ISSN: 0975-766X CODEN: IJPTFI Available Online … Yadollahpour*et al. International Journal of Pharmacy & Technology IJPT ... Due to high cellular adsorption of ... we aim to discuss

Ali Yadollahpour*et al. International Journal of Pharmacy & Technology

IJPT| Sep-2016 | Vol. 8 | Issue No.3 | 14737-14748 Page 14737

ISSN: 0975-766X

CODEN: IJPTFI

Available Online through Research Article

www.ijptonline.com A REVIEW OF THE FEASIBILITY AND CLINICAL APPLICATIONS OF MAGNETIC

NANOPARTICLES AS CONTRAST AGENTS IN MAGNETIC RESONANCE IMAGING

Ali Yadollahpour*, Mostafa Jalilifar, Samaneh Rashidi

2Department of Medical Physics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences,

Ahvaz, Iran.

Email: [email protected]

Received on 02-07-2016 Accepted on 26-07-2016

Abstract

Applications of magnetic nanoparticles (MNPs) as Magnetic resonance imaging (MRI) contrast agent have been

widely developed during recent years. MNPs have some unique featuresthat make them interesting option in

biomedical applications. While almost all contrast agents for MRI affect both T1 and T2,the selective effects of MNPs

on one of T1 or T2 is usually more prominent, leading to the division of these probes to contrast agents of T1 and T2.

Among MNPs, paramagnetic NPs can affect T1relaxivity, called as T1- weighted contrast agent, whereas super

paramagnetic NPs are known as T2-weighted contrast agent. Due to high cellular adsorption of MNPs, they can

provide helpful differences between different cell types. The present study reviews the recent advances in

applications of MNPs as contrast agents in MRI and focuses on the clinical applications of these techniques in

different diseases.

Keywords: Magnetic nanoparticles, Magnetic Resonance Imaging, Contrast Agents, Clinical Applications, Disorders

1. Introduction

Emerging nanotechnology allowsscientists to work at the cellular levels to reachconsiderableadvances in the life

sciences. The unique size and physicochemical characteristics of nanoparticles (NPs) provides several advantages.

Although applications of NPs in life sciencesare still remain rarely, the amazing features of these particles forecast

greatfuture (1).

Among the wide spectrum of NPs which have beeninvestigated for biomedical applications, magnetic NPs (MNPs)

have absorbed considerableinterest. MNPs have some unique features, leading to increasing the interest of employing

them into biomedical applications. First, they can susceptible to magnetic field and they can be moved under the

influence ofmagnetic field. Next, their surface can be coated by functional groups which provide specific



physicochemical properties and versatility.In addition, their size can easily be controlled by managing experimental

conditions which make them appropriate to different applications(2, 3). Some of other important features of MNPs

for biomedical applications are injectability, biocompatibility, and high-level accumulation in the target. These

features make MNPs a goodoption for radiology and magnetic resonance (MR) imaging and etc(4). The important

biomedical application of MNPs are: a)MRI contrast enhancement agents (4-6), b) drug delivery(7, 8), c) magnetic

cell sorting schemes (9), d) nano biosensors (10), and e) Magnetic Fluid Hyperthermia(11).

Also the surfaces of SPIONscanhave several biomedical applications such as: drug carrier properties, magnetic

resonance imaging (MRI) contrast agents, and local heat induction (hyperthermia).For each application,MNPs must

havespecificfeatures(2, 3).For example, for data storage, in order to show information bits, particles must have a

stable, switchable magnetic statethat temperaturefluctuationscannot affect them.In addition,the nanoparticles must be

stable in water at pH 7 and in a physiological solution for diagnostic applications(12).

Using MNPsrepresentconsiderable new phenomenaincluding high field irreversibility, high saturationfield, and

superparamagnetism. These characteristics are mainly because of finite size and surface effects(13).

In this regard, applications of MNPs have gain considerable research attention both in diagnosis and treatment (14-

19). Each magnetic contrast agent should have some characteristics such as high magnetic susceptibility and high

saturation magnetization.

This papercomprehensively reviews the current clinical applications of MNPs as contrast agents in MRI for different

disorders. In addition, the practical challenges and important problems and limitations of using as contrast agent are

discussed and finally the clinical applications of MNPs as contrast agents in MRI techniques are reviewed.

2. MRI principles

MRI is a safe techniquethat appliedexternal magnetic fields to induce high resolution and high-contrastimages to

show tissue structure. MRItechnique is based on the response of proton spin under theexternal magnetic field. In the

presence of magnetic field, protons line up themselves in the direction of the applied field and their spins rotate

around the axis of field. Afterward, application of theRadio Frequency (RF) pulse leads to perturbation of aligned

protons. In this situation, the protons are transferred to an excited condition and then they return to their original

status(20). An MRI imagecan be generated from two relaxation procedures, T1-recovery (longitudinal relaxation

time) and T2-decay (transverse relaxation). The contrast of MRI image would be produces from the differences

between proton density, T1-recovery and T2-decay. Protons with lower T1 time generate high intensity signal and



protons which have longer T2 creates weaker signal and induce saturation phenomenon. T1-based images

demonstrate anatomical structures of body. So, they are preferred when clear image from structures of body is

required. T2-weighted images are generated by removing the effect of phase inhomogeneties of the applied magnetic

field. They give great pathological information in the case of appearing abnormal fluid in the background of normal

tissue. Due to the differences between fluid content of organs and tissues, MRI approach is widely used in medicine.

The ability of modern techniques of MRI in the distinction between damaged, tumoral and inflammatory tissue

depends on the utilized contrast agents. The most common contrast agents are paramagnetic metal ions such as Fe3+

,

Mn2+

or rare earth metals like Gd3+

which are known as T1 contrast agents. However, these materials have some

disadvantages such as toxicity and produce environmental problems. Therefore, many researchhave focused on using

biocompatible MNPs as the T2 contrast agents(21).In this regard, several scientists have offered promoting usual

contrast agents by enhancing their circulation time and decreasing their toxicity.

3) Contrast agents for MRI

In the majority of tissues, inherent changes of T1 and T2 are very small. Therefore, it is very common to use

substances to increase the contrast between the target and surrounding tissues. While almost all contrast agents for

MRI affect both T1 and T2 their effect on one of T1 or T2 is usually more prominent, leading to the division of these

probes to contrast agents of T1 and T2. The MR signal intensity has inverse relationship with relaxation rate of tissue.

Contrast agents can affect T1 and T2 in a way of changing relaxation rate of related to the T1 and T2. T1 contrast

agents improve the contrast of T1 images through increasing the MR signals'intensity while contrast of T2 images can

be increased by reducing the MR signal intensity. Now, we would like to survey T1 and T2contrast agents

individually. It was reported that the geometry of MNPs can affect their relaxation time, leading to alteration of T1

and T2 in MRI. In this regard, larger MNPs with their higher surface areaand long blood half-life caused to

improvement of T2 relaxivity for MRI(22).

4) Current applications of contrast agents

4.1) Paramagnetic materials

Paramagnetic materials improve T1-weighted image contrast by lengthening T1 relaxation time. Gdas a strong

paramagnetic material has been reportedly a promising candidate of contrast agent for imaging of central nervous

system disorders because of its ability to pass through the blood brain barrier fractures (BBB). Clinical applications

of Gd include detecting tumors before and after surgery, inflammation, and infection disorders, Infarction,



posttraumatic injuries. Also, it can be useful to improve normal contrast in extra-axial regions of BBB such as

pituitary gland, choroid plexus, and pineal gland. It was offered that Gd can detect any blockage or slow flow in the

brain artery. Also metastatic disorders can be showed clear using Gd especially at higher dose.

Furthermore, spinal cord injuries can be detected by employing Gd. In some cases, using Gd provide the possibility

of determining boundaries of injury and as well as it can clear some other anomalies such as syrinx. Additionally,

metastatic injuries of bone can be visualized by using Gd in MRI. In the case of assessing bone injuries by utilizing

Gd in T1-weightening images, it is necessary to use fat saturation techniques. Since both fat of bone marrow and Gd-

induced signal are bright, it is difficult to detect injuries. Thus, fat saturation technique suppresses the signal of fat of

bone marrow, leading to visualizing inner bone sites. SPIONs are another useful option which suppresses fat of bone

marrow and finally detects bone injuries.Gd coated with DTPA usually uses as contrast agent to detect the disease in

specified injuries. In this cases, the aggregation of Gd-DTPA in the interstitial space reveals damaged BBB (23)(24).

4.2) Applications of SPIONs in Clinical Setting

As mentioned above, SPIONs can improve the contrast of T2-weighted images by decreasing T2 relaxation time.

Now, we aim to discuss some applications of SPIONs in different classified diseases:

4.2.1) Bowel Imaging

Bowel opacification detection may be useful in specific conditions. For example, it is important to evaluate

pancreatic disorders and detect bowel pelvic injuries.MR bowel contrast is performed by two methods including

negative and positive(25). Negative bowel contrast agents reduce the motion artifacts and noises of associated to

bowel peristalsis whereas positive contrast agent action is based on enhancement of artifacts and noises(26).In this

regard, employing negative SPIOs leads to emergence of signal void from intestinal loops which may visualize intra-

abdominal lesions signal both in T2 and T1- weighted images. Also, negative SPIOs increase the contrast of MR

urography images by removing the annoying signals arising from fluid included adjacent bowel loops (27).

4.2.2) Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a chronicdisorder of the central nervous system (28) represented by inflammation and

axonalloss. At the early stages in the progression of MS injury, infiltration of inflammatory cells through damaged

BBB will be occurred(29, 30). (31, 32).With emerging MRI, considerable revolution was produced in visualizing and

diagnosis of MS (33, 34). Except Gd which can be useful T1-weighted images contrast in MS disorders,

USPIONsdisplays applicable potential to highlight inflammation in cellular level in MS disease (35).In addition,



USPIO can detect the distribution of injuries. Injection time of USPIONs play an important role in detecting injuries

in different sites so that if they are injected at the early steps of injury, they only visualize the lesion of caudal region

of brainstem, while they can demonstrate injuries in the mid regions of brain in the case of injection at theadvance

steps of the disease(36).

4.2.3.) Axonal Injury

Axonal injury refers to vast lesions in white matter of brain which can be diffused over widespread areas. Axonal

injury is difficult to detect specially with CT scan and other microscopic image techniques. MRI is more sensitive

than these microscopic techniques. However, MRI may also fail to detectaxonal injuries, because it visualizes the

injury using edema signs, which may not be present. USPIOs display great potential to enhance the contrast of MRI

in case of axonal injures and axonal loss (37).

4.2.4) Ischemic lesions imaging:

Using SPIONs provide the possibility to highlight ischemic injuries much earlier than conventional MRI. In this case,

SPIONs are used as T2-contrast agent so that increasing concentration of SPIONs in the ischemic injured sites

decreases the MR signal intensity, leading to visualizing differences between ischemic leisure and normal tissues.

4.2.5) Application of SPIONs in reticuloendothelial system imaging

4.2.5.1) Bone marrow imaging:

In order to visualize bone marrow injuries, bone marrow MRI can be an appropriate tool. Difficulty in bone marrow

detecting relates to the patients with red marrow hyperplasia. USPIOs provide the possibility to detect small tumors

and as well as determine the abnormal marrow from normal (38). Furthermore, USPIOs can be used as T2 contrast

agent to visualize soft tissue component of large injuries. In this condition, with aggregation of USPIO in the tumor

margins, the MR signal intensity is reduced(39, 40). Moreover, Breg et al (1999) reported that using SPIOs can detect

the vertebral marrow injuries in a way of decreasing the relaxation time of vertebral marrow in normal cases(41).

4.2.5.2) Lymph node imaging

It is very difficult to specified metastatic lymph nodes from normal lymph nodes without contrast agent. There is no

difference in the signal intensity of normal and metastatic lymph nodes. Also, it is not possible to detect differences

between metastatic nodes with normal size and large reactive lymph nodes. In order to solve this problem, it was

suggested that USPIOs as contrast agent can be appropriate choice for visualizing metastatic and normal nodes from

each other(42-44). With intravenous injection of USPIOs, it was absorbed by normal nodes, causing to decrease the



MR signal intensity of normal nodes on T2-weighted image whereas any differences in the MR signal intensity of

metastatic nodes was not observed (42). In some cases, the differences between lymph nodes have been detected by

their size but this strategy cannot be reliable(45). Metastatic nodes may be missed if the size of nodes is considered as

classified factor (42). In this area, one example is detection of benign from metastatic nodes which is difficult to

identify. Vassallo et al (1994) offered that SPIOs can be appropriate option to visualize tumor nodes from reactive in

a way of increasing the cancer node sensitivity. Also, reactive lymph nodes have functional macrophages(46). It was

reported that the excellent time for imaging using contrast agent is 24h after SPIO injection(44). Due to intravenously

injection of USPIO, it is feasible to detect all lymph nodes of body with a single injection. In addition, it is possible to

inject these contrast agents intramuscularly. In this condition, the contrast agent can be derived to the nearest lymph

nodes to the injection area(6).

4.2.5.3) Liver and spleen imaging

With intravenous injection of SPIOs, they rapidly concentrate in the RES cells of spleen and liver. As mentioned,

these materials reduce the MR signal intensity in T2-weighting image leading to increase of MRI contrast. It was

showed that SPIOs can not affect the signal intensity and thus contrast agent of the superficial injuries without RES

cells. However, using SPIONs can be a useful option in increasing tumor-to-liver contrast on T2-weighted MRI(47).

Seneterre et al (1996) demonstrated that using ferumoxide can increase the visualization of metastatic lesions(48).

Also, contrast-enhanced T2 image was observed as a result of ferumoxide injection in liver lesions (49).

The contrast- enhanced effects of SPIOs were investigated in MR angiography of liver artery and venous system. It

was reported that aggregation of SPIOs in a way of trapping by phagocytes suppressed background signal of liver,

leading to increase of MRI contrast(50). Additionally, SPIOs were used to visualize hemangiomas from malignant

livertumors. Due to higher SPIO absorption of hemangiomas as compared with malignant during both distribution

stage (when SPIONs still remain in circulation) and retention phase of SPION injection, T1relaxivity is increased,

leading to increase of MR signal intensity of hemangiomas on T1- weighted image. Therefore, hemangiomas become

more bright than malignant tumors(51). In fact, the amount of raising T1-weighted image signal intensity and

reducing T2-weighted image signal intensity are considerably higher comparing with malignant liver tumors (52, 53).

4.2.6) Application of SPIO for MR angiography

Since 1996 several studies have attended to use USPIOs for MR angiography in humans (54, 55). These materials

should be injected as a form of blood pool agents. The main privilege of employing USPIOs for MR angiography



technique is their ability to increase acquisition time and also they prevent increasing interstitial background. In this

regard, it was demonstrated that using AMI-277 can improve detection of renal artery length and right coronary

artery(54, 55). Taylor et al (1999) conducted an extensive study for examining the effect of using NC 100150 in

coronary artery detection.

They injected NC 100150 to 18 healthy persons to investigate its effect on the quality of coronary MR angiography.

They reported that, using NC 100150 led to improvement of coronary artery visualization while major side effect was

not observed(21).

Furthermore, Ahlstrom et al (1999) reported that injection of NC 100150 can increase the quality of MR angiography

of the pulmonary vasculature (22). Also, the contrast-enhanced effect of NC100150 was investigated in a

gastriotestinal bleeding. It was proved that using NC100150 can be a useful choice for improvement of detecting all

bleeding sites in animals with aggregation of these materials in the peritoneal and intestines sites (56).

5) Conclusion

The recent advances in MNPs as MRI contrast agents haveprovided the possibility to improve the quality of MRI,

leading toimprove diagnosis of disorders.

MNPs can affect the sensitivity of detection with MR imaging techniques in a way of increasing T1 or decreasing T2

relaxation time of adjacent water protons. Paramagnetic NPs are known as T1 contrast agents because they often

actbased on increasing T1.Gd is the most important T1 contrast agent which is widely used to improve T1-weighting

images.Using Gd may produce some side effects such as headache, nausea, and gastrointestinal disturbances. Unlike

paramagnetic NPs, SPIONs increase the T2-weighting image contrasts by reducing T2 of adjacent water protons. The

size of these MNPs plays an important role in determining their applications. SPIONs with the range size of 10-60

nm are great option for acting as contrast agent.

These materials can be helpful in a way of diagnosing small tumors, detecting characteristics and differences of normal

and injured bone marrow and some central nervous system disorders. Using these materials may produce similar side

effects with Gd.

In addition, SPIONs may lead to inducing backache and sometimes hypotension.In order to reduce toxicity and

increase the stability of SPIONs, they should be coated by stable and a biocompatible material which is one of the

most important problems in development of using SPIONs in biomedical applications. Moreover, the dose of injected

SPIONs should be controlled because high dose of SPIONs may produce serious problems.



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Corresponding Author:

Ali Yadollahpour*,

Email: [email protected]

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ISSN: 0975-766X CODEN: IJPTFI Available Online … Yadollahpour*et al. International Journal of Pharmacy & Technology IJPT ... Due to high cellular adsorption of ... we aim to discuss