Radiopharmacy
Radiopharmacy encompasses studies related to the pharmaceutical, chemical, physical, biochemical, and biological aspects of radiopharmaceuticals. Radiopharmacy comprises a rational understanding of the design, preparation and quality control of radiopharmaceuticals, the relationship between the physiochemical and biological properties of radiopharmaceuticals and their clinical application, as well as radiopharmaceuticals chemistry and issues related to the management, selection, storage, dispensing, and proper use of radiopharmaceuticals.
Basic Properties of Radio-Isotopes
A nuclide is a species of atom characterized by its mass number, its atomic number and its nuclear energy state. Atoms with different masses and the same atomic number are called isotopes. A radionuclide is a nuclide which is not in a stable energy state, and can gain stability by the emission of radiation which can be particulate (α, β+, β–, e–) or electromagnetic (γ or X). The way in which a radionuclide decays is dependent upon the size of the nucleus and the neutron proton ratio.
Radiopharmaceuticals are medicinal formulations containing radioisotopes which are safe for administration in humans for diagnosis, mitigation, or treatment of a disease. Radioiodine (iodine-131), for example, was first introduced in 1946 for the treatment of thyroid cancer, and remains the most efficacious method for the treatment of hyperthyroidism and thyroid cancer.
The most commonly used reactor produced isotopes in medical applications are molybdenum-99 (for production of technetium-99m), iodine-131, phosphorus-32, chromium-51, strontium-89, samarium-153, rhenium-186 and lutetium-177.
Currently there are over 100 radiopharmaceuticals developed using either reactor or cyclotron produced radioisotopes and which are used for the diagnosis of several common diseases and the therapy of a few selected diseases, including cancer.
Radiopharmaceuticals production, unlike conventional pharmaceuticals production, is still on a relatively small scale.
Characteristics of Radiopharmaceuticals
A radiopharmaceutical is a pharmaceutical that incorporates one or more radionuclides (radioactive isotopes). Radiopharmaceuticals are used for diagnosis or therapeutic treatment of human diseases; hence nearly 95% of radiopharmaceuticals are used for diagnostic purposes, while the rest is used for therapy. In the case of therapeutic radiopharmaceuticals, radiation is what produces the therapeutic effect.
A radiopharmaceutical can be as simple as a radioactive element such as 133Xe, a simple salt such as 131I-NaI, or a labelled compound such as 131I-iodinated proteins and 99mTc-labeled compounds.
Usually, radiopharmaceuticals contain at least two major components:
- A radionuclide that provides the desired radiation characteristics.
- A chemical compound with structural or chemical properties that determine the in vivo distribution and physiological behaviour of the radiopharmaceutical.
Radiopharmaceuticals should have several specific characteristics that are a combination of the properties of the radionuclide used as the label and of the final radiopharmaceutical molecule itself.
The major characteristics of radiopharmaceuticals include:
- The mass amount administered is low
- No intrinsic pharmacological effect
- For diagnostic use- no disturbance of physiologic parameters
- For therapeutic use- radiation produces the desired therapy
- Should clear rapidly from background tissue
- Be rapidly excreted after the study is completed
Nuclear medicine
Nuclear medicine is the branch of medicine concerned with the use of radionuclides in the study and the diagnosis of diseases. The radionuclides are used for:
- The assessment of organ function
- The detection of disease
- The treatment of some diseases and
- The monitoring of the effects of treatment
Gamma rays are used for imaging while beta rays are used for therapy in nuclear medicine. Nuclear medicine shows the functions of the organs and less anatomical information. Computed tomography, magnetic resonance, ultrasonography and plain films show the anatomy of the organs and less of the functions.
Decay of radionuclides
Radionuclides are unstable nuclei that are stabilised upon radioactive decay. Approximately 3000 nuclides have been discovered so far; most of these are unstable, but only about 30 of these are routinely used in nuclear medicine. Most of these are artificial radionuclides, which may be produced by irradiation in nuclear reactors, cyclotrons, or large linear accelerators. A radionuclide may decay by emitting different types of ionising radiation: alpha (α), beta (β-), positron (β+) and gamma (γ) radiation. Depending on the radiation characteristics of the radionuclide, the radiopharmaceutical is used either for diagnosis or for therapy.
Types of decay
α- emission
Alpha decay is characterised by the emission of an alpha particle from the nucleus. Their clinical use is very limited, and they are mainly used for research purpose. Usually occurs in nuclides whose atomic number is greater than 82.
88226Ra→86222Rn+24He+ γ
β-emission
Neutron rich radionuclides disintegrate by beta (β-) decay. Beta emitting radionuclides are also used in radiopharmaceuticals mainly for therapeutic purposes. This process is typical of nuclei containing too many neutrons for stability.
n→p+–
1532P→1632S+–
β+ or positron decay
Positron (β+) decay occurs in proton rich nuclei. Positron emitters are used to label radiopharmaceuticals for diagnostic purposes by imaging.
n→p++
1122Na→1022Ne+++ γ
++ e–→2γ
Gamma-emission
Gamma radiation is characterised as electromagnetic radiation. It is monoenergetic and accompanies many nuclear transformations. The energy of the photon is equal to hv where h is the Planck’s constant and v is the frequency.
Electron capture
This occurs in nuclides whose nuclei possess too many protons for stability and where the energy change in the transformation is not sufficient for the formation of a + particle. The nucleus captures an orbital electron, usually from the K shell, and a consequence the proton number of the nucleus is reduced by one. The outer orbital electrons of the atom fill the vacancy in the K shell with the production of characteristic X-rays. In achieving a stable energy state the nucleus may emit γ-photons in addition to orbital-generated X-rays.
Isomeric transition (IT)
γ-transitions in the nucleus usually have an extremely short half–life and the radiation is given off simultaneously with the β-particles. Sometimes however, the γ-transition is forbidden according selection rules and this results in a measurable half-life for the γ-decay. E.g. 137mBa, 99mTe, 111mIn.
Internal conversion
In this process, a γ-photon emitted by the nucleus interacts with an orbital electron and this results in the orbital electron being ejected from the atom with an energy equal to that of the γ-photon minus the energy of the electron. The process is usually accompanied by the emission of X-rays. E.g. X-ray emitting radionuclides: 125I (27 keV), 197Hg (69keV) and 113Sn (0.24 MeV).
Rate of decay of a radionuclide
The decay of a radionuclide follows the exponential law:
N=Noe-λt
Where N is the number of radioactive atoms present at time t, No is the number of radioactive atoms present at t = 0 and λ is the decay constant and is a measure of the number of atoms disintegrating in unit time. The above equation can be obtained by integrating the rate equation for the decay process:
–dNdt=λN
Where –dNdt is the rate of decay (activity). It is more usual to express λ in terms of the half-life of the radionuclide t1/2, this being defined as the time required for the activity to decrease by one half of its initial value. When t = t1/2, N = No/2 and substitution of these values in equation above gives the relationship:
λ=ln 2t1/2=0.693t1/2
Radioactivity units
Radioactivity is expressed in Becquerels (Bq) as the SI-unit. One Becquerel is defined as one disintegration per second (dps). Normally, activities used in radiopharmacy are in the range of megabecquerels (MBq) or gigabecquerels (GBq). There is a non-SI-unit for radioactivity called Curie (Ci), which is used in some occasions. One Ci represents the disintegration of one g of radium. The equivalence between the Bq and the Ci is as follows:
1 Bq = 2.7 x 10-11 Ci
1 Ci = 37 GBq
1 mCi = 1 x10-3Ci = 3.7 x 107 d.s-1
1 µCi = 1 x 10-6Ci = 3.7 x 104 d.s-1
Every radionuclide is characterised by a half-life, which is defined as the time required to reduce its initial activity to one half. It is usually denoted by t., and is unique for a given radionuclide.
The specific activity of a radionuclide is the activity expressed per unit quantity of material e.g. µCi.cm-3, mCi.mmol-1.
Principles of radiation protection
Production, transportation and use of radiopharmaceuticals, as radioactive products, are governed by regulatory agencies dealing with radiation protection and nuclear safety. Only licensed personnel in an authorised facility are authorised to handle and use radiopharmaceuticals. The general principles of radiation protection are:
- Justification: All procedures involving radioactive material must be justified.
- Optimisation: The radiation exposure to any individual should be as low as reasonably achievable. This principle is the widely known ALARA concept (as low as reasonably achievable).
- Limitation: The radiation dose received by the personnel handling radioactive material will never exceed the legally established dose limits.
When planning facilities and procedures for handling of radioactive materials according to the ALARA principle, it is important to keep in mind the basic principles for reduction of radiation doses:
- Time: The shorter the time of exposure to radiation, the lower the dose to the operator.
- Distance: The radiation dose decreases with a factor equal to the square root of the distance from the radiation source. The operator’s distance from the source can be increased by using forceps, tongs, or manipulators in handling the radioactive material.
- Shielding: The radiation dose can be reduced by placing shielding material between the source and the operator.
Formulation and production of radiopharmaceuticals
When designing a radiopharmaceutical, one should have in mind the potential hazard the product may have to the patient. The goal must be to have a maximum amount of photons with a minimum radiation exposure of the patient.
The function of the carrier molecule in a radiopharmaceutical is to carry the radioactivity to the target organ, and to make sure the radioactivity stays there. The uptake of radioactivity should be as specific as possible, in order to minimise irradiation of other organs and parts of the body. This is particularly important when using radiopharmaceuticals for therapy. But also for use in diagnostics, it is desirable that the radiopharmaceutical is localised preferentially in the organ under study since the activity from non-target areas can obscure the structural details of the pictures of the target organ. It is therefore important to know the specific uptake in an organ for a potential chemical carrier, and also the rate of leaking out of the organ/organ system. Thus, the target-to-background activity ratio should be large. In a radiolabelled compound, atoms or groups of atoms of a molecule are substituted by similar or different radioactive atoms or groups of atoms.
Manufacturing of radiopharmaceuticals is potentially hazardous. Both small- and large scale production must take place on premises designed, constructed, and maintained to suit the operations to be carried out. Premises must be designed with two important aspects in mind:
- The product should not be contaminated by the operator.
- The operator and the environment should be protected from contamination by the radioactive product.
This is the basic principle of GRP – Good Radiopharmaceutical Practice.
Reconstitution of pharmaceuticals
The manufacturer’s recommendations should be followed closely as many pharmaceutical kits have specific reconstitution instructions in terms of the activity and volume to be added to the kit. Recommended incubation times also vary and must be adhered to. Some radiopharmaceuticals must be refrigerated after preparation. Therefore consideration should be given to the provision of suitably shielded refrigeration facilities.
Quality control of radiopharmaceuticals
All quality control procedures that are applied to non-radioactive pharmaceuticals are in principle applicable to radiopharmaceuticals. In addition, tests for radionuclidic and radiochemical purity must be carried out. Furthermore, since radiopharmaceuticals are short-lived products, methods used for quality control should be fast and effective. Still, some radiopharmaceuticals with very short half-lives may have to be distributed and used after assessment of batch documentation even though all quality control tests have not been completed. Hospital departments dealing with radiopharmaceuticals should have a programme for quality control of products before administration to the patient.
Physicochemical tests
- Physical characteristics- solutions should contain no particulate matter
- pH should be about 7.4
- Radiochemical purity
- Chemical purity (the fraction of the material in the desired form)
Biological tests
- Sterility
- Pyrogenicity
- Toxicity- acute and chronic effects and safe dosage levels must be established
Ideal radionuclide
Properties of the ideal diagnostic radionuclide include:
- Pure gamma emitter, with gamma energy within the range of 100 – 250 keV, to match the optimum scanning range of a gamma camera.
- A half-life which is suitable for diagnostic use i.e. 1.5 X test duration.
- High target – background ratio.
- Low dose rate to both patient and personnel.
- Non-toxicity of radiopharmaceuticals.
- Chemical stability during use.
- Inexpensive and readily available.
- Ease of preparation and appropriate quality control.
Calculation of activity
Example calculation of activity to add to vial
The activity of a sample of 131I was 500 µCi/ml at noon on Monday. Calculate its activity at 4.00 pm on Thursday (Half-life of 131I = 8 days).
The equation to calculate radioactive decay is: N = Noe-λt
- Calculating λ
λ is the decay constant which for any radionuclide is defined as:
λ=ln 2 t1/2
λ=0.6938 x 24
ln Nt – ln No = – λt
No = 500 µCi/ml
t = the time from noon Monday to 4 pm Thursday = 76 h
ln Nt = ln 500 = – (0.693/8×24) x 76
ln Nt = 6.218 -0.2743
= 5.944
Hence, Nt = 381.1 µCi/ml
Therapeutic Radiopharmaceuticals
Rapidly dividing cells are particularly sensitive to damage by radiation. For this reason, some cancerous growths can be controlled or eliminated by irradiating the area containing the growth.
Radionuclide therapy employing radiopharmaceuticals labelled with beta emitting radionuclides is emerging as an important part of nuclear medicine. In addition to the management of thyroid cancer, radionuclide therapy is utilized for bone pain palliation, providing significant improvement in the quality of life of cancer patients suffering from pain associated with bone metastasis as well as for the treatment of joint pain, as in rheumatoid arthritis. Though the sale of therapeutic radiopharmaceuticals is currently much lower compared to that of diagnostic products, a steep increase over the next years is predicted since several new products for treating lymphoma, colon cancer, lung cancer, prostate cancer, bone cancer and other persistent cancers are expected to enter the market.
For some medical conditions, it is useful to destroy or weaken malfunctioning cells using radiation. The radioisotope that generates the radiation can be localised in the required organ in the same way it is used for diagnosis- through a radioactive element following its usual biological path, or through the element being attached to a suitable biological compound. In most cases, it is beta radiation which causes the destruction of the damaged cells. This is radionuclide therapy (RNT) or radiotherapy. Short-range radiotherapy is known as brachytherapy, and this is becoming the main means of treatment.
External irradiation (sometimes called teletherapy) can be carried out using a gamma beam from a radioactive cobalt-60 source, though in developed countries the much more versatile linear accelerators are now being utilised as a high-energy x-ray source (gamma and x-rays are much the same). An external radiation procedure is known as the gamma knife radiosurgery, and involves focusing gamma radiation from 201 sources of cobalt-60 sources on a precise area of the brain with a cancerous tumour. Worldwide, over 30,000 patients are treated annually, generally as outpatients.
Although radiotherapy is less common than diagnostic use of radioactive material in medicine, it is nevertheless widespread, important and growing. An ideal therapeutic radioisotope is a strong beta emitter with just enough gamma to enable imaging, e.g. lutetium-177. This is prepared from ytterbium-176 which is irradiated to become Yb-177 which decays rapidly to Lu-177. Yttrium-90 is used for treatment of cancer, particularly non-Hodgkin’s lymphoma, and its more widespread use is envisaged, including for arthritis treatment. Lu-177 and Y-90 are becoming the main RNT agents.
Iodine-131 and phosphorus-32 are also used for therapy. Iodine-131 is used to treat the thyroid for cancers and other abnormal conditions such as hyperthyroidism (over-active thyroid). In a disease called Polycythemia vera, an excess of red blood cells is produced in the bone marrow. Phosphorus-32 is used to control this excess.
A new and still experimental procedure uses boron-10, which concentrates in the tumour. The patient is then irradiated with neutrons which are strongly absorbed by the boron, to produce high-energy alpha particles which kill the cancer.
For targeted alpha therapy (TAT), actinium-225 is readily available, from which the daughter bismuth-213 can be obtained (via 3 alpha decays) to label targeting molecules. The bismuth is obtained by elution from an Ac-225/Bi-213 generator similar to the Mo-99/Tc-99 one. Bi-213 has a 46-minute half-life. The actinium-225 (half-life 10 days) is formed from radioactive decay of radium-225, the decay product of long-lived thorium-229, which is obtained from decay of uranium-233, which is formed from Th-232 by neutron capture in a nuclear reactor.
Another radionuclide recovered from used nuclear fuel is lead-212, with half-life of 10.6 hours, which can be attached to monoclonal antibodies for cancer treatment. Its decay chain includes the short-lived isotopes bismuth-212 by beta decay, polonium-212 by beta decay and thallium-208 by alpha decay of the bismuth, with further alpha and beta decays respectively to Pb-208, all over about an hour.
Radionuclide therapy has progressively become successful in treating persistent disease and doing so with low toxic side-effects. With any therapeutic procedure the aim is to confine the radiation to well-defined target volumes of the patient. The doses per therapeutic procedure are typically 20-60 Gy.
Considerable medical research is being conducted worldwide into the use of radionuclides attached to highly specific biological chemicals such as immunoglobulin molecules (monoclonal antibodies). The eventual tagging of these cells with a therapeutic dose of radiation may lead to the regression- or even cure of some diseases.
Advantages over chemotherapy and external beam irradiation
- No pharmacological effects
- Radiopharmaceutical therapy exposes neighbouring malignant cells to lethal irradiation even if the nuclide is not bound to them
- Radiopharmaceutical therapy is selective; high target to non-target ratio can be achieved
- Radiopharmaceutical therapy delivers a hyper fractionated dose compared to external beam irradiation.
Development of sophisticated molecular carriers and the availability of radionuclides in high purity and adequate specific activity are contributing towards the successful application of radionuclide therapy.
Radiopharmaceuticals for bone pain palliation
Persons suffering from breast, lung and prostate cancer develop metastasis in bones in the advanced stage of their diseases and therapeutic radiopharmaceuticals containing radionuclides such as strontium-89, samarium-153 and rhenium-186/188 are used for effective palliation of pain from skeletal metastases.
Radiopharmaceuticals for primary cancer treatment
Targeted radionuclide therapy involves the use of radiopharmaceuticals to selectively deliver cytotoxic (toxic to cells) levels of radiation to a disease site, as this would potentially deliver the absorbed radiation dose more selectively to cancerous tissues.
Radiopharmaceuticals for radiosynoviorthesis
Radiosynoviorthesis or radiosynovectomy is a technique wherein a radiopharmaceutical is delivered into the affected synovial compartment (the interior of joints that is lubricated by fluid) of patients suffering from joint pain, as in the case of rheumatoid arthritis. Beta-emitting radiolabelled colloids are widely used for this purpose. Several radiopharmaceuticals have been developed using phosphorus-32, yttrium-90, samarium-153, holmium-166, erbium-169, lutetium-177, rhenium-186, etc. and some of them are registered for human use. The radiation properties of each therapeutic isotope determine their respective use and applicability for the joint size.
Waste management procedures
Non-radioactive waste should be separated from radioactive waste to minimise storage requirements; and it should be disposed of as normal hospital waste. Shielded waste bins should be lined with plastic liners that can be easily removed when full.