A new formulation of poly(MAOTIB) nanoparticles as an efficient contrast agent for in vivo X-ray imaging.

Polymeric nanoparticles (PNPs) are gaining increasing importance as nanocarriers or contrasting material for preclinical diagnosis by micro-CT scanner. Here, we investigated a straightforward approach to produce a biocompatible, radiopaque, and stable polymer-based nanoparticle contrast agent, which was evaluated on mice. To this end, we used a nanoprecipitation dropping technique to obtain PEGylated PNPs from a preformed iodinated homopolymer, poly(MAOTIB), synthesized by radical polymerization of 2-methacryloyloxyethyl(2,3,5-triiodobenzoate) monomer (MAOTIB). The process developed allows an accurate control of the nanoparticle properties (mean size can range from 140 nm to 200 nm, tuned according to the formulation parameters) along with unprecedented important X-ray attenuation properties (concentration of iodine around 59 mg I/mL) compatible with a follow-up in vivo study. Routine characterizations such as FTIR, DSC, GPC, TGA, 1H and 13C NMR, and finally SEM were accomplished to obtain the main properties of the optimal contrast agent. Owing to excellent colloidal stability against physiological conditions evaluated in the presence of fetal bovine serum, the selected PNPs suspension was administered to mice. Monitoring and quantification by micro-CT showed that iodinated PNPs are endowed strong X-ray attenuation capacity toward blood pool and underwent a rapid and passive accumulation in the liver and spleen. STATEMENT OF SIGNIFICANCE: The design of X-ray contrast agents for preclinical imaging is still highly challenging. To date, the best contrast agents reported are based on iodinated lipids or inorganic materials such as gold. In literature, several attempts were undertaken to create polymer-based X-ray contrast agents, but their applicability in vivo was limited to their low contrasting properties. Polymer-based contrast agents present the advantages of an easy surface modification for future application in targeting. Herein, we develop a novel approach to design polymer-based nanoparticle X-ray contrast agent (polymerization of a highly iodine-loaded monomer (MAOTIB)), leading to an iodine concentration of 59 mg/mL. We showed their high efficiency in vivo in mice, in terms of providing a strong signal in blood and then accumulating in the liver and spleen.

Block-copolymer of polyethylene glycol and polylysine as a carrier of organic iodine: design of long-circulating particulate contrast medium for X-ray computed tomography.

In order to obtain small, polymer-stabilized particulate carriers for organic iodine to serve as a contrast agent for X-ray computed tomography (CT) an attempt was made to design a carrier based on polymeric micelles. Here we describe the synthesis of an iodine-containing amphiphilic block-copolymer which can micellize in aqueous solutions. The two blocks of the copolymer consisted of methoxypoly(ethyleneglycol) and poly[epsilon,N-(triiodobenzoyl)-L-lysine]. Upon dispersion in water, the block copolymer formed particles with average diameter 80 nm and iodine content up to 44.7%. The particles start to dissociate to the individual polymeric chains in the concentration range of 0.05-0.5 microM in water at 23 degrees C. Upon intravenous injection at 250 mg of iodine/kg (570 mg of the agent/kg) in rabbits the medium demonstrated exceptional 24 hr half-life in the blood substantiating corona/core structure of the particles with PEG chains protecting the iodine-containing core. The possible use of these particulates as contrast medium for X-ray computed tomography is discussed.

Iodinated methacrylate copolymers as X-ray opaque denture base acrylics.

OBJECTIVES: The purpose of this study was to evaluate novel iodinated methacrylate copolymers as X-ray opaque denture base resins. METHODS: The synthesis of specific monomers and suspension copolymerization with methyl methacrylate to produce copolymer beads. The resulting beads were processed in an identical manner to standard PMMA to produce test-pieces for mechanical testing. RESULTS: Samples prepared from beads containing 25 wt% of the iodinated copolymer exhibited an X-ray opacity equivalent to that exhibited by a similar thickness of aluminium. Furthermore, the appearance and mechanical properties were comparable to standard PMMA, while thermal stability proved superior. CONCLUSION: These novel iodinated methacrylate monomers show promise not only as polymerizable additives to methyl methacrylate to produce an X-ray opaque denture base but also as thermally stable copolymerizable additives to other applications where X-ray opacity would be advantageous.

Synthesis, isomerism and characterization of iopentol.

The synthesis of iopentol is described, and the IR, NMR and FAB MS data of the compound are discussed. Iopentol exists as a mixture of several diastereomers and conformers. This topic is discussed in some detail. The kinetics of the isomerization from pure exo-iopentol to an equilibrium mixture of exo- and endo-iopentol is measured by HPLC and 1H NMR spectroscopy. At 40 degrees C the endo:exo ratio is calculated from the HPLC experiments to be 0.26. The time it takes endo-iopentol to reach half of its equilibrium concentration, and the equilibration time are calculated to be 0.8 h and 5.0 h, respectively. Iopentol may exist as exo/endo pairs of four racemates. Neither GC, HPLC, IR nor high field NMR spectroscopy were suited to reveal the diastereomeric composition of the product.

Synthesis and characterization of iodixanol.

Iodixanol (Visipaque) is a new nonionic roentgen contrast medium intended for general use. Visipaque is a pharmaceutical formulation of iodixanol which is isotonic and iso-osmotic with blood. Two synthetic routes from 5-nitro-isophthalic acid to iodixanol are described. The chemical structure is confirmed spectroscopical data ((1)H-NMR, (13)C-NMR, FAB-MS, UV, IR and Raman). Chromotographic characteristics are related to the isomerism of iodixanol.

Synthesis, analysis and toxicity of some compounds which may be formed during the synthesis of iopentol.

The process developed for the synthesis of iopentol consists of several steps. Nine possible impurities from the synthesis of iopentol have been synthesized and one has been isolated from iopentol mother liquor. These substances have been analysed by HPLC methods developed for routine control of iopentol bulk substance. Capacity factors have been calculated for each compound which relate its position in the chromatogram to iopentol. Some of the synthesized compounds have never been found in iopentol and their toxicities have therefore not been determined. Approximate intravenous LD50 values in mice have been determined for the remaining compounds. Taking into consideration these results and the small quantities in which the impurities are present, it is unlikely that they will affect the safety of the final product.

Synthesis, analysis and toxicity of three compounds formed during the synthesis of iodixanol.

The origin of 4-acetyl-2-[N-acetyl-3,5-bis(2,3-dihydroxypropylcarbamoyl)- 2,4,6-triiodoanilinomethyl]-5,7-diiodo-3,4-dihydro-2H-benzo[1,4]ox azine- 6,8-dicarboxylic acid bis(2,3-dihydroxypropylamide) = N-acetyl cyclized iodixanol, 2-[N-acetyl-3,5-bis-(2,3-dihydroxypropylcarbamoyl)-2,4,6- triiodoanilinomethyl]-5,7-diiodo-3,4-dihydro-2H-benzo[1,4]oxazine- 6,8-dicarboxylic acid bis(2,3-dihydroxypropylamide) = cyclized iodixanol and 5,5'-(N-acetyl-2-hydroxypropane-1,3-diyldiamino)bis[N,N'-bis(2,3- dihydroxypropyl)-2,4,6-triiodoisophthalamide] = deacetyl iodixanol in the manufacturing process of the X-ray contrast agent 3,3',5,5'-tetrakis(2,3-dihydroxypropylcarbamoyl)-2,2',4,4',6,6'-++ +hexaiodo- N,N'-(2-hydroxypropane-1,3-diyl)diacetanilide = iodixanol is discussed and their synthesis and purification are described. Their physical and toxicological properties, and analytical and spectroscopic data are summarized.