Physical and chemical properties, fate after antibody metabolism in vivo, and the nature of the emitted radiation, are all factors that must be taken into account when deciding a radionuclide for RIT. Cytotoxic radionuclides may be divided into three groups of radiochemicals: halogens (Iodine, 211At); metals (90Y, 67Cu, 213Bi, 212Bi); and transitional elements (186Re). Radionuclides can be further categorized into four types of cytotoxic agents: pure beta emitters (67Cu and 90Y); alpha emitters (213Bi, 211At); beta emitters that emit gamma radi-

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ation ( Lu, Re, I); and Auger emitters and radionuclides that decay by internal conversion, including 125I and 67Ga.

A variety of thyroid disorders have been treated effectively for decades with 131I (iodine), and its biologic behavior is well understood. 131I has gamma emissions suitable for imaging, though a radiation safety liability sometimes requires hospi-talization after therapy (17). Its long half-life is probably ideal for therapy with intact immunoglobulins, and the labeling process is relatively straightforward (18).

131I is not the optimal nuclide when conjugated with antibodies that are internalized into tumor cells via clathrin-coated pits following antibody -antigen interaction (19). This leads to dehalogenation of the complex and release of the radionuclide, thus decreasing tumor radiation-absorbed dose. The use of residualizing linkers that provide stronger binding of the halide to the antibody has been explored to overcome this limitation (20).

Radiometals, unlike radioiodine are usually attached to antibodies by che-lates, and do not detach from the antibody following internalization. 90Y (yttrium), a pure beta-emitting radiometal, has been widely studied in RIT (21). 90Y is an attractive choice for several reasons. The high-energy betaminus emission of Y-90 can be effective in bulky tumors, and its pure beta emission allows for outpatient therapy. A limitation of yttrium, however, is its affinity for bone. When 90Y is detached from the chelating agent after metabolism of the radiolabeled construct, the bone marrow can receive unacceptably high levels of radioactivity. Lutitium-177 (177Lu) may be a suitable alternative in this regard as its half-life and other physical characteristics are similar to 131I, and its gamma emission allows for external imaging (22).

Rhenium is a transitional element, and both 186Re (rhenium) and 188Re have been linked to antibodies. Developments in radiochemistry have made possible stable attachment of these isotopes to proteins. 188Re is produced from a Tungsten-188 generator (permitting elution on site) (23), and its 17-hour halflife holds promise for locoregional therapies or for therapies with rapidly clearing molecules. Because of its physical properties, including longer half-life, 186Re has been more extensively studied. Rhenium nuclides emit photons that allow for external imaging with conventional nuclear medicine equipment. Early clinical trials have exploited the 186Re gamma emissions to provide dosimetry analyses of absorbed doses to tumors and normal organs, and have demonstrated its safety for use in RIT for solid tumors (24).

Alpha particles are high-energy helium nuclei with high linear energy transfer (LET). In addition to having short half-lives, the range of energy deposition is only 50-80 mm. Alpha particles hold interest for RIT, as their high linear-energy deposition can deliver lethal radiation to small tumor clusters. However, the recoil energy of alpha decay has precluded stable attachment of these radionuclides to proteins. Advances in radiochemistry addressing this problem have led to a renewed interest in alpha particles. Cyclotron-produced astatine (At-211) is under investigation as therapy for several tumor types. Clinical trials have been reported using 211At-labeled chimeric anti-tenascin antibody 81C6 for gliomas (25). Bismuth-213 [213Bi—eluted from a actinium-225 (Ac-225) generator] has a short (46 minutes) half-life and is being studied in hematologic neoplasms (26).

In vivo generators of alpha particles are being investigated for their ability to deliver cytotoxic particles to micrometastases. These "nanogenerators" overcome the limitations posed by the short half-lives of most alpha particles (27), though the problems associated with recoil following alpha decay and the production of nonmetal daughters, francium and astatine (which then may not remain attached to the chelate), are significant.

Auger emitters deposit high LET over extremely short distances, and are therefore most effective when the decay occurs in the nucleus, and less so when the decay occurs in the cytoplasm (28). 125I is the prototypical radionuclide, but its long decay half time renders it less than optimal for therapy. Other similar radionuclides that have been studied, although not with antibodies, have included mIn (indium). In both cases, the amount of radioactivity necessary is economically prohibitive. A radionuclide that is gaining increasing attention in this category is 67Ga (gallium). Improvements in chelation chemistry have resulted in stable radioimmunoconjugates with 67Ga, and clinical trials are planned.

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