1. C27
Gold Nanoparticles

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3. Objectives Define a CT Scan. Discuss the use of CT contrast agents.
Discuss gold nanoparticles interactions with the body.
Differentiate between gold nanoparticles and iodine contrast agent.
The discovery and usage of gold nanoparticles.
Future of imaging using nanoparticles as a ct contrast agent.

4. Table of Contents F. Different Contrasts Used Iodine
What is CT?
How Does CT Contrast Work
Iodine Contrast
Risk Factors
What Makes Gold Nanoparticles Special?
Gold Nanoparticles
How They Work
Interactions With the Body
F. Different Contrasts Used
Iodine
Gold Nanoparticles
G. Discovery
H. Case Study
I. Future of CT Contrast
J. Conclusion
K. References

5. What is CT? Computed tomography is also known as CT
Cross-sectional images that can be reformatted into in multiple planes or 3D images
Uses a motorized x-ray tube that is rotating in a donut-shaped gantry
The patients will move in and out of the gantry while the x-ray tube spins around them
This thin beam of x-rays are shot
through the patients onto detectors
More in depth viewing of the
anatomy than a diagnostic x-ray

6. How does CT Contrast Work
CT uses an iodine based contrast which has a short blood half-life
Contrast is injected through an IV to highlight the vessels and organs of the body
Dense structures can be well
visualized while soft tissue cannot
Contrast is used to visualize blockages
in the blood vessels or cancerous
growths
Cancers can be easily missed due to size and lack of appropriate contrast

7. How Does CT Contrast WORK (Continued)
Iohexol has a benzene core with three iodine atoms for CT
contrast and three amide and six alcohol groups for water
solubility and low osmolality1

8. Risk Factors
Risk factors of using iodine based contrast is renal function and allergic reactions
GFR >30 for renal function and 13 hour allergy preparation for an allergic reaction
If a patient is on dialysis and their GFR is below 30 they are still able to receive the contrast dye
Normal symptoms of contrast are:
1. warm, flushed feeling through your body
2. you feel like you are urinating
3. metallic taste in your mouth

9. What Makes Gold Nanoparticles Special?
Usually about nanometers and are used as tracers along with a contrast agent
Gold nanoparticles are particularly useful in Photo-thermal therapy (PTT)
PTT is a minimally invasive technique for cancer treatment that uses laser-activated photo-absorbers to convert photon energy into heat to induce cell destruction via apoptosis, necroptosis, and/or necrosis3,7
Gold is a good conductor of heat and electricity, making it a useful candidate as a photo-thermal sensitizing agent

10. Gold Nanoparticles
Gold Nanoparticles are also referred to as colloidal gold or nano-gold
Gold nanoparticles absorb light strongly and convert photon energy into heat quickly and efficiently

11. Gold Nanoparticles (Continued)
According to Recent Advances in Cancer Therapy Based on Dual Mode Gold Nanoparticles, “One “competitive edge” of NP is that they can be attached to specific cancer cell targets with non-invasive implementation increasing the cellular uptake efficiency, selectivity and localization in tumor cells and tissue.”3,7 `

12. Gold Nanoparticle (Continued)
With their “enhanced permeability and retention effect,” meaning they have the ability to collect in a tumor much more than they would in normal tissue
Widely applied coating polymer is polyethylene glycol (PEG),which is neutral in charge and highly hydrophilic, preventing nonspecific protein adsorption on the surface of the nanoparticles8
The blood circulation time is lengthened by the uptake of reticuloendothelial system8
Polyelectrolyte layer-by-layer wrapping, coating with proteins such as bovine serum albumin74 or silica75 coatings 8 `

13. Different Contrasts Used
The k-edge of iodine has a keV of 33.2 and when scanned between kV it is found that the iodine contrast attenuates better at 80 kV
The K-edge of gold is 80.7 keV, the gold will attenuate better than iodine contrast when the kV is at 120 kV rather than 80 KV
Higher kV, the preferred contrast would be gold nanoparticles instead of iodine
“Gold produces about 2.1 times the contrast of iodine scanned at 120 kV”1
NP last longer in the body than iodine contrast, NP can last up to 15 hours, reducing the amount of repeat injections of contrast for exams done later in the day
No allergies are noted from using gold nanoparticles and there is no effect of the renal system, therefore the patients GFR does not need to be >30

14. Gold Vs. Iodine in Simulated Blood Vessels

15. Discovery
Colloidal gold has been around since ancient times and was originally used to stain glass.
It was rediscovered by Michael Faraday in the 1850s and almost immediately became one of science’s favorite substances
Dr. James F. Hainfeld, displayed the use of gold nanoparticles as a contrast agent in CT in a study he did on mice to detect tumors.
With that, Popovtzer used the gold nanoparticles
to target head and neck cancer pAssively and actively.
(Case study discussed later)

16. Discovery (Continued)
In 2005 it was discovered that coating bacteria with nano-gold renders it extremely useful as a coating for electronic wiring.
The bacteria carry a negative charge and the nano-gold carries a positive charge after being treated with nitric acid.
These coated bacteria are able to absorb water and conduct a more efficient electrical current after the gold has been introduced, making them more efficient and more cost-effective elements of electronic production.
Medical researchers are still investigating the possibilities for silver nanoparticles, but lab technicians have found that injecting gold nanoparticles into rats can relieve many symptoms of rheumatoid arthritis.

17. HAINFELD’S Initial Discovery
Micro-CT planar X-ray :
Kidneys in live mouse 60
minutes after iV injection of
A. gold nanoparticles
B. “iodine contrast medium (Omnipaque H). Arrow: 100 nm ureter (Bar = 51 mm) (High-resolution image).” 9
C. “Cancer imaging: X-ray of mouse hind legs showing accumulation of gold and significant contrast (white, arrow) in tumor growing on leg on left,” “Longer residence time in blood results in a significantly higher tumor”9
D. “Micro-CT showing resolution available with gold nanoparticle contrast agents: 3 nm section of mouse abdomen after gold nanoparticle injection, showing branching of inferior vena cava and 25 µm blood vessels”9

18. Case Study: Mice and Gold Nanoparticle
What kind of cancer was being detected?
Head and neck squamous cell carcinoma (SCC)
What the nanoparticles are:
In this case study 30 nanometers was the size of gold nanoparticles used. They were anti-EFGR or anti- epidermal growth factor targeted because SCC has a high EFGR. They were all uniform narrow spheres and were prepared using sodium citrate.
Human head and neck cancer tumors were formed in mice in order to experiment the ability of CT to detect tumors with the use of gold nanoparticles.
The tumor was approximately 4-5 mm in diameter and was undetectable without the use of gold nanoparticles.

19. In Vivo CT imaging
Active tumor targeting is more efficient than passive tumor targeting based on the results below.
There is distinct elevated tumor uptake and retention with active targeting.
Passive tumor targeting makes the gold nanoparticles rapidly clear from the tumor and accumulate in the liver, kidneys and spleen. This is because passive targeting “takes advantage of the leaky nature of the tumor vasculature.” Although the contrast reaches the tumor it is actively cleared.
The signal or the CT number of the organ post injection in the active study was significantly higher in the active study when compared to the passive study.

21. Mice Images Explained
“In vivo X-ray computed tomography (CT) volume-rendered images of (A) mouse before injection of gold nanoparticles (GNPs), (B) mouse 6 hours postinjection of nonspecific immunoglobulin G GNPs as a passive targeting experiment, and (C) mouse 6 hours post injection of anti-epidermal growth factor receptor (EGFR)-coated GNPs that specifically targeted the squamous cell carcinoma head and neck tumor. The anti-EGFR-targeted GNPs show clear contrast enhancement of the tumor (C, yellow arrow), which was undetectable without the GNPs contrast agents (A, yellow arrow). CT numbers represent the average Hounsfield units (HU) of the whole tumor area. All scans were performed using a clinical CT at 80 kVp, 500 mAs, collimation × 64 mm and pitch size (64 detector CT scanner, LightSpeed VCT; GE Healthcare, Little Chalfont, UK).” 10

22. Results 0-3 hours into the experiment after injection:
No difference was observed between the accumulation of active and passive targeted particles.
3-6 hours later:
Steady elevations in accumulation of actively targeted gold nanoparticles, and non targeted particles were slowly cleared from the tumor.
At 6 hours:
Maximum accumulation of the actively targeted nanoparticles.
The CT number of the tumor at this point was over fives times higher than the CT number of the same tumor in the same mouse before the injection of gold nanoparticles

23. Case Study Conclusion
In conclusion, molecular CT imaging is possible with gold nanoparticles.
Targeted gold nanoparticles display a higher attenuation on CT x-ray than iodine contrast.
Distinct assembly of particles on a cancerous tumor sight, make it easy to differentiate from other abnormalities in the body.
The CT number was five times more in active tumor targeting when compared to passive targeting.

24. Future of CT Contrast
Imaging is one of the most important roles in cancer diagnosis, treatment, and radiation treatment and planning
Imaging modalities such as MRI, CT and ultrasound cannot detect tumors smaller than 0.5 centimeters
CT is not currently a molecular imaging tool, but because of high demand due to cost, speed and high attenuation of bones, fluid, and tissues when contrast is used, molecular imaging would give CT a one-up to other diagnostic imaging modalities
“Gold nanoparticles provide a high degree of flexibility in terms of functional groups for coating and targeting, and have also proved to be nontoxic and biocompatible in vivo”6
The FDA has approved gold nanoparticle use in in-vitro and in clinical trials as cancer and cardiovascular treatments

25. Conclusion
Gold nanoparticles are new and are just beginning to emerge as a molecular contrast agent.
It is foreseen that gold nanoparticles have a bright future given the results found thus far.
Main points to take away:
Gold nanoparticles attenuate at a higher level than iodine contrast.
They have been FDA approved to be used in clinical trials.
They have already been successful in the testing done on mice .
Gold nanoparticles last longer than iodine contrast, 24 hours vs. a few minutes in body can make a big difference in the health and cost for the patient.
Cancer is the number two killer in the U.S., therefore any advancements made in early detection of cancer is a step in the right direction.

26. References
1. Cormode DP, Naha PC, Fayad ZA. Nanoparticle Contrast Agents for Computed Tomography: A Focus on Micelles. Contrast media & molecular imaging. Published January Accessed January 1, 2018.
2. Molnar H. Tumor Ablation. Johns Hopkins Medicine, based in Baltimore, Maryland. Published April 14, Accessed January 1, 2018.
3. Enhanced permeability and retention effect. Wikipedia. Published December 31, Accessed January 2, 2018.
4. Computed Tomography (CT). National Institute of Biomedical Imaging and Bioengineering. Published February 2, Accessed January 1, 2018.

27. References (Continued)
5. Galper MW, Saung MT, Fuster V, et al. Effect of computed tomography scanning parameters on gold nanoparticle and iodine contrast. Investigative radiology. Published August Accessed January 3, 2018.
6. Popovtzer R, Agrawal A, Kotov NA, et al. Targeted Gold Nanoparticles enable Molecular CT Imaging of Cancer. Nano letters. Published December Accessed January 3, 2018.
7. Spyratou E, Makropoulou M, Efstathopoulos EP, Georgakilas AG, Sihver L. Recent Advances in Cancer Therapy Based on Dual Mode Gold Nanoparticles. Cancers. Accessed January 3, 2018.
8. Mieszawska AJ, Mulder WJM, Fayad ZA, Cormode DP. Multifunctional gold nanoparticles for diagnosis and therapy of disease. Molecular pharmaceutics. Published March 4, Accessed January 4, 2018.

28. References (continued)
9. Available at: Accessed February 3, 2018.
10. Reuveni T, Motiei M, Romman Z, Popovtzer A, Popovtzer R. Targeted gold nanoparticles enable molecular CT imaging of cancer: an in vivo study. International Journal of Nanomedicine. Published Accessed February 1, 2018.
11. Medscape Log In. Accessed March 27, 2018.
12. Shilpi S, Khatri K. Gold Nanoparticles as Carrier(s) for Drug Targeting and Imaging Published August 31, Accessed March 27, 2018.