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Research Service, H.S. Truman Memorial VA Hospital, Columbia, Missouri
Department of Radiology and Research Reactor, University of Missouri, Columbia, Missouri
Central Research, Dow Chemical Co., Midland, Michigan
Correspondence: For reprints contact: W.A. Volkert, Research Service, H.S. Truman Memorial VA Hospital, Columbia, MO 65211.
ABSTRACT
The development of effective therapeutic radiopharmaceuticals requires careful consideration in the selection of the radionuclide. The in vivo targeting and clearance properties of the carrier molecule must be balanced with the decay properties of the attached radionuclide. Radionuclides for therapeutic applications fall into three general categories: beta-particle emitters, alpha-particle emitters, and Auger and Coster-Kronig-electron emitters following electron capture.
Alpha particles and Auger electrons deposit their energy over short distances with a high LET that limits the ability of cells to repair damage to DNA. Despite their high levels of cytotoxicity, the relatively short range of alpha particles requires binding of the carrier molecule to most cancer cells within a tumor in order to be effective. Because of the extremely short range of Auger electrons, the radionuclide must be carried directly into the nucleus to elicit high radiotoxicity, making it necessary to deliver the radionuclide to every cell within a tumor cell population. These characteristics impose rigid restrictions on the nature of the carrier molecules for these types of particle emitters but successful targeting of these types of radionuclides could result in high therapeutic ratios.
Most beta-emitting radionuclides are produced in nuclear rectors via neutron capture reactions; however, a few are produced in charged-particle accelerators. For radionuclides produced by direct neutron activation, the quantities and specific activities that can be produced are determined in large part by the cross-section of the target isotope and the flux of the reactor. Many applications (e.g., therapeutic bone agents, radiolabeled microspheres, radiocolloids) do not require high-specific activities and can therefore utilize the wide range of radionuclides that can be produced in sufficient quantity by direct neutron activation.
Other applications (e.g., MAb labeling) require high-specific activity radionuclides in order to deliver a sufficient number of radionuclide atoms to the target site without saturating the target or compromising the integrity of the carrier molecule. Most radionuclides, produced at NCA levels in reactors, are produced via indirect reactions (Table 4). High-specific activity beta emitters can also be obtained from radionuclide generator systems where the longer-lived parent radionuclide may be obtained from direct neutron activation, as a fission product, or from charged-particle accelerators.
It is essential that the half-life of a radionuclide used in RNT be compatible with the rates of localization in target tissues and clearance of the carrier molecule from normal tissues. This consideration is especially important for the various MAbs and their fragments that are currently under investigation as carrier molecules for RIT. The proper choice of half-life for a RNT agent has implications on the dose delivered to both target and normal tissue, the dose rate, the feasibility of multidose treatment regimes, and in some cases the widespread availability of the agent.
It is also important that the energy (and thus range) of the beta particles emitted from RNT agents be compatible with the microdistribution of the radionuclide with respect to both target and normal tissues. Too low an energy in combination with an inhomogeneous distribution of the carrier molecule may result in incomplete irradiation of the target. If the range of the beta particles is too large with respect to the size of the target, the result is a decreased dose to the target and an increased dose to adjacent normal tissues. If the adjacent tissue is very radiosensitive (such as bone marrow), this process can limit the efficacy of the agent.
The biochemical nature of the radionuclide is important in determining the sites and rates of any redistribution of radioactivity upon metabolism of the carrier molecule and can thus have an effect on the therapeutic ratio of the agent. The chemical nature of the radionuclide should be a primary consideration in determining the method of attachment of the radionuclide to the carrier molecule. Favorable chemical and biochemical properties in addition to ready availability at moderate cost are responsible for the continued use of 131I in a variety of RNT applications.
Clearly, there are several radionuclides with a spectrum of chemical and physical properties currently available. These and others form the basis for designing and formulating more sophisticated therapeutic radiopharmaceuticals in the coming decade.
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