.

Radioisotopes used for therapy can be applied to the target tissue either from an external source or on administration to the patient as a drug.

1. External source application of radiation has the advantages of dura-tion and amount of dose titration, with direct observation of the target tissue, and of being able to remove the radiation source—and terminate treatment—at any time. Radioisotopes used for external therapy are exemplified by cobalt (60Co) and cesium (137Cs). They have been used for the treatment of undesired lesions.

2. Internal application, or administration of the radiotherapy agent to the patient, has a limitation that the source of radiation cannot be removed once administered. Therefore, the amount of radio-isotope administered to the patient must be carefully controlled. Radioisotopes that have been used for internal therapy include gold (198Au), iridium (192Ir), phosphorus (32P as sodium phosphate), yttrium (90Y), iodine (131I as sodium iodide), and palladium (103P).

·           Colloidal gold (198Au) suspensions have been used in the cases of fluid accumulation in the abdomen (peritoneal cavity) or chest (plural cavity), associated with malignant tumors. The colloidal suspension diffuses throughout the fluid and, over time, tends to aggregate at the surface of the cavity.

·           Nylon ribbons containing iridium (192Ir) seeds at periodic inter-vals can be implanted into the interstitial cavity, such as abdom-inal, for the treatment of tumors. These ribbons are surgically removable.

·           Radiophosphorus (32P) can be injected parenterally as a solution of a highly soluble sodium salt. The phosphorus tends to accumu-late in rapidly proliferating cells and tissues. Accordingly, it has been used for the treatment of polycythemia vera (too many red blood cells produced by the bone marrow) and chronic granulo-cytic or myeloid leukemia (too many blood cells produced by the bone marrow). At relatively high doses (1.5–5 mCi), 32P accu-mulates in the bone marrow and can suppress the production of blood cells.

·           Yttrium (90Y) has a strong affinity for chelating agents, which can be used for targeting carriers. Yttrium chelate with pentetic acid or diethylenetriaminepentaacetic acid (DTPA) can be used for localization to the lymphatics, and its chelate with ethylenediami-netetraacetic acid (EDTA) can lead to localization in the bone.

·           Iodine (131I), used as a water-soluble salt, sodium iodide, is per-haps the most commonly known radioisotope used for the treat-ment of goiter, Graves’ disease, and thyroid cancer. Iodine is selectively taken up by the thyroid gland in the neck. The uptake of radioactive iodine can cause localized tissue destruction by radiation produced within the gland. Targeted uptake of 131I by select tissues can be achieved by incorporation into compounds such as metaiodobenzylguanidine (mIBG). The 131I-labeled mIBG is selectively taken up by the adrenal medullary tissues and can be used to treat carcinomas of or metastases from the adrenal medullary glands.

·           Radioimmunotherapy is the targeting of radioisotopes to spe-cific cells, tissues, and tumor types by covalent conjugation of a radioisotope to monoclonal antibodies or their antigen-binding fragments. For example, 131I can be conjugated to antibodies by using N-hydroxysuccinimide (NHS) to produce radiolabeled antibodies. Copper isotope, 67Cu, can be conjugated to anti-bodies by using the chelating agent [6-p-nitrobenzyl]-l,4,8,ll-tetraazacyclotetradecane-N, N′, N″, N‴ tetraacetate (TETA) for radioimmunotherapy.

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