The medicinal chemistry of gallium appears to be dominated by the striking similarity in chemical behavior between Ga3+ and ferric iron (Fe3+). This similarity, as has been noted,9 is due to the close correspondence between the two ions in a number of parameters, including ionic radius and factors relating to bond formation (such as electronegativity, ionization potential and electron affinity). Gallium is thus expected to follow many of the same chemical pathways as ferric iron in the body, and to be able to occupy the ferric iron site in some proteins and chelates.
It is the differences between the two ions, however, that allow for gallium's therapeutic potential and that minimize its toxicity. The first major difference is that Ga3+ is essentially irreducible under physiological conditions, whereas Fe3+ is readily reducible to Fe2+ (a much more soluble and significantly larger ion). This difference means that, in vivo, Ga3+ does not enter Fe2+-bearing molecules such as heme (a fundamental component of hemoglobin and myo-globin, as well as cytochromes and numerous other enzymes) and thus does not interfere with oxygen transport and other vital functions. It also means that when Ga3+ substitutes for Fe3+ in a redox-active enzyme, it cannot participate in redox reactions, making the enzyme non-functional. Furthermore, Ga3+ will not participate in Fenton-type redox reactions, in which hydroxyl and other highly reactive oxygen-bearing free radicals are produced; such reactions make unbound iron ions highly toxic when present in blood plasma. The other major difference is that Fe3+ is even less soluble in neutral aqueous solutions than is Ga3+: at pH 7.4 and 25 °C, the solubility of Fe3+ (in equilibrium with FeO(OH)) is only approximately 10~18M, compared to the analogous figure of approximately 10~6M for Ga3+.14 This difference means that whereas essentially all Fe3+ is protein-bound or chelated in blood plasma, small but potentially significant amounts of gallate (Ga(OH)4~) can exist at equilibrium, which can participate in activities not available to the protein-bound metal.
Because unbound iron ions are highly toxic, iron is maintained bound to a series of proteins and small molecules when it is absorbed and transported throughout the body.20 In blood plasma, iron exists predominately as Fe3+ bound to transferrin (TF), which is the major iron transport protein. Similarly, at equilibrium, nearly all Ga3+ in blood plasma is bound to TF.9,13 Metal-bearing TF, particularly when saturated with two metal ions, can bind to transferrin receptor (TFR) on cell membranes; this complex is taken up by endocytosis, the metal is released from TF as the endosome is acidified to pH 5.5, and the TF and TFR are recycled.20 TFR is expressed in all nucleated cells, but at the highest levels in many neoplastic cells, as well as in normal hepatocytes; Kupffer cells; erythroid precursors; and cells of the basal epidermis, endocrine pancreas, seminiferous tubules and mucosal epithelium.21 23 These cells all have a high need for iron: rapidly proliferating cells, particularly neoplastic cells, must manufacture the Fe3+-bearing enzyme ribonucleotide reductase, which is essential for DNA synthesis; erythroid precursors (mainly in the marrow) reduce Fe3+ to Fe2+ to produce hemoglobin and related molecules; and liver cells as well as macrophages absorb and store iron to regulate overall iron levels.
The iron-binding capacity of TF in blood plasma is normally approximately 3.3 mg of Fe3+/ml (referred to as the total iron-binding capacity), though normally only about 33% of the available metal-binding sites (two per TF molecule) are occupied by Fe3+.24 Thus, at normal iron saturation levels, plasma TF has the capacity to bind as much as approximately 2.7 mg/ml (40 mM) of Ga3+; if Ga3+ concentrations exceed this level, then significant amounts of gallate will form, together with traces of Ga(OH)3 and gallium citrate.9
Gallium also binds to the Fe3+ sites of lactoferrin, a protein closely related structurally to transferrin. Lactoferrin binds Fe3+ and Ga3+ more avidly than does TF, and can remove Ga3+ from TF.25 Apolactoferrin exerts anti-microbial activity by locally sequestering iron, an essential nutrient, and occurs in amounts of approximately 0.5-1 mg/ml in epithelial secretions such as milk, tears, seminal fluid and nasal discharge.26,27 It is also secreted at sites of infection and inflam-
Ferritin, a very large (440 kDa) protein used for iron storage, will also bind gallium. Gallium can be transferred to ferritin from transferrin or lactoferrin, with ATP and other phosphate-bearing compounds acting as mediators.31,32 Ferritin is present in most cell types, but is concentrated in Kupffer cells of the liver and other tissue macrophages, and in duodenal mucosal cells, particularly when there is abundant iron in the diet.20,24
The binding of gallium to transferrin, lactoferrin and ferritin accounts for much of the tissue distribution observed when gallium radioisotopes are administered. 67Ga is found to concentrate most highly in many tumors and at sites of inflammation and infection.33 35 Many tumors overexpress TFR, and the avidity of tumors for 67Ga has been correlated to transferrin receptor 1 (TFR1; CD71) expression.14,36 39 Exceptions to this generalization exist however, and gallium appears to enter some 67Ga-avid tumors by TFR1-independent mechanisms.40 42 A second membrane-bound transferrin receptor (TFR2a) has been described,43 which is most highly expressed in hepatocytes, some erythroid cells and the crypt cells of the duodenum (which sense plasma iron levels and then, when they mature into villi enterocytes, regulate dietary iron absorption).43 45 Some of the reported non-transferrin-receptor-mediated gallium uptake is likely through TFR2a. Little information is available on the direct uptake by cells of gallium bound to low molecular weight (LMW) molecules; it is noted, however, that Ga3+, as well as Fe3+ and other trivalent or tetravalent metal ions, greatly upregulates the uptake of LWM-bound Fe by monocytes, macrophages, neutrophils and myeloid cells, as well as the binding of transferrin and lactoferrin to cell membranes.46 The mechanism of LMW-bound ferric iron absorption may apply to LMW-bound gallium.
The concentration of 67Ga at sites of inflammation and infection likely stems from its binding to lactoferrin, as well as from uptake by some leukocytes35,47,48 and, when present, bacteria.49,50
Although gallium is avidly taken up by a wide range of proliferating cancer cells, it is not concentrated by rapidly proliferating normal cells, such as gastrointestinal mucosal cells, hematopoietic cells of the bone marrow and elsewhere, and the transient cells of hair follicles; significant 67Ga accumulations do not occur at these sites. The reasons for the lack of accumulation in normal proliferating tissue have not been explored, but are likely due in part to local recycling of iron, so that little new uptake of iron (or gallium) from plasma occurs.
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