Gold nanoparticles in chemotherapy and radiotherapy is the use of colloidal gold in therapeutic treatments, often for cancer or arthritis. Gold nanoparticle technology shows promise in the advancement of cancer treatments. Some of the properties that gold nanoparticles possess, such as small size, non-toxicity and non-immunogenicity make these molecules useful candidates for targeted drug delivery systems. With tumor-targeting delivery vectors becoming smaller, the ability to by-pass the natural barriers and obstacles of the body becomes more probable. To increase specificity and likelihood of drug delivery, tumor specific ligands may be grafted onto the particles along with the chemotherapeutic drug molecules, to allow these molecules to circulate throughout the tumor without being redistributed into the body.
Physical properties
Size
Gold nanoparticles range in size depending on which therapy they are being used for. In photothermal cancer therapy, many gold nanoparticle molecules are used in each test and they must all be uniform in size. Including PEG coating, the nanoparticles measured to be ~130 nm in diameter. Gold nanoparticles that act as drug delivery systems in conjugation with chemotherapeutic drugs typically range in size from 10 to 100 nm.
Surface area plays a very important role in drug delivery and per mg of gold, as diameters decrease, the surface areas needed to transport drugs increase to the point where a single 1mL volume of 1.8 nm spherical gold nanoparticles have the same surface area as a cell phone.Gold Nanoparticle Properties and Applications
Drug vectorization requires greater specificity, and are synthesized within the single digit measurements ranging from 3-7 nm.
Antibacterial treatments are testing different sizes for cell type targeting; 10, 20 and 40 nm.
Color
Due to the ability to tune the size and absorption of AuNPs, these molecules can vary in the colors they emit. Colors of AuNP solutions typically range from wine red to pale blue. These colors play a necessary role in the synthesis of AuNPs as indicators of reduction. The color of AuNPs can be modified by the application of pressure which reddish the nanoparticles.
Synthesis For more on synthesis of AuNPs for medical use, see Colloidal gold
Other synthesis may include cell type targeting. A tumor consists of a multitude of cell types, and thus targeting a single type of cell is ineffective and potentially dangerous. At most, this type of targeting would only have a minor effect on killing the tumor. Tumors are constantly changing and thus phenotype targeting is rendered useless. Two main problems persist: how to get to the target and how to destroy a variety of cells.
Treatments
Photothermal cancer therapy
A direct method of accessing and destroying tumour cells can be accomplished by photothermal cancer therapy or photodynamic therapy (PDT). This procedure is known to treat small tumours that are difficult to access and avoids the drawbacks (adverse effects) of conventional methods, including the unnecessary destruction of healthy tissues. The cells are destroyed by exposure to light, rupturing membranes causing the release of digestive enzymes. AuNPs have high absorption cross sections requiring only minimal input of irradiation energy. Human breast carcinoma cells infused with metal nanoparticles in vitro have been shown to have an increase in morbidity with exposure to near infrared (NIR). Short term exposure in vivo (4–6 minutes) to NIR had undergone the same effect. Hirsch et al observed that extreme heating in tumours would cause irreversible tissue damage including coagulation, cell shrinkage and loss of nuclear straining. Results of their in vivo nanoshell therapy of mice revealed penetration of the tumor ~5mm.The metal particles were tuned to high absorption and scattering, resulting in effective conversion of light into heat covering a large surface area. The El-Sayed group studied AuNP effects in vitro and in vivo. They determined that the NIR wavelengths were converted into heat on the picosecond timescale, allowing for short exposure of CW to minimize possible exposure to healthy cells. In vitro, photothermal therapy was used in oral epithelial cell lines, (HSC 313 and HOC 3 Clone 8) and one benign epithelial cell line (HaCaT). El-Sayed et al found that the malignant cells that had undergone incubation in AuNPs conjugated with anti-epithelial growth factor receptor (EGFR) required half the energy to destroy a cell than a benign cell. Their material included gold coated silica nanoshells that could selectively absorb NIR waves. The particles were tuned by varying the thickness of the Au shell and changing the size of the silica core. In exposing these particles to NIR, the efficacy of Au was measured through the decrease of EFGR in oral squamous carcinoma cells. There are various biotechnological advances for in vivo delivery of drugs. To effectively target the malignant cells, the AuNPs were conjugated by polyethylene glycol, a process known as PEGylation. This masks the foreign particles from the immune system such that it arrives at its destination and increases circulation time in the system. Antibody conjugation lines the surface of the nanoparticle with cell markers to limit spread only to malignant cells. In vivo testing of mice that developed murine colon carcinoma tumour cells. They were injected with the solution of AuNPs that were allowed to spread after 6 hours. Surrounding cells were swabbed with PEG and exposed to laser treatment for detection of abnormal heating indicating areas where Au nanoshells may have gathered. The injected area was also swabbed with PEG to maximize light penetration.
Despite the unquestionable success of gold nanorods or nanoshells as photothermal agents in preclinical research, they have yet to obtain the approval for clinical use because their size is above the renal excretion threshold. In 2019, the first NIR-absorbing plasmonic ultrasmall-in-nano architecture has been reported, and jointly combine: (i) an efficient photothermal conversion suitable for multiple hyperthermia treatments, and (ii) renal excretion of the building blocks after the therapeutic action.
Radiofrequency therapy
X-ray radiography procedures involves the diagnosis of cancer cells through the process of image acquisition. These techniques rely on the absorption of x-rays on the exposed tissue in order to improve image quality. In certain radiological procedures such as Radiofrequency therapy, a contrast agent is injected into the targeted cancer tissue and result in increased x-ray attenuation.
Radiofrequency therapy treatment involves the destruction of tumor cancer tissue cells through the differential heating of cancer tissue by radio-frequency diathermy. This differential heating is a result of the blood supply in the body carrying away the heat and cooling the heated tissue.
Gold nanoparticles are excellent absorbers of x-rays, due to its high atomic number of 197Au. This allows for a higher mass of the element, providing for a greater area of x-ray absorption. By acting as a contrast agent and injected into cancerous tumor cells, it would result in a higher dose of the cancerous tissue being exposed during radiotherapy treatment. Additionally gold nanoparticles are more efficiently removed from cells of healthy tissue, in comparison with cancer cells - a feature that makes them a promising radiosensitizers
Angiogenesis therapy
Angiogenesis is a process involving the formation of new blood vessels from pre-existing vessels. It involves the degradation of the extracellular matrix, activation, migration, proliferation, and differentiation of endothelial cells into vessels. It is said to play a large part in the growth and spread of cancer cells.
The process of angiogenesis involves the use of both promoters and inhibitors, balancing the process by only forming new blood vessels when needed. Examples of promoters include Vascular Endothelial Growth Factor (VEGF) and fibroblast growth factor (FGF) Examples of inhibitors include Vascular Endothelial Growth Factor Receptor 1, etc.
Tumor progression occurs as a result of the transition from a tumor in the dormant proliferation stage to the active stage as a result of oxygen and nutrients. This active stage leads to a state of cellular hypoxia, which causes an increased regulation of pro-angiogenesis proteins such as VEGF. This results in the spreading of inflammatory proteins and cancer cells alongside the newly created blood vessels.
AuNPs have the ability to inhibit angiogenesis by directly coordinating to heparin binding growth factors. They inhibit phosphorylation of proteins responsible for angiogenesis in a dose dependent matter. At concentrations 335-670 nM, almost complete inhibition of phosphorylation was observed. As a consequence of angiogenesis, rheumatoid arthritis has been found to develop due to the greater ability to spread inflammatory proteins. Through the inhibition of angiogenesis, the reduction of rheumatoid arthritis is prevalent. In addition, angiogenic inhibitors have a critical limitation due to the instability of biological conditions and high dosage required. To counter this, an emerging strategy for the development of therapies targeting tumor-associated angiogenesis through the use of nanotechnology and anti-angiogenic agents was developed, known as anti-angiogenic therapy. This approach solved the limitation instability by speeding up the delivery of angiogenesis inhibitors.
Gold nanoparticles display anti-angiogenic properties by inhibiting the function of pro-angiogenic heparin-binding growth factors (HG – GFs), with prime examples being the vascular endothelial growth factor 165 (VEGF165) and the basic fibroblast growth factor (bFGF) - both of which are pro-angiogenic promoters. Studies by Rochelle R. Arvizo, et al. have shown that the use of AuNPs of various size and surface charge plays an important role in its inhibitory effects.
In today's biological fields, the use of nanotechnology has allowed for the indirect use of AuNPs to deliver DNA to mammalian cells; thereby reducing tumor agents and increasing efficiency of electron transfer by modulating the activity of glucose oxidase. Current ongoing research by the Mayo Clinic laboratories includes the examination of AuNPs as messengers to deliver reagents capable of manipulating the angiogenic response in vivo.
Current angiogenic inhibitors used today which are approved by the USFDA to treat cancer is Ayastin, Nexavar, Sutent and Affinitor.
Anti-bacterial therapy Gold nanoparticles are used as bacteria targeting particles in antibacterial therapy. The therapy targets bacteria with light absorbing gold nanoparticles (10 nm, 20 nm, 40 nm) conjugated with specific antibodies, thus selectively kill bacteria using laser.
Studies has shown the effectiveness of this method on killing Staphylococcus aureus, which is significant human pathogen responsible for a wide range of diseases such as skin and wound infections, toxic shock syndrome, septic arthritis, endocarditis, and osteomyelitis. In this system, the bacteria damage is caused by inducing strong laser which leads to overheating effects accompanied by the bubble-formation phenomena around clustered gold nanoparticles.