Gallium maltolate
Encyclopedia
Gallium maltolate is a coordination complex consisting of a trivalent gallium
cation coordinated to three maltol
ate ligand
s. The compound is undergoing clinical and preclinical testing as a potential therapeutic agent for cancer, infectious disease, and inflammatory disease. It appears to
have low toxicity when administered orally, without the renal toxicity observed for intravenously administered gallium nitrate. This is probably because gallium absorbed into the body from oral gallium maltolate becomes nearly entirely protein bound, whereas gallium from intravenous gallium nitrate tends to form anionic gallium hydroxide (Ga(OH)4-; gallate) in the blood, which is rapidly excreted in the urine and may be renally toxic.
: the bioavailability is several times higher than that of gallium salts such as gallium nitrate and gallium trichloride
. Gallium is antiproliferative to pathologically proliferating cells, particularly cancer cells and some bacteria, due primarily to its ability to mimic ferric iron (Fe3+). Ferric iron is essential for DNA
synthesis, as it is present in the active site of the enzyme ribonucleotide reductase
, which catalyzes the conversion of ribonucleotides to the deoxyribonucleotides required for DNA. Gallium is taken up by the rapidly proliferating cells, but it is not functional for DNA synthesis, so the cells cannot reproduce and they ultimately die by apoptosis
. Normally reproducing cells take up little gallium (as is known from gallium scan
s), and gallium is not incorporated into hemoglobin
, accounting for the relatively low toxicity of gallium.
The anti-inflammatory activity of gallium appears to involve the down-regulation of inflammatory T cell
s and macrophage
s, as well as possible interference with matrix metalloproteinase
s. Because many iron compounds are pro-inflammatory, the ability of gallium to act as a non-functional iron mimic may contribute to its anti-inflammatory activity.
Dr. Christopher Chitambar and his associates at the Medical College of Wisconsin
have found that gallium maltolate is active against several lymphoma
cell lines, including those resistant to gallium nitrate.
Gallium maltolate is being studied as a potential treatment for primary liver cancer (hepatocellular carcinoma
; HCC). In vitro experiments demonstrated efficacy against all HCC cell lines tested and a clinical case study produced very encouraging results in a patient with advanced HCC who had not responded to therapy with sorafenib
The activity of gallium against infection-related biofilms, particularly those caused by Pseudomonas aeruginosa
, is being studied by Dr. Pradeep Singh at the University of Washington
, and by others, who have reported encouraging results in mice.
Pulmonary P. aeruginosa biofilms are responsible for many fatalities in cystic fibrosis and immunocompromised patients; in general, bacterial biofilms are responsible for significant morbidity and mortality. In related research, locally administered gallium maltolate has shown potent efficacy against P. aeruginosa in a mouse burn/infection model.
Oral gallium maltolate is also being investigated as a treatment for Rhodococcus equi
foal pneumonia, a common and often fatal disease of newborn horses. R. equi can also infect humans with AIDS or who are otherwise immunocompromized. The veterinary studies are being conducted by researchers at Texas A&M University
, led by Dr. Ronald Martens, Dr. Noah Cohen, and Dr. M. Keith Chaffin.
Gallium
Gallium is a chemical element that has the symbol Ga and atomic number 31. Elemental gallium does not occur in nature, but as the gallium salt in trace amounts in bauxite and zinc ores. A soft silvery metallic poor metal, elemental gallium is a brittle solid at low temperatures. As it liquefies...
cation coordinated to three maltol
Maltol
Maltol is a naturally occurring organic compound that is used primarily as a flavor enhancer. It is found in the bark of larch tree, in pine needles, and in roasted malt . It is a white crystalline powder that is soluble in hot water, chloroform, and other polar solvents...
ate ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s. The compound is undergoing clinical and preclinical testing as a potential therapeutic agent for cancer, infectious disease, and inflammatory disease. It appears to
have low toxicity when administered orally, without the renal toxicity observed for intravenously administered gallium nitrate. This is probably because gallium absorbed into the body from oral gallium maltolate becomes nearly entirely protein bound, whereas gallium from intravenous gallium nitrate tends to form anionic gallium hydroxide (Ga(OH)4-; gallate) in the blood, which is rapidly excreted in the urine and may be renally toxic.
Chemical properties
Gallium maltolate is stable in aqueous solutions between about pH 5 and 8, and it has significant solubility in both water and lipids (octanol:water partition coefficient = 0.41).Therapeutic activity
Gallium maltolate is able to deliver gallium with high oral bioavailabilityBioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
: the bioavailability is several times higher than that of gallium salts such as gallium nitrate and gallium trichloride
Gallium trichloride
Gallium trichloride is the chemical compound with the formula GaCl3. Solid gallium trichloride exists as a dimer with the formula Ga2Cl6. It is colourless and soluble in virtually all solvents, which is unusual for a metal halide. It is the main precursor to most derivatives of gallium and a...
. Gallium is antiproliferative to pathologically proliferating cells, particularly cancer cells and some bacteria, due primarily to its ability to mimic ferric iron (Fe3+). Ferric iron is essential for DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
synthesis, as it is present in the active site of the enzyme ribonucleotide reductase
Ribonucleotide reductase
Ribonucleotide reductase is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. Deoxyribonucleotides in turn are used in the synthesis of DNA. The reaction catalyzed by RNR is strictly conserved in all living organisms...
, which catalyzes the conversion of ribonucleotides to the deoxyribonucleotides required for DNA. Gallium is taken up by the rapidly proliferating cells, but it is not functional for DNA synthesis, so the cells cannot reproduce and they ultimately die by apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Normally reproducing cells take up little gallium (as is known from gallium scan
Gallium scan
A gallium scan or gallium 67 scan is a type of nuclear medicine study that uses a radioactive tracer to obtain images of a specific type of tissue, or disease state of tissue. Gallium salts like gallium citrate and gallium nitrate are used. The form of salt is not important, since it is the freely...
s), and gallium is not incorporated into hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
, accounting for the relatively low toxicity of gallium.
The anti-inflammatory activity of gallium appears to involve the down-regulation of inflammatory T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s and macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s, as well as possible interference with matrix metalloproteinase
Matrix metalloproteinase
Matrix metalloproteinases are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily....
s. Because many iron compounds are pro-inflammatory, the ability of gallium to act as a non-functional iron mimic may contribute to its anti-inflammatory activity.
Pharmaceutical development
Gallium maltolate was invented and patented by Dr. Lawrence R. Bernstein (e.g., U.S. Patent No. 5,574,027).Dr. Christopher Chitambar and his associates at the Medical College of Wisconsin
Medical College of Wisconsin
Medical College of Wisconsin is a private, freestanding medical school and graduate school located in Milwaukee, Wisconsin, United States. It was formerly affiliated with Marquette University....
have found that gallium maltolate is active against several lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
cell lines, including those resistant to gallium nitrate.
Gallium maltolate is being studied as a potential treatment for primary liver cancer (hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
; HCC). In vitro experiments demonstrated efficacy against all HCC cell lines tested and a clinical case study produced very encouraging results in a patient with advanced HCC who had not responded to therapy with sorafenib
Sorafenib
Sorafenib , is a drug approved for the treatment of primary kidney cancer and advanced primary liver cancer ....
The activity of gallium against infection-related biofilms, particularly those caused by Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...
, is being studied by Dr. Pradeep Singh at the University of Washington
University of Washington
University of Washington is a public research university, founded in 1861 in Seattle, Washington, United States. The UW is the largest university in the Northwest and the oldest public university on the West Coast. The university has three campuses, with its largest campus in the University...
, and by others, who have reported encouraging results in mice.
Pulmonary P. aeruginosa biofilms are responsible for many fatalities in cystic fibrosis and immunocompromised patients; in general, bacterial biofilms are responsible for significant morbidity and mortality. In related research, locally administered gallium maltolate has shown potent efficacy against P. aeruginosa in a mouse burn/infection model.
Oral gallium maltolate is also being investigated as a treatment for Rhodococcus equi
Rhodococcus equi
Rhodococcus equi is a Gram-positive coccobacillus bacterium. The organism is commonly found in dry and dusty soil and can be important for diseases of domesticated animals . The frequency of infection can reach near 60 percent. R. equi is an important pathogen causing pneumonia in foals. Since...
foal pneumonia, a common and often fatal disease of newborn horses. R. equi can also infect humans with AIDS or who are otherwise immunocompromized. The veterinary studies are being conducted by researchers at Texas A&M University
Texas A&M University
Texas A&M University is a coeducational public research university located in College Station, Texas . It is the flagship institution of the Texas A&M University System. The sixth-largest university in the United States, A&M's enrollment for Fall 2011 was over 50,000 for the first time in school...
, led by Dr. Ronald Martens, Dr. Noah Cohen, and Dr. M. Keith Chaffin.