Background

[PubMed]

Ioxilan carbonate particles (IX-C particles) are X-ray contrast agent preparations developed for contrast enhancement of the liver in computed tomography (CT) imaging (1-3). Water-soluble, intravenous ioxilan injection is commercially available as an X-ray contrast agent for excretory urography and contrast enhanced computed tomographic (CECT) imaging of the head and body. However, IX-C as insoluble particles is not commercially available.

X-ray imaging (planar and tomographic) techniques depend on tissue density differences that provide the image contrast produced by X-ray attenuation between the area of interest and surrounding tissues (4). Contrast enhancement (opacification) with use of contrast agents increases the degree of contrast and improves the differentiation of pathologic processes from normal tissues. Because iodine, an element of high atomic density, causes high attenuation of X-rays within the diagnostic energy spectrum, water-soluble and reasonably safe iodinated contrast agents in intravenous injectable forms have been developed for clinical applications (5, 6). Water-soluble, intravenous X-ray contrast agents are generally organic iodine compounds that contain one or more tri-iodinated benzene rings. When injected intravenously, they are largely distributed in the extracellular fluid space and excreted unchanged by the kidneys. Contrast enhancement of a region of interest depends on the route of administration, delivery of the agent to the area by blood flow, and the final iodine concentration in the region (7, 8). There are two basic types of these compounds: ionic and nonionic agents (9).

Rapid i.v. injection of water-soluble X-ray contrast agents can be performed with dynamic computed tomography to improve the detectability of liver lesions (1-3). However, there are many limitations associated with this approach. Particulate contrast media have also been developed for selective opacification of the liver. This approach is based on the fact that particles are effectively taken up by the phagocytic cells (Kupffer cells) of the reticuloendothelial system (RES). Several particulate contrast agents have been developed. These particulate contrast agents can be classified into three groups: 1) emulsion of liposoluble oil; 2) encapsulation of water-soluble X-ray contrast agents in liposomes or polymeric microspheres; and 3) the lipophilic prodrugs derived from water-soluble contrast agents (1, 10). As a low-osmolar nonionic monomer, ioxilan was developed in an effort to increase the safety and tolerance of X-ray contrast agents (11, 12). The development of ioxilan was based on the belief that the introduction of a double methylene as a hydrophobic region and masking it with a hydrophilic hydroxyl group could lower the osmolality without adversely affecting the biological tolerance (13). Li et al. (1) prepared a biodegradable IX-C particle preparation based on the cyclic carbonate of ioxilan. IX-C particles serve as the prodrug of ioxilan that is targeted to the RES phagocytic cells. It is expected that IX-C particles are degraded inside the phagocytic cells to release the original nonionic, water-soluble ioxilan.

Synthesis

[PubMed]

Li et al. (1) prepared IX-C particles by a solvent extraction/evaporation method. IX-C was initially prepared by mixing carbonyldiimidazole with ioxilan in dimethyl sulfoxide (DMSO) over a period of 30 min (14). The mixture was then stirred at 70 ºC overnight. A catalytic amount of sodium methoxide was added, and the reaction was terminated by diluting the DMSO with methylene chloride and washing with cold water. The yield of IX-C was 50%. IX-C obtained from this procedure was dissolved in methylene chloride and acetone (3:1 v/v). The IX-C solution was added to an aqueous solution of polyvinyl alcohol (PVA) and emulsified with a tissue homogenizer for 1 min. The mixture was then stirred at 400 rpm for 4 hrs. The resulting emulsion was centrifuged at 3,000 rpm, resuspended in distilled water, filtered by a 5-μm filter, and finally centrifuged again. This process was repeated three times to produce particles in the size between 0.36 to 5.54 μm (97%). For preparing particles with a narrower size distribution, the particles were separated further by density gradient centrifugation using colloidal suspension of silica (Percoll). These particles were suspended in a gradient system composed of pure water, 50% Percoll in water, and 100% Percoll. The suspension was centrifuged at 1,000 rpm for 10 min. The microparticles in the middle layer were in the size between 0.64 to 4.17 μm. These microparticles were washed three times in water by centrifugation (3,000 rpm for 10 min). When IX-C was dissolved in dimethylformamide and emulsified into an aqueous solution of PVA, IX-C nanoparticles in the size between 158 and 433 nm (97%) were formed. These particles were collected and washed with water by centrifugation at 10,000 rpm for 10 min.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Li et al. (1) used the scanning electron microscope and submicron particle analyzer to examine the IX-C microparticles. The microparticle preparation had an average diameter of 1-2 μm, and 95% are ranging between 0.6 and 2.0 μm. These particles were spherical with smooth surfaces, and the iodine content was 45%. In another similar study, Li et al. (3) reported that the IX-C nanoparticles had an average diameter of 290-300 nm

In a stability study of the IX-C microparticles (1), no immediate particle aggregation was observed when the microparticles were suspended in saline or in 0.1% Tween 80 solution. IX-C microparticles started to crumble and disintegrate after incubated in saline at 37 ºC for 2 wks. The particles were also stable when first mixed with the slightly acidic rat or rabbit plasma at 37 ºC. In 6 days, these particles were completely dissolved in plasma. The IX-C microparticles were completely dissolved in 0.1 N sodium hydroxide at 37 ºC within 1 h. Using reverse-phase high performance liquid chromatography (HPLC) analysis and Fast Atom Bombardment Mass spectroscopy, it was shown that the degradation of IX-C particles yielded ioxilan and carbon dioxide.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

References

1.

Li C. , Kan Z. , Yang D.J. , Kuang L.R. , Liu C.W. , Wright K.C. , Wallace S. Preparation, characterization, and evaluation of ioxilan carbonate particles for computed tomography contrast enhancement of liver. Invest Radiol. 1994; 29 (11):1006–13. [PubMed: 7890508]

2.

Li C. , McCuskey P. , Yang D.J. , Kan Z. , Wallace S. Development of biodegradable ioxilan carbonate particles for contrast enhancement of the liver in computed tomography scanning: toxicity assessment. Suppl 2Acad Radiol. 1996; 3 :S227–8. [PubMed: 8796568]

3.

Li C. , Yu D. , Kan Z. , Yang D.J. , Tansey W. , Kuang L.R. , Wallace S. Biodistribution of cyclic carbonate of ioxilan: a radiopaque particulate macrophage imaging agent. Acad Radiol. 1996; 3 (6):500–6. [PubMed: 8796708]

4. Hoey, G.B. and K.R. Smith, Chemistry of X-ray contrast media, in Radiocontrast agents, M. Sovak, Editor. 1984, Springer-Verlag: New York. p. 23-125.

5.

Wallingford V.H. The development of organic iodine compounds as x-ray contrast media. J Am Pharm Assoc Am Pharm Assoc (Baltim). 1953; 42 (12):721–8. [PubMed: 13108780]

6. Swanson, D.P. and M.B. Alpern, Contrast media for computed tomography: Intravascular, intracavitary, xenon, reticuloendothelial, in Pharmaceuticals in medical imaging, D.P. Swanson, H. M. Chilton and J. H. Thrall, Editor. 1990, Macmillan Publishing Company: New York. p. 99-124.

7.

Sovak M. , Ranganathan R. , Lang J.H. , Lasser E.C. and Concepts in design of improved intravascular contrast agents. European Society of cardiovascular Radiology, Uppsala, (May): p. 25-27. 1977

8.

Almen T. Contrast agent design. Some aspects on the synthesis of water soluble contrast agents of low osmolality. J Theor Biol. 1969; 24 (2):216–26. [PubMed: 5822653]

9.

Almen T. Development of nonionic contrast media Invest Radiol 198520Suppl1S2–9. [PubMed: 2579043]

10. Cheng, K.T. and S.E. Seltzer, Liposome-encapsulated contrast agents in diagnostic imaging, in Contrast Media: Biological Effects and Clinical Application, Z. Parvex, R. Moncada, and M. Sovak, Editors. 1987, CRC Press, Inc.: Boca Raton, Florida. p. 73-87.

11.

Callantine M.R. , Sovak M. , Lu H.P. Ioxilan. Initial clinical observations. Suppl 1Invest Radiol. 1990; 25 :S107–8. [PubMed: 2283219]

12.

Katzberg R.W. , Donahue L.A. , Morris T.W. , Ventura J.A. , Krutchen A.E. , Proskin H.M. , Sovak M. , Cos L.R. Ioxilan, a third generation low osmolality nonionic contrast medium. Systemic and renal hemodynamic effects. Invest Radiol. 1990; 25 (1):46–51. [PubMed: 2404899]

13.

Sovak M. The need for improved contrast media. Ioxilan: updating design theory. Suppl 1Invest Radiol. 1988; 23 :S79–83. [PubMed: 3058636]

14.

Kutney J.P. , Ratcliffe A.H. A novel and mild procedure for preparation of cyclic carbonates: an excellent protecting group for vicinal diols. Synth. Commun. 1975; 5 :47–52.