Abstract
Cancer is one of the leading causes of death worldwide. In the last two decades, the development of nanotechnology has facilitated our ability to design new nanoparticles for the diagnosis and treatment of cancer. In this chapter, we reviewed the applications of gold nanoparticles as contrast agents for cancer imaging, including optical imaging, photoacoustic imaging, and X-ray–based imaging. We also reviewed their applications as delivery carriers for small molecule drugs, therapeutic genes, vaccines, and adjuvants and as therapeutic agents by themselves in cancer treatment, including photothermal therapy, photodynamic therapy, and radiation therapy.
Keywords
- gold nanoparticles
- cancer
- cancer imaging
- cancer treatment
- localized surface plasmon resonance
1. Introduction
With over 7 million new deaths per year, cancer remains one of the leading causes of death worldwide. The mortality of cancer is estimated to reach 13.1 million in the next two decades. Surgery, radiation therapy, and chemotherapy are key players in treatment of cancer. These treatments slow the progression of disease and prolong the survival of patients. Nonetheless, new treatments are in urgent need due to the greater understanding of the complexity of genetic and environmental factors. Recently, the development of nanotechnology has facilitated our ability to design new nanoparticles for the diagnosis and treatment of cancer [1].
Due to their unique physical and chemical properties, gold nanoparticles (ranging from 1 to 100 nm in one dimension at least) have attracted remarkable attention in recent years [2]. The gold nanoparticles are suitable for drug delivery given their large surface area to volume ratio. Owing to localized surface plasmon resonance (LSPR), gold nanoparticles, such as gold nanorods, nanocages, nanoshells, and nanostars, have strong light scattering and/or absorbance and have been extensively explored for bioimaging, cancer treatment, and both. In addition, given the strong binding affinity of gold to thiol and amine groups, the surface of gold nanoparticles can be easily functionalized with biomolecules such as DNA, siRNA, peptides, antibodies, and receptors. Gold nanoparticles also have a long history for clinical applications (for the treatment of rheumatoid arthritis) [3].
2. Gold nanoparticles in cancer imaging
2.1. Light scattering–based imaging
The scattering cross section of gold nanoparticles increases with the growth of their size. In general, gold nanoparticles can scatter light with the cross section more than 1 million times stronger than that of the emission from a fluorescent dye. Gold nanoparticles with a diameter greater than 10 nm can be visualized by dark-field scattering microscopy. Compared to a fluorescent dye, the gold nanoparticles are photostable and the scattering light does not blink. These features make gold nanoparticles attractive imaging probes for optical imaging.
Different shapes of gold nanoparticles, such as gold nanorods, nanocages, and nanostars, have been tested by dark-field scattering microscopy. In 2003, Sokolov
Another imaging modality based on light scattering is optical coherence tomography (OCT). OCT captures the changes in phase and intensity from the scattered light to provide optical cross-sectional images of tissues. It employs NIR light to produce a three-dimensional image of tissues with micrometer resolution. Gobin
2.2. Photoacoustic imaging
The photoacoustic imaging (PAI) is based on the acoustic waves generated by the thermal expansion of materials induced by optical excitation. When a pulsed laser irradiates materials, the temperature rise of the materials produces ultrasonic waves by periodic thermal expansion. The images of PAI are then constructed by detection of the ultrasonic waves. Since the ultrasonic wave penetrates deeper than light in tissues, the imaging volume and depth of PAI are significantly higher than those of optical imaging.
Gold nanoparticles have been highly attractive for PAI due to their excellent photothermal conversion ability and tunable optical properties. Jokerst
2.3. X-ray– based imaging
Computed tomography (CT) is one of the most widely used diagnostic imaging modalities for cancer. It can obtain whole volume 3D anatomical images with high spatial resolution in a cost-effective fashion. However, the contrast between different types of soft tissues is poor on CT images; thus, contrast agents, like iodine-based compounds, need to be injected to differentiate tumors from healthy tissues.
Since the attenuation of X-rays depends greatly on the atomic numbers of elements, gold has a stronger X-ray attenuation coefficient than other elements naturally existed in human bodies. Therefore, the accumulation of gold nanoparticles in tumors can significantly increase X-ray attenuation, resulting in high contrast between tumor and healthy tissues on CT images. Deoxyglucose-labeled gold nanoparticles are described as potential CT contrast agents [15]. The cancer cell samples showed significant contrast enhancement after incubation with these gold nanoparticles on multiple CT slices. The use of acetylated dendrimer-entrapped gold nanoparticles to image cancer
The surface of gold nanoparticles can be easily functionalized with tumor-targeting moieties, such as ligands, antibodies, and aptamers, to selectively image tumors via active targeting strategy. For example, Hainfeld
3. Gold nanoparticles in drug delivery
3.1. Small molecule drug delivery
Gold nanoparticles have been explored as drug carriers due to the following advantages: (1) the large surface area provides high loading capacity for drug loading and improves the hydrophilicity and stability of drugs; (2) the ability to modify surface with targeting ligands to enhance the tumor selective accumulation compared to free drugs; (3) the passive targeting ability to tumor site due to their leaky neovessels, which is called enhanced permeability and retention(EPR) effect; and (4) the controlled release of loaded drugs in response to internal or external stimulus.
The enhanced tumor accumulation of gold nanoparticles can be utilized for drug delivery to increase therapeutic potent and reduce side effects. Xiao
Gold nanoparticles can release loaded drugs in response to external stimulus like light. You
Some gold nanoparticles are designed to behave dramatically to various internal stimuli in the microenvironment of tumors. For instance, Wang
3.2. Gene delivery
Gene therapy attempts to treat cancer by altering the dysregulated gene expression of tumor cells. The successful regulation of gene expression requires compaction of DNA/RNA, rapid cellular uptake and endosomal escape, protection from degradation in blood stream and cytoplasm, and effective delivery of DNA/RNA to the nucleus. Therefore, carriers for efficient and safe DNA/RNA delivery are critical for the development of gene therapy.
Gold nanoparticles provide a potent platform for therapeutic gene delivery. Braun
3.3. Adjuvant and vaccine delivery
Immunotherapy is a burgeoning therapeutic modality for cancer treatment. The goal of immunotherapy is to harness the host immune system to attack and eradicate cancer cells [28]. There are several ways to enhance the innate power of immune system to fight cancer. Using cancer vaccine is one of the most extensively studied approaches to boost the immune system’s response [29].
Gold nanoparticles are promising for delivery of cancer vaccine, because they preferentially accumulate within tissues and cells of the immune system, and have a large surface area for vaccine loading. Lin
Since the tumor cells can secrete immunosuppressive cytokines and/or attract immune suppressive cells to evade the attack from immune system, co-delivery of adjuvants with vaccine has been explored to elicit a stronger CTL response to existing tumors. In one study, Lee
4. Gold nanoparticles in cancer treatment
4.1. Photothermal therapy
Photothermal therapy (PTT) is a central application of gold nanoparticles in cancer treatment. Gold nanoparticles absorb incident photons and convert them to heat to destroy cancer cells. Due to their unique optical properties as a result of LSPR, gold nanoparticles absorb light with extremely high efficiency (cross section at ~10 9 M−1 cm−1), which ensures effective PTT at relatively low radiation energy. The abnormal vascular structure of tumor is inefficient in dissipating heat, thus the tumors are more sensitive to hyperthermia than healthy tissues. When irradiated by light, the heat generated by gold nanoparticles causes biomolecule denaturation and cellular membrane disruption and kills tumor cells [33].
The wavelength of incident light is important for PTT. The NIR light has maximal penetration in tissues because most components of biotissues, including water, hemoglobin, skin, and other pigments, show minimal absorption and scattering of light in this region. Typically, the NIR light can reach ~1 cm deep in human body. Various nanoparticles that can absorb NIR light have been synthesized and tested for PPT, including nanorods, nanoshells, nanocages, nanostars, nanovesicles, and so on. Hirsch
Selective PTT has been demonstrated by using tumor-targeting gold nanoparticles. One strategy for selective PTT is to design immune-targeted gold nanoparticles against receptors overexpressed by cancer cells. For instance, in an experiment designed by Huang
One strategy to increase the therapeutic index of PTT is to increase the photothermal conversion efficacy of gold nanoparticles. Higher photothermal conversion efficacy means lower laser power density required for tumor ablation and less damage to skin and other healthy tissues. Chen
Reversing the thermoresistance of malignant cells is another pathway to enhance the therapeutic effect of PTT. Recently, Wang
Due to the effect of surface melting, gold nanoparticles may undergo laser-induced shape transformation far below the bulk melting point and lose the photothermal conversion ability. Gold nanoparticles are easier to reshape under irradiation of a pulse laser than under that of a continuous wave laser because the light energy is harder to release from the lattice of gold nanoparticles to surrounding tissues upon pulse laser irradiation [43]. Takahashi et al. [44] demonstrated that gold nanorods were reshaped into spherical nanoparticles under pulsed NIR laser irradiation and did not kill cells upon successive laser irradiation. Wang et al. compared the photothermal stability of gold nanorods, nanohexapods, and nanocages under pulsed laser irradiation. They showed that gold nanorods started to melt at 15 mW/cm2, whereas nanohexapods and nanocages started to melt at 25 mW/cm2. Chen
4.2. Photodynamic therapy
The principle of photodynamic therapy (PDT) has been known for over 100 years. PDT involves three nontoxic components, photosensitizer, light, and oxygen, that are needed to generate singlet oxygen (1O2) or/and reactive oxygen species (ROS) to kill cells. Generally, the photosensitizer is administrated to localize in tumor first, activated by light of a specific wavelength to transfer energy from light to molecular oxygen, and damage cells by the generated 1O2 and ROS. Since 1O2 and ROS quench after a very short time, PDT is a localized treatment similar to PTT. However, due to the poor solubility of most photosensitizers, it is challenging to deliver them to tumor with high specificity for treatment.
To address this challenge, gold nanoparticles are engineered as carriers of photosensitizer. Camerin et al. [46] bound Zn(II)-phthalocyanine disulfide (C11Pc), a photosensitizer bearing hexyl chains and a sulfur terminated C11 chain, with gold nanoparticles and investigated the photodynamic therapeutic effect in a melanoma mice model. Compared with free C11Pc, the ratio between the amount of photosensitizer recovered from melanoma and skin increased from 2.3 to 5.5 for gold nanoparticles bound C11Pc at 24 h after injection. The nanoparticle-bound C11Pc also showed a better antitumor effect than that of free C11Pc at the same concentration.
With rational design, the PDT and PTT effect of photosensitizer-loaded gold nanoparticles can be combined to further enhance the therapeutic efficacy via synergistic effect. Jang
Certain gold nanoparticles have the ability to generate 1O2 and ROS upon light irradiation, allowing them to act as photosensitizers by themselves rather than as delivery vehicles. Krpetić
4.3. Photon-based radiation therapy
Radiation therapy (RT) is a major component of the modern therapeutic modalities of cancer. Photon-based radiation therapy uses high-energy gamma rays, typically 8–18 MeV for deep tumors, to control the growth of tumor by causing DNA damage
When gamma rays excited core electrons near the atomic nucleus of elements, low energy electrons may be released by a so-called Auger de-excitation processes. Gold nanoparticles have high atomic number and are more likely to generate Auger electrons when compared to light elements of biological tissues. The Auger electrons are effective in breaking DNA and only damage cells in a short distance less than the size of a single cell. This short-range therapeutic effect makes gold nanoparticles potent to selectively sensitize tumor cells to photon-based radiation therapy. Hainfeld
One problem of using ultrasmall nanoparticles is the relatively short half-life due to the rapid excretion from kidney. To reduce the dosage of gold, larger nanoparticles with tumor-targeting moieties have been exploited. In one study, thio-glucose bound gold nanoparticles were synthesized as a sensitizer to enhance radiation therapy for ovarian cancer cells [54]. Since malignant cells metabolize faster than healthy cells, the glucose coating of gold nanoparticles resulted in an ~31% increase of cell uptake compared to that of naked nanoparticles. As a result, the inhibition of cell proliferation increased 30.48% for 90 kV and 26.88% for 6 MV gamma ray irradiation. In another report, 30 nm gold nanoparticles were conjugated to Herceptin, a monoclonal antibody against Her2, to target MDA-MB-361 in a subcutaneous mice model [55]. After gamma ray irradiation, the tumors treated with gold nanoparticles resulted in 46% tumor regression, whereas the tumors treated by gamma ray alone increased 16% in tumor volume.
Although larger gold nanoparticles achieve improved accumulation in specific tumors due to the EPR (enhanced penetration and retention) effect, some authors argue that as gold nanoparticles become larger, more of the secondary electrons occur in the core of the nanoparticles, thus reducing the dose delivered to the cytoplasm around the nanoparticles. Therefore, the best size range of gold nanoparticles for photon-based radiation therapy is still under debate.
4.4. Ion-based radiation therapy
Ion-based radiation therapy is another type of RT. Instead of utilizing high-energy gamma rays, ion-based radiation therapy uses ion beams as the radiation source, such as the ions of hydrogen (protons), helium, carbon, or oxygen. The ion radiation is attractive because it has a strong LET near the end of the track, which is called the Bragg peak. The location of Bragg peak can be extended by increasing the energy of the ion so that the volume of irradiation can be better defined in ion irradiation than in photon irradiation.
One of the proposed mechanisms for radiosensitization of gold nanoparticles is that the ion beams excite surface plasmons and thus increase the yield of secondary electrons. Li
5. Future perspectives
As discussed above, the extensive research on gold nanoparticles over the past decade has indicated their potential for a rich variety of applications in cancer imaging and treatment. Many advances were enabled by the understanding of the chemical synthesis and biobehavior of gold nanoparticles. These understandings will certainly lead to more practical clinical applications. The use of gold nanoparticles for drug delivery and photothermal therapy was proved for phase I and phase II clinical trials [59].
Although gold nanoparticles offer an attractive platform for new novel modalities for cancer imaging and treatment, it is very important to carefully and precisely study their toxicity in potential applications for human. Although the gold is relatively inert for biotissues, these nanoparticles tend to remain in the body, especially in liver and spleen for a long time. Thus, the long-term toxicity of nanoparticles is an issue for their use in humans. Since the reported biodistribution and toxicity vary greatly with the size, shape, and coating of gold nanoparticles, it seems that the safety of gold nanoparticles is dependent on many factors, and so, this needs to be examined for every single synthetic formula and application [60].
One unique property of gold nanoparticles is their LSPR effect, which enables a variety of imaging and treatment modalities, such as light scattering imaging, photothermal therapy, photodynamic therapy, and so on. However, the penetration depth of light in biotissues is no more than several centimeters and cannot reach most tumors in human body. Combining other imaging and therapeutic modalities may provide a strategy to overcome this limitation [61].
Acknowledgments
This project is financially supported by the National Key Basic Research Program of the P.R. China (program no. 2014CB744504), the National Natural Science Foundation of China (program no. 81501588), and the Natural Science Foundation of Jiangsu Province (program no. BK20140734).
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