Comparison Study between the Contrast Media of Iodine and Iodine Nanoparticles in Physicochemical Properties in CT-scan Imaging

INTRODUCTION 
Research that talks about the use of iodine as a contrast media in computed tomography imaging is the only contrast medium currently used, as of the iodine nanoparticles solution [1-5]. Computed tomography (CT) is a full-body imaging technique based on x-rays and widely used in medicine. Contrast agents clinically approved for CT imaging are small iodized particles or barium suspensions. Nanoparticles have several advantages over small-molecule CT contrast agents, such as long blood pool dwell times, cell traceability and targeted imaging applications. The required large doses of contrast agent require careful toxicology studies prior to clinical translation [6]. Suspensions of nanoparticles from the iodinated polymer are evaluated as a contrast agent for computed tomography (CT). Intravenous injection of iodized polymer nanoparticles provides mice with a clear visualization of the cardiovascular system over a period of several hours followed by a gradual accumulation in the liver and spleen. This substance is a “pooling” contrast agent with a very long stay in the bloodstream [3].
    X-ray iodine attenuation is not effective in clinical computed tomography that uses high-energy X-rays. Due to these limitations, nanoscale iodized contrast agents have been developed that can increase circulation time and reduce adverse effects. In addition to iodine, nanoparticles based on heavy atoms such as gold, lanthanides and tantalum are used as more efficient CT contrast agents [7]. Nanoparticles (NPs) are being used as novel contrast agents that represent a promising strategy for non-invasive diagnostics. Advances in nanotechnology will provide improved sensitivity and specificity for tumor imaging, enabling early detection of metastases. Nanoparticles are consistent with the development of targeted contrast agents, which are used as contrast agents and the benefits / concerns associated with their use in clinical procedures [8].
Medical imaging techniques allow for the rapid diagnosis and evaluation of a wide range of diseases. In order to increase its sensitivity and utility, many imaging techniques such as computed tomography and magnetic resonance imaging rely on contrast agents administered intravenously. While the current generation of contrast agents has enabled rapid diagnosis, they still have many unwanted defects including a lack of tissue specificity and systemic toxicity problems. Through advances in nanotechnology and materials science, researchers are now creating a new generation of contrast agents that overcome many of these challenges and are able to provide more sensitive and specific information [9,10].
In this study iodine nanoparticle was used as alternative contrast medium of micro iodine solution in different organs of rabbit to monitoring the time remaining in the organ for good diagnosis in CT-scan. 

MATERIALS AND METHODS
GE Healthcare USA Iodine contrast Iohexol (Omnipaque 350 mg I/ml) was the contrast media utilized in CT-scan. Anesthesia materials used in sedation include ketamine 10% from Alfasan Company (Holland), xylazine 2% from Alfasan (Holland). Blood samples of rabbits and other chemicals and solvents were of annular grade and were used as received by the manufacturers. Deionized water was used to prepare aqueous solutions. 

Preparation of nanoparticles of Iohexol contrast medium
Lyophilization instrument 
Lyophilization instrument from LABCONCO Company (USA) was used for the preparation of Iopromide nanoparticles from micro-particles by deep freezing technique as shown in Fig. 1. 

CT-Scan apparatuses
The CT-Scan screw type United Imaging Computed Tomography X ray System UCT520, Shanghai United Imaging Healthcare, China.
After preparing the rabbit for examination and in the case of anesthesia with the specified dose of the contrast, the rabbit was lying on the examination table to perform the spiral CT-Scan as shown in Fig. 2. 

Preparation of rabbit groups for the CT scan
Three groups of rabbits weighing between 1.5 to 2 kg were all before the acquisition, rabbits were anesthetized with ketamine and xylocaine prior to the examination, then, placed on the scanner table and immobilized. The iodinated Nano-solution was injected directly into the heart muscle, Scans were performed before administration for the 1st control group. 
The 2nd group had their hearts injected  with micro iodinated contrast at doses of (1,2,3,4,5ml) respectively, The 3rd group had their hearts injected  with Nano iodinated contrast at doses of (0.5, 1, 1.5, 2 and 2.5ml) exams were taken for each group at different time intervals of (0min, 5min, 10min, 20min, 30min and 1hour) respectively ,the scan was with the following parameters, 1.5mm slice thickness at an increment of 1.5mm using 100kv and 75mAs radiation dose, then Hounsfield numbers measurements were taken of the brain, heart and the abdominal organs.
The Hounsfield unit (HU): radiolucency Absorption coefficient unit of a substance; HU is normalized to water, where water = 0 HU, air = -1000 HU and bone = 1000 HU [11,12], the HU values in the CT-scan were measured for each CT exam at all times by placing a region of interest in the brain, heart, liver, and kidney.

RESULTS AND DISCUSSION
In the current study, the rabbits were used in the computed tomography (CT-scan) examination, the iodine solution, and the iodine nanoparticles contrast media to compare the effectiveness of nanoparticles within its survival in the different organs during the examination by comparing with time remaining in the organ.  
The study included different organs of rabbits such as the heart, kidney, liver, bladder, and brain using iodine and iodine nanoparticles as contrast media to monitoring the [13] contrast media in 0, 5, 10, 20, 30, and 60 minutes as shown in table 1.   

Study the Heart Organ
Table 1 illustrated the HU values of the heart organ after injected with each of iodine and iodine nanoparticles in the same concentration (1.5 ml of 350 mg/ml) after different times, 0, 5, 10, 30, and 60 minutes which find the high HU values in the iodine NPs comparing with the iodine micro particles, addition to the remaining the nano contrast medium in the heart organ for longer time (HU value at 0 minute has 215 after 30 minutes has 120) while the iodine micro particles decreased in the HU values in the same time (HU value at 0 minute has 204 after 30 minutes has 74) as shown in tabl1 and Fig. 3, these phenomena of using the nano iodine contrast medium is very important for monitoring the heart and the vessels imaging by CT-Scan technique for easy diagnostic method.

Study the Brain organ
Another study for using nano iodine contrast medium is monitoring the CT-scan imaging of the brain organ of rabbit the value of HU is 54 after 0 minutes and the contrast still remaining in the brain after one hour with 50 HU value as shown in table 2, also iodine NPs can be used as a good contrast medium for diagnostic the brain problems with easy method.

Study the Kidney Organ  
There are two positions in the CT-scan imaging of kidney organ of the rabbit was studied in this work, cortex kidney imaging and medulla kidney imaging. The results were found after using iodine nanoparticles as a contrast medium, and comparing with iodine micro particles as in the following:
In the cortex kidney organ, the HU value in iodine NPs after 0 minutes has 275 and after 60 minutes has 378 which still in the kidney with more resolution in a long time, which enhanced the resolution of the image. While, the HU value in iodine micro particles when using in the cortex kidney has 278 after 0 minutes and decreased to 125 after 60 minutes, the resolution of kidney image has low clearness comparing with the using iodine NPs, these results can see in table 3 and Fig. 4.
In the medulla kidney image can be seen the same phenomena as in the cortex kidney, it was found that the values of HU in the medulla kidney of the rabbit when using iodine nanoparticles has 222 after 0 minutes and enhanced the resolution of imaging to 437 after 60 minutes, this jump of the resolution means that nanoparticles of iodine set in the kidney for a long time because the nano size of the iodine particles [14]. While the iodine micro particles were decreased the HU value after 60 minutes from 1145 to 271, the resolution of medulla kidney imaging has a lower value after passing the time, so using iodine NPs in diagnostic kidney diseases is more efficient than using iodine micro particles in CT-scan [15].
Study the Liver Organ                    
The liver organ of the rabbit was studied for both iodine and iodine NPs which have    good results through using iodine NPs comparing the iodine micro particles.
The resolution of the liver image was studied by using iodine NPs in CT-scan technique has HU value after 0 minutes 121 and still remaining with the same value 122 after 60 minutes, the resolution of CT scan image is to save in the value for a longer time. But, iodine micro particles cannot save the contrast medium of iodine for loge time in the organ because the size of the particles has bigger than nanoparticles. The HU values of the liver after 0 minute has 182 decreased to 95 after 60 minutes, so the liver cannot save with the micro iodine contrast medium for a long time as shown in table 4 and Fig. 5. 

Study the Bladder Organ 
In the same CT-scan examination of bladder organ by using iodine in micro and nanoparticles at different times to monitoring the resolution of the imaging by HU values, it was found that iodine NPs contrast medium plays an important role for using as alternative contrast medium from the iodine micro particles, the HU value of bladder organ has 1284 after 5 minutes and 2650 after 60 minutes which has a good resolution of the imaging for the bladder organ, so, iodine NPs contrast medium can be used with safety way to monitoring the working of this organ by CT-scan examination as shown in table 5. 

Cyclic voltammetry study
Iodine nanoparticles can be used as an alternative contrast method in a CT scan to diagnose tumors and abdominal organs safely and with good visualization, which helps the doctor give more brightness and high resolution to the image, in addition to the long time remaining in the organs, which gives the doctor the correct decision to give a good diagnosis.
Fig. 6 shows the periodic graph of iodine in a healthy blood medium that found an oxidation capacity of a peak current of -0.8 V, so iodine acts as an oxidizing reagent [16].
Fig. 7 illustrated the cyclic voltammogram of iodine nanoparticles in blood medium to fine the effect of nanoparticles on the blood components of rabbit  
In this study, the rabbit was used in vivo study by CT-Scan with iodine nanoparticles of contrast medium as an alternative of iodine solution, the imaging of CT for the different rabbit organs. 

CONCLUSION 
Through the study of the contrast media which used in the CT-Scan device and comparing them to the nano contrast media that given them some physical and chemical properties, it can be concluded that:
1. The results showed by using nanoparticle of iodine, it gives high resolution images with a lower concentration than using in micro-iodine
2. The half-life of the nano iodine in different organs is more than the period in which it remains, which gives a distinctive feature in facilitating the follow-up of important organs such as the heart and blood vessels to identify the problems that afflict them.
3. The nano contrast media are characterized by their ability to give high-definition images without side effects compared to micro-contrast media as in the iodine solution.
4. The electrochemical study showed that nano iodine solution is an antioxidant compound, as there are no oxidation current peaks in its cyclic voltammogram, but rather reduction current peaks in it, while in the micro-iodine composition, oxidation current peaks appear in the cyclic voltammogram of the iodine in blood medium, which causes blood oxidation, and gives a dangerous toxicity.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interests regarding the publication of this manuscript.