Improved MRI Cancer Imaging Using Gadolinium As the Contrast Agent in Short Single Walled

Improved MRI Cancer Imaging Using Gadolinium as the Contrast Agent in Short Single Walled Carbon Nanotubes

Dr. Mary Frame McMahon

Group C

Juan Bastidas

Eric D’Ambrosio

Mohammad Reda El Mkhantar

James Mutino

Peter Nazaroff

Jaekang Yoo

Faculty Advisor Dr. Balaji Sitharaman

Undergraduate TA Samantha Rossano

Background

Cancer is a disease that has been found in humans and other animals since the beginning and has become recently more infamous. According to the American Cancer Society website over 13 million people in the United States have had some sort of invasive cancer, and that one in three Americans will have some sort of cancer in their lifetime[1].

Cancer is a disease caused by unregulated cell growth of abnormal cells. Cells become cancer cells because of some sort of DNA damage. DNA damage can come from a wide range of places; mutations can be genetically inherited, caused by some malfunction in cellular mitosis or caused by external forces such as radiation[1]. There are even viruses known as Oncoviruses, which can cause cancer[1].

Cells become cancerous when they continue to grow and proliferate when they shouldn’t be. In eukaryotic cells, cell division occurs by two processes, mitosis and meiosis. Meiosis is only used to create gametes for sexual reproduction. Mitosis occurs in humans for reasons such as growth and repair and is usually regulated by certain checkpoints. The first checkpoint is known as the G1 checkpoint or the restriction checkpoint[6]. This checkpoint is where the cell decides whether it should divide, delay division or enter a resting phase. Their surrounding cells, or environmental conditions signal healthy human cells when it is time to enter mitosis [6]. Cancerous cells proliferate no matter what kind of external signaling they receive[1].

Cancer cells can sometimes form into clumps that are known as tumors. Many methods for detecting cancer involve the imaging of tumors, however some cancers such as leukemia (cancer of the blood cells) do not form tumors and some tumors aren’t cancerous [1]. Tumors that are benign can grow and press up against other organs, but will not spread. The spreading of cancerous cells from their point of origin to other organs is known as metastasis[6]. Tumors that are capable of metastasis are known as malignant tumors[1].

The first recorded description of cancer was in Egypt around 3000 B.C. and refers to 8 cases of tumors on the breast [1]. The origin of the word Cancer comes from the Greek “carcinos” and “carcinomas”, which Hippocrates used to describe tumors that did or did not cause ulcers[1]. Like most other diseases, the lack of technology severely limited our early understanding of cancer. The development of certain enabling technologies and improvements in cancer imaging has improved our understanding of this disease dramatically.

Until the 19thcentury and the development of the modern microscope, most information from cancer came from autopsies. During the 1700s John Hunter, the Scottish surgeon, suggested that certain cancers could be removed[2]. However without any sort of imaging technology a surgeon would be forced to go into surgery blind and try to find the tumor and hopefully it could be removed.

With the invention of the compound light microscope and the work of Rudolf Virchow the study of cancer pathology was born. Virchow used microscopes to study cancerous tissues at the microscopic level[2]. His work allowed him to study the damage that cancer did to tissues, and also allowed the study of tumors once they had been removed to obtain a better diagnosis.

The 19th century also saw an increase in cancer imaging technology. Inventions such as the gastroscope and the cystoscope were invented in the late 1800s and used to detect cancer in the lower esophagus/stomach and bladder, respectively [2]. In 1896 Dr. Franz Konig used the newly invented x-ray to examine a leg that he had amputated and discovered that there was a sarcoma of the tibia [2]. The invention of the X-ray and the discovery that it can be used to find tumors inside of the body started the modern age of cancer imaging and paved the way for more advanced imaging techniques[2].

During the twentieth century we observed the use of our most advanced technologies in the field of cancer imaging and the invention of techniques that we use today. In 1902 Willem Einthoven took the first ECG reading; ECG’s are used to diagnose renal cancer [2]. In 1941 George Papanicolaou invented the technique known as the Pap smear for detecting pre-cancerous and cancerous cells inside the female genital tract [2]. In 1951 Raul Leborgne used a cone and compression pad to X-ray human breasts in order to image breast cancer, and paved the way for the modern mammogram [2].

The 1970s saw monumental improvement in cancer imaging and gave birth two three of our modern forms of noninvasive medical imaging. In 1972 Godfrey Hounsfield used X-ray imaging and computer assisted analysis to create cross sections of organs and other body parts[2]. This invention is known as the CT scan.

In 1974 the first positron emission topography scanner was used[2]. PET scanners use the detection of radiation from chemicals introduced to the body to produce a high-resolution computerized image, which show biochemical activity of observed structures. In 1973 one of the most important inventions in modern cancer imaging came into existence[2]. Magnetic resonance imaging reads a radio frequency emitted by excited hydrogen atoms in the body as the result of a large and uniform magnetic field[13].

Before MRI, we used x-ray to investigate human body[6]. There are two ways to use X-ray, conventional x-ray imaging and computer tomography[6].

To begin with, x-ray is a form of electromagnetic radiation. It can pass through solid objects so that it can be used to create images of human body, in which the image is a spatial map of the object’s susceptibility to penetration by the rays[6]. X-rays have two useful properties for imaging[6]. First, X-rays penetrate the human body translucently at certain wavelengths [6]. It means the rays pass through the body, also, they are partially absorbed as they penetrate at the same time [6]. The denser tissue density there is in the path of the x-rays, the more the fraction of radiation that is absorbed[6]. Second, x-rays have the ability to expose photographic film like visible light[6].

For conventional x-ray imaging, the x-ray beam penetrated through a body and will expose film[6]. An x-ray image is a negative image[6]. The film is darker where the tissue of the body is less dense and lighter where is moredense, which means dark parts occur where the body has lighter elements such as flesh, allowing more x-rays to penetrate through [6]. In contrast, light regions occur where the body is dense with heavier elements such a bones, which allows fewer x-rays to expose the film[6]. In other words, an x-ray image is like a shadow[6]. The conventional x-ray process can just make two-dimensional image with three-dimensional body [6]. It just represents the penetration of radiation through the body onto a two-dimensional plane [6]. This kind of imageis called a projection[6]. X-ray images can be used in medical inspection because it can show fractures and breaks in bones, fluid in lungs, cavities in teeth and cancer in breasts[6]. If there is a big difference in the density of the tissue, such as with soft tissue and air, bone and soft tissue, or water and soft tissue, it can provide good contrast and make nice images [6]. The most common applications of x-ray imaging is the chest x-ray, which physicians use to search infection within the lungs, fractures in the bones of the rib cage, and certain kinds of heart disease[6].

However, CT uses x-raysin a different way. It uses x-ray to produceimagesof specific areas of the scanned object, which allows the user to see what is inside it without cutting it open [6]. When the patient goes into the CT imaging system, rotating x-ray sources workwithin the circular opening, and x-ray detectors also rotates in synchrony all around the patient [7]. The x-raysource makes a narrow, fan-shaped beam [7]. The patient is moved into x-ray generator and the detectors and it can create an image of one cross-section through the body at a time[6]. The table moves the patient’s position to image each slice[6]. Computer will process all the data to prepare a series of imageslices into a three-dimensional view of the certain organ or body region [7]. However, since CT uses x-rays to make images, there can be a risk of damage to DNA in human body, which can cause cancer [7]. In comparison, MRI does not use x-rays and there is less chance to expose to damage [6].

MRI, which is used as device in this paper, is a medical imaging technique by visualizing internal structures of the body[6]. It provides detailed three-dimensional images, especially of soft tissue that cannot easily be imaged in other modalities, such as CT [6]. MRI is also pretty versatile. We can use it in many different ways such biochemical composition, tissue function, and molecular diffusion, as well as structure [6]. MR scans properties of the magnetic dipole (spin) of atomic nuclei at magnetic fields[6]. It uses hydrogen nuclei (protons), which will be aligned in a large magnetic field[6]. When a person is placed into the magnetic field of an MR scanner, the magnetic moment vectors of their hydrogen nuclei align parallel with the direction of the field[6]. A short radio frequency of electromagnetic radiation is applied in a plane perpendicular to magnetic field, creating a new magnetic field, which is called transverse magnetic field[6]. This radio frequency is known as the resonance frequency that flips the spin of the protons in the magnetic field[6]. After the electromagnetic field is off, the hydrogen nuclei spontaneously begin to return to their original equilibrium configuration[6]. During this process, they release RF energy, which can be found by the receiver coils surrounding the person[6]. The produced signals are recordedand the resulting data are processed to generate an image[6].Hydrogen nuclei in different parts return to their original equilibrium configuration at different relaxation rates [6]. The returning time to equilibrium position is categorized by the longitudinal relaxation time (T1) and the transverse relaxation time (T2)[6]. The amount of brightness in MR is resulted by proton density, T1 relaxation, and T2 relaxation within the particular tissue[6]. T1 relaxation shows nice contrast for different types of soft tissue, while T2 relaxation is good for pathology[6].

MRI imaging has improved since 1973 with the advancement of computers and the technology surrounding the MRI [2]. However the MRI scanner is still limited in resolution by the T1 relaxation times of hydrogen atoms, which is about 3600 ms [33]. Finding small masses of tissue that don’t belong can be difficult with this limited resolution [33]. In order to identify tumors in a more efficient way there needs to be better contrast in MRI imaging[33].

Thanks to the nature of the MRI machine, there are certain chemicals and chemical compounds that improve the contrast of MRI images. The fact that MRI becomes common in use of medical purpose has made the invention of a new kind of pharmacological products, which is called contrast agents [8]. MRI contrast agents are injected to enhance the image of blood vessels, tumors or inflammation[8]. By far the most common is the gadolinium-based agents [8]. Gadolinium is a high paramagnetic ion with seven unpaired electrons and has comparably long electronic relaxation time, which makes it an excellent relaxation agent[8]. It disturbs the local magnetic field of nearby protons and results in a shortening T1 and T2 relaxation time[8]. It means relaxation rate increases, either longitudinal (1/T1) or transverse (1/T2)[8].

These MRI contrast agents have a shorter T1 time then hydrogen atoms and help MRI images produce a more detailed image of the area in question[8]. Most MRI contrast agents are derivatives of the Gadolinium^3+ ion[4].

Gadolinium is a silvery white metal that is malleable and ductile [3]. What makes Gadolinium important as a contrast agent is it’s symmetry, magnetism and the fact that it has the highest number of unpaired electron spins (7 unpaired electrons) [3] , which gives Gd(III) at 5 ppm a T1 time of 1600 ms [33]. This shortened T1 relaxation time produces a clearer image in an MRI and makes spotting things like tumors much easier[5].

Gadolinium is a very useful tool in cancer imaging, but unfortunately there are some problems that can arise from its use. Gadolinium has been known to cause a rare but serious disease in some people who have kidney problems [4]. This disease is called Nephrogenic Systematic Fibrosis (NSF) and causes fibrosis in the skin and connective tissue and can even result in death [4]. If there was a way that Gd(III) could be in the body so that it could improve MRI contrast but be encapsulated so that it does not react with any parts of the body then this problem could potentially be eliminated[4].

Ultra short carbon nanotubes allow for gadolinium to be present in the area of the body being imaged, without exposing the ion directly to anything else in the body. Carbon nanotubesare a cylinder-shaped nano-material, which is made of carbon [9]. They havea lot of kinds of structures, length, thickness, and number of layers [9]. Carbon nanotubes usually have up to 50 nm diameters [10]. Their lengths are typically several microns, but recently they can be made much longer, and measured in centimeters [10].Carbon nanotube was highlighted from when we could research and deal with carbon tubules in nano-meter dimensions [9].

Carbon nanotubes are usually produced by threemethods: arc-discharge, laser ablation, and chemicalvapor deposition [10]. Among three methods, the last one is the most widely usedcommercial method to prepare carbon nanotubes [10]. Thisprocess generally involves reaction of a metal catalyst with ahydrocarbon at very high temperatures toproduce carbon nanotube [10]. Nanotubes, which are made by chemical vapor deposition, commonly have metalcatalysts on the surface of outside of thenanotube [10]. Because metal catalysts, typically nickel can be usedto make carbon nanotubes bigger, there can be a problem with carbon nanotubes being cytotoxic [10]. Therefore a purification stepis highly required before we can use carbon nanotubes forbiomedical applications [10].

There are also several methods for purifying carbonnanotubes [10]. The most popular method is refluxing carbon nanotubes in anoxidizing acid such as nitric acid [10]. This process includes oxidizing andremoving the metal catalysts fromboth the inside and outside of the tube [10]. Besides, any defects in the tube can also be oxidizedwhile it makes additional groups of carboxylic acids along the tube [10]. These carboxylic acid groups can bemore functionalizedallowing tuning of the surfacechemistry of the nanotube [10].

Carbon nanotubes become popular for biomedical applications because of its composition, high aspect ratio and properties [10]. The number of articles about it has been doubling each year since the year 2000 [10].

Design Criteria

In the invention of Shortened Carbon Nanotubes in [21] by Wilson and Bolskar, they illustrate a carbon nanotube of a distance end to end in range from 20 nm to 50 nm [21], and containing gadolinium as a contrast agent [21], which is able to significantly improve the level of detail in the MRI, therefore increasing its image quality [21]. In fact, we want to expand the relaxivity [11], known as the variation of the proton’s relaxation rate divided by its particular molarity, and the standard units are mM^-1*s^-1 [11].

In order for this specific invention [21] to work perfectly, we have several special conditions in [21] which will further be discussed here.

The design in [21] includes a carbon nanotube, meaning a category of fullerene, containing an extended cylinder that is composed of 5 and 6 components in each ring [21]. There can be single walled carbon nanotubes, which include only one cylinder around an axis [21], and there can also be multi-walled carbon nanotubes, which enclose two or more than two cylinder of carbons around a specific axis [21]. Moreover, their sizes might vary, and so the ideal carbon nanotubes for the invention in [21] will be a single walled carbon nanotube and in the range of 20 nm to 50 nm [21].

There is a big difference between both single walled and multi walled shortened carbon nanotubes [21]. In this paper the main focus is on single walled carbon nanotubes [21]. Carbon nanotubes are all composed of folding graphite layers into carbon cylinders which can form single layers or multiple layers [20]. Single walled carbon nanotubes are the best choice for bio imaging in such circumstances as an MRI [20]. This is because in general, single walled have a smaller diameter then multi walled nanotubes [20]. The first big issue with multi walled carbon nanotubes is that it is more difficult to fill them with contrast agents [20]. Transport of the contrast agent into the nanotubes is reliant on holes opening in the tubes at high temperatures [19]. There is little to no open gates (holes) in multi walled carbon nanotubes since there is not much change in voltage at the walls [20]. This being said it is much harder for contrast agents such as gadolinium to permeate the nanotube [20]. The opposite is true for single walled carbon nanotubes which are much more permeable under the same conditions [20]. Single walled nanotubes have a much higher conductance at the walls when heated, which provides a higher carrying density and ability to transfer through holes in the walls [20]. The second big issue with multi walled carbon nanotubes is that they will have much more trouble showing up in bio-imaging then single walled [20]. This lowers resolution in imaging because of the thicker diameter of the walls, and the fact that there is a low open gate effect so electrons are not detected as easily from the outside of the nanotube [20]. Actually, multi walled carbon nanotubes throw off the ability to see the contrast agents within since they have a larger electronic structure themselves [20].