Synthesis and Preclinical Characterization of a Cationic Iodinated Imaging Contrast Agent (CA4+) and Its Use for Quantitative Computed Tomography of Ex Vivo Human Hip Cartilage

Contrast agents that go beyond qualitative visualization and enable quantitative assessments of functional tissue performance represent the next generation of clinically useful imaging tools. An optimized and efficient large-scale synthesis of a cationic iodinated contrast agent (CA4+) is described for imaging articular cartilage. Contrast-enhanced CT (CECT) using CA4+ reveals significantly greater agent uptake of CA4+ in articular cartilage compared to that of similar anionic or nonionic agents, and CA4+ uptake follows Donnan equilibrium theory. The CA4+ CECT attenuation obtained from imaging ex vivo human hip cartilage correlates with the glycosaminoglycan content, equilibrium modulus, and coefficient of friction, which are key indicators of cartilage functional performance and osteoarthritis stage. Finally, preliminary toxicity studies in a rat model show no adverse events, and a pharmacokinetics study documents a peak plasma concentration 30 min after dosing, with the agent no longer present in vivo at 96 h via excretion in the urine

Synthesis and Preclinical Characterization of a Cationic Iodinated Imaging Contrast Agent (CA4+) and Its Use for Quantitative Computed Tomography of Ex Vivo Human Hip Cartilage

Contrast agents that go beyond qualitative visualization and enable quantitative assessments of functional tissue performance represent the next generation of clinically useful imaging tools. An optimized and efficient large-scale synthesis of a cationic iodinated contrast agent (CA4+) is described for imaging articular cartilage. Contrast-enhanced CT (CECT) using CA4+ reveals significantly greater agent uptake of CA4+ in articular cartilage compared to that of similar anionic or nonionic agents, and CA4+ uptake follows Donnan equilibrium theory. The CA4+ CECT attenuation obtained from imaging ex vivo human hip cartilage correlates with the glycosaminoglycan content, equilibrium modulus, and coefficient of friction, which are key indicators of cartilage functional performance and osteoarthritis stage. Finally, preliminary toxicity studies in a rat model show no adverse events, and a pharmacokinetics study documents a peak plasma concentration 30 min after dosing, with the agent no longer present in vivo at 96 h via excretion in the urine

Quantitative dual contrast CT technique for evaluation of articular cartilage properties

Impact injuries\ua0of cartilage may initiate post-traumatic degeneration, making early detection of injury imperative for timely surgical or pharmaceutical interventions. Cationic (positively-charged) CT contrast agents detect loss of cartilage proteoglycans (PGs) more sensitively than anionic (negatively-charged) or non-ionic (non-charged, i.e., electrically neutral) agents. However, degeneration related loss of PGs and increase in water content have opposite effects on the diffusion of the cationic agent, lowering its sensitivity. In contrast to cationic agents, diffusion of non-ionic agents is governed only by steric hindrance and water content\ua0of cartilage. We hypothesize that sensitivity of\ua0an iodine(I)-based cationic agent may be enhanced by simultaneous use of a non-ionic gadolinium(Gd)-based agent. We introduce a quantitative dual energy CT technique (QDECT) for simultaneous quantification of two contrast agents in cartilage. We employ this technique to improve the sensitivity of cationic CA4+ (q =+4) by normalizing its partition in cartilage with that of non-ionic gadoteridol. The technique was evaluated with measurements of contrast agent mixtures of known composition and human osteochondral samples (n = 57) after immersion (72\ua0h) in mixture of CA4+ and gadoteridol. Samples were arthroscopically graded and biomechanically tested prior to QDECT (50/100\ua0kV). QDECT determined contrast agent mixture compositions correlated with the true compositions (R = 0.99, average error = 2.27%). Normalizing CA4+ partition in cartilage with that of gadoteridol improved correlation with equilibrium modulus (from ρ = 0.701 to 0.795). To conclude, QDECT enables simultaneous quantification of I and Gd contrast agents improving diagnosis of cartilage integrity and biomechanical status