Bismuth (Z = 83) is a soft gray metal that occurs in nature commonly as bismite (Bi₂O₃), bismutite ((BiO)₂CO₃), or bismuthinite (Bi₂S₃). The metallic form of this element is usually obtained as a byproduct from copper, lead, tin, molybdenum and tungsten smelting. Bismuth is a relatively rare element with the abundance in the Earth’s crust estimated to be about 0.2 ppm, approximately about twice as abundant as gold. When freshly produced, it is a brittle metal with a silvery white color, but often exhibits a pink tint after exposure to air due to surface oxidation. Among metals, bismuth is the most diamagnetic element, has the lowest thermal conductivity, and exhibits the highest Hall effect. Because of its wide temperature range between the melting point (T _melt = 271 °C) and boiling point (T _boil = 1560 °C), and low neutron absorption cross section, liquid bismuth is used as a coolant in nuclear reactors. The density of bismuth, d = 9.78 g/cm³ is ~86 % of the density for lead, d = 11.32 g/cm³, making bismuth useful as a nontoxic replacement for lead in ceramic glazes, fishing sinkers, food-processing equipment, free-machining brasses for plumbing applications, lubricating greases, and ammunition for waterfowl hunting [15]. There is only one naturally occurring isotope of bismuth, that has long been considered as the heaviest stable isotope. In 2003, however, was found to decay via alpha-emission with a half-life to be 1.9 × 10¹⁹ years, more than a billion times longer than the current estimated age of the universe [16]. For all practical purposes, bismuth is still treated as nonradioactive.

Bismuth has two oxidation states, Bi(III) and Bi(V). The latter is a powerful oxidant in aqueous solution with a redox potential of E° = 2.03 V for Bi(V)/Bi(III). Under the physiological conditions, Bi(III) is the most common and the only stable form of the element. The inorganic Bi(III) salts of sulfate, perchlorate, nitrate, as well as halides, except fluoride, all appear to be soluble in water, but hydrolyze to form insoluble hydroxide or oxyhydroxide products in neutral solution [15]. In acidic solution, such hydrolytic reactions are complex, and products formed are sensitive to the pH value, as well as the presence of different counter ions. These products are commonly referred to as “basic,” “oxy-”, or “sub-” salts with the formation of the bismuthyl ion (BiO⁺) or various polynuclear clusters of low aqueous solubility [17]. As a heavy metal, the toxicity of bismuth is much lower than that of its heavy-metal neighbors, such as mercury, thallium, lead, and polonium [18]. Because of its low solubility in the blood, bismuth is readily cleared from urine, and exhibits no long-term carcinogenic, mutagenic or teratogenic effects. Its biological half-life for whole-body retention is about 5 days, although it may remain in the kidney for years in patients treated with bismuth compounds [19].

The use of bismuth compounds in medicine can be traced back to the Middle Ages, although the first full account of such use did not appear until 1786 for the treatment of dyspepsia [19]. A decade later, bismuth compounds were used as antisyphilitic drugs. In the late nineteenth century, a variety of bismuth compounds mixed with iodoform were promoted as a surgical wound dressing owing to its antimicrobial and antibacterial properties. The use of various bismuth compounds, such as subnitrate, subgallate, subcitrate, subcarbonate and subsalicylate to treat syphilis, hypertension, infections, skin conditions and gastrointestinal disorders lasted until 1950s after penicillin and several other antibiotics had become widely available [18]. Currently, the only continued medicinal application of bismuth is for the treatment of diarrhea and dyspepsia using bismuth subsalicylate (Pepto-Bismol^®; the Procter & Gamble Company, Cincinnati, OH, USA), or bismuth subcitrate (De-Nol^®; Gist Brocades, Delft, The Netherlands) [18, 19]. On the other hand, bismuth oxychloride (BiOCl) found in nature as the mineral bismoclite has been used as a pigment in cosmetics since the ancient Egyptian Times. Owing to its layered structure, BiOCl refracts light chromatically, resulting in an iridescent appearance resembling nacre of pearl [20].

Bismuth compounds have high X-ray attenuation efficiency, and thus can provide sufficient contrast enhancement at low dosage levels when they are employed as CT imaging agents. Furthermore, the biocompatible and nontoxic nature of bismuth represents an extremely attractive feature for many molecular compounds of bismuth to function as effective CT imaging agents. However, the very first requirement of an effective CT imaging agent is the high solubility of the compound, as a high concentration is necessary for an intravenous administration to produce sufficient contrast in CT imaging due to the intrinsic low contrast sensitivity of the X-ray CT modality. Additionally, the typical ionic, covalent or coordination complexes of bismuth may bind to proteins or other biomolecules or undergo transmetallation reactions with endogenous ions, such as Ca²⁺, Mg²⁺, Mn²⁺, and Zn²⁺, thus altering their pharmacological characteristics when administrated intravenously.

Use of bismuth-based nanoparticles, rather than bismuth-containing ionic or covalent compounds, to develop CT imaging agents have potential to circumvent the high-osmolality or poor-solubility limitations of its ionic or covalent compounds. It should be noted that thus far the small-molecule platform has not yet afforded clinically useful bismuth-containing CT contrast agents. On the other hand, there has been an important paradigm shift to use various nanoparticles for the development of new-generation imaging agents in different imaging modalities including X-ray CT imaging [21, 22]. Additionally, particulate-imaging agents can have a greater blood circulation half-life than the molecular counterparts, thus increasing the time window for imaging [23]. Furthermore, surface-modifications via ionic or covalent attachment of a targeting agent on nanoparticles provide possibilities to develop organ-specific imaging agents [24, 25].