The application of gold nanoparticles as a promising therapeutic approach in breast and ovarian cancer

Abstract

The development of specialized nanoparticles (NPs) for use in the detection and treatment of cancer is increasing. In the last few years, gold nanoparticles (AuNPs) have been greatly studied in biological and photothermal therapeutic status. AuNPs can bind to a wide range of organic molecules, and their synthesis is easy. In this review, we summarize the characteristics of AuNPs, their contributions to tumor destruction, their toxicity, and their potential in the treatment of breast and ovarian cancer.

Keywords::

• breast
• cancer
• gold
• nanoparticle
• ovary

Introduction

The use of nanoparticles (NPs) in the diagnosis and treatment of cancer is developing (Zwicke et al. 2012, Yan et al. 2003). Angiogenesis, the formation of new blood vessels, is essential for the growth and progression of tumors (Mukherjee et al. 2005, Carmeliet and Jain 2000). It has been argued that gold nanoparticles (AuNPs) could be used in almost all medical applications—diag nostics, therapy, prevention, and hygiene (Khlebtsov and Dykman 2011). AuNPs have recently been demonstrated in cell imaging (Briñas et al. 2008), targeted drug delivery (Chithrani et al. 2006), cancer diagnostics, and therapeutic applications (Hoek and Stillman 2003, Hainfeld et al. 2008).

A wealth of information on how to obtain and use colloidal gold in biology and medicine, as well as how it functions, can be found in books and reviews (Dykman and Khlebtsov 2011). Treatment with high specificity and low side effects is the goal of modern therapy. Clinical applications of recombinant protein drugs have been limited due to their low bioavailability, rapid clearance in vivo, systemic cytotoxicity, and high production cost (11) (Ledley 1996). In the last few years, AuNPs have been greatly studied for their biological and photothermal therapeutic status (Huang et al. 2008) (Figure 1). AuNPs can bind to a wide range of organic molecules (Chen et al. 2008), and their synthesis is easy (Paciotti et al. 2004). AuNPs have also been used as a platform for novel experimental cancer therapy (Paciotti et al. 2004, Baptista 2012). It was estimated that in 2013, 91,730 women would be diagnosed with a gynecologic cancer and some 28,080 would die from the disease. The American Cancer Society estimated that about 232,670 new cases of invasive breast cancer would be diagnosed in women in 2014. With respect to ovarian cancer, 22,240 new cases and 14,030 deaths had been estimated.

Figure 1. Improved and sustained therapeutic effect of chemotherapeutic agents using nanotechnology. (A) Oral or intravenous route for delivery of conventional formulations and nanocarriers. (B) Pictorial structures of various drug delivery devices such as polymer–drug conjugates, dendrimers, polymer micelles, polymer NPs, and lipid NPs/capsules. (C) Immunoconjugate nanosystem route for improved therapeutic efficacy. Adapted from (Yallapu et al. 2010).

Breast cancer is the most common cancer in women. Early diagnosis and appropriate treatment are essential. Noninvasive diagnostic methods are especially needed for the screening (Rajadhyaksha et al. 1995). In this review, we summarize the characteristics of AuNPs, their contributions to tumor destruction, their toxicity, and their potential in the treatment of breast and ovarian cancer.

Biological properties of gold nanoparticles

Gold is one of the first metals to have been discovered (Dykman and Khlebtsov 2011). Gold compounds were used in Chinese culture and in India since early 2500–2600 BC (17)(Kumar et al. 2011). They utilized it for medicinal purposes (Mahdihassan 1985).

Inorganic NPs such as gold, silver, and copper have resplendent colors due to the presence of the surface plasmon resonance (SPR) band (Brongersma 2003). The SPR induces a strong absorption of the incident light, and thus can be measured using a UV-Vis absorption spectrometer (20) (Link et al. 1999). AuNPs might also reduce angiogenesis. The vascular endothelial growth factor/vascular permeability factor (VEGF/ VPF; refs. (Senger et al. 1986, Leung et al. 1989)) and the basic fibroblast growth factor (bFGF; ref. (Risau 1997)) are two critical cytokines for the stimulation of angiogenesis.

AuNPs can also be tuned by surface modifications, such as coating the core with a layer of silica (Jain et al. 2006). AuNPs show the SPR band at around 520 nm in the visible region. The SPR band is affected by the particle size (Jain et al. 2006, Link and El-Sayed 1999).

AuNPs have strong binding affinity towards thiols, disulfides, phosphine, and amines (Sastry et al. 2002).

The strong affinity of gold towards thiol and amine functionalities (according to the SHAB principle) allows many different biological ligands such as DNA, peptides, proteins, antibodies, viruses, and receptors to coat the gold surface (Love et al. 2005). AuNPs have been in active use in the identification of chemical and biological agents (Maunsbach and Afzelius 1998).

AuNPs are used as a probe for electron microscopy or as a vehicle to deliver biomolecules into cells (Figure 2). Recently, Bhattacharya et al. showed that AuNPs can be used as active agents to interfere directly with the cellular processes, and that they possess antiangiogenic and antitumor properties (Mukherjee et al. 2005). For example, in 2001, there was an investigation of AuNPs that had been functionalized with cationic quaternary ammonium groups and then electrostatically bound to plasmid DNA. This composite particle could protect the DNA from enzymatic degradation and could regulate DNA transcription of T7 RNA polymerase (McIntosh et al. 2001, Han et al. 2006). Sokolov et al. used AuNPs conjugated to epidermal growth factor receptor (EGFR) antibody for identification of precancerous lesions. This receptor is overexpressed in cervical cancer cells. Therefore, treatment with these gold conjugates enhances the finding of cervical cancer cells due to the raised SPR scattering of the AuNPs by laser scanning confocal reflectance (Sokolov et al. 2003).

AuNPs were used for therapeutic purposes in 1997, when the successful application of colloidal gold in a patient with rheumatoid arthritis was first reported (Richards et al. 2002). AuNPs were used to enhance cancer apoptosis by radiotherapy (Hainfeld et al. 2004).

Figure 2. (A and B) Comparison of scattering properties of AuNPs (A) and polystyrene NPs (B) of the same size (B). (C and D) Comparison of reflectance images of SiHa cells labeled with BSA/Au conjugates (C) and anti-EGFR gold conjugates (D). (E and F) Comparison of reflectance images of cervical biopsies labeled with anti-EGFR antibodies/AuNP conjugates for normal tissue (E) and abnormal tissue (F). Due to strong scattering from targeted AuNPs, cancer cells and tissues can be differentiated from normal ones. All images were taken by a laser scanning confocal microscope in reflectance mode. Adapted from (Huang and El-Sayed 2010) (68).

NPs can be used for site-specific delivery of cytotoxic drugs, with the potential to reduce toxicity and reduce harmful side effects (Peer et al. 2007).

The options of using AuNPs conjugated with the following antitumor agents were proposed: prospidin (Dykman and Khlebtsov 2011), tamoxifen (Dreaden et al. 2012), and Herceptin (Eghtedari et al. 2008).

Many cancerous cells in the breast, ovary, brain, and kidney have overexpression of folate receptors (FR) (Toffoli et al. 1997). Recently, gold nanoconjugates (AuNCs) were synthesized, to use the FR on different cancer cells. Polyethylene glycol (PEG) was used as a target. It is a linker between folic acid and adapted drug molecules. PEGylated molecules minimize the toxic effects. They also aid in stabilization during blood circulation, with minimal degradation and nonimmunogenicity (Dixit et al. 2006).

AuNPs in breast cancer research

Rapid selective detection of cancer cells is an important challenge for the diagnosis and treatment of tumors (Revenko et al. 2010). Wentong Lu has shown that when multifunctional oval-shaped AuNPs are mixed with the breast cancer SK-BR-3 cell line, a distinct color change occurs and two-photon scattering intensity increases by about 13-fold. Our experimental data of the HaCaT noncancerous cell line and of the MDA-MB-231 breast cancer cell line clearly demonstrate that our colorimetric and TPS assays are highly sensitive to SK-BR-3 and can distinguish from other breast cancer cell lines which express low levels of HER-2 (Lu et al. 2010).

Dreaden EC has shown enhanced potency and selective intracellular delivery of tamoxifen using AuNPs targeted to ER(+) breast cancer cells in vitro (Dreaden et al. 2009).

It was found that AuNC–Her could escape the endolysosomal pathway and enter the nucleus of cancer cells to enhance the therapeutic efficacy of Herceptin. The nuclear localization effect of AuNC–Her enhances the anticancer therapeutic efficacy of Herceptin, as evidenced by the induction of DNA damage (Wang et al. 2011).

AuNPs conjugate with Herceptin. It increases the uptake of AuNPs and the drug to overcome Herceptin resistance. It is essential for treating breast cancer cells (Nahta and Esteva 2006).

Application of 300 kVp (peak cells led to 5.1 times more DNA double-strand breaks in Herceptin–PEG–AuNPs than in PEG–AuNPs (Chattopadhyay et al. 2010). Herceptin–AuNR conjugates have also been shown to be taken up into tumor cell endosomes and lysosomes rather than attaching to the cellular membrane (Chen and Irudayaraj 2009).

Although Herceptin has been shown to be effective against HER-2 overexpression in breast cancer, some patients who receive it develop resistance to the agent (Nahta and Esteva 2006).

Au3Cu1 nanoshells have also been found to be effective contrast agents for MRI (Su et al. 2007). The use of AuNPs is also being explored in ‘‘theranostics,’’ applications in which diagnosis and treatment are combined. Multifunctional NPs made of magnetic NPs, AuNS, and upconversion NPs could accumulate in tumors, enabling detection by upconversion luminescence and MRI, to increase survival from photothermal treatment combined with a magnetic field (Cheng et al. 2012).

AuNPs have been used to detect breast cancer in several diverse applications, ranging from the evaluation of pathology specimens to noninvasive in vivo imaging. Park et al. found that two-photon-induced photoluminescence (TPIP) could be used to visualize tumor cells embedded with gold, in vivo (Park et al. 2008).

The transferrin receptor participates in cellular proliferation, and overexpression of the transferrin receptor has been observed in breast tumors. Thus, the tumoral intake of AuNPs would be enhanced by conjugating them with transferrin (Li et al. 2009). Breast cancer cells also have a high expression level of receptors for luteinizing hormone-releasing hormone (LHRH) (Jin et al. 2008). Dumbbell-shaped AuFe3O4 nanoparticles conjugated with a trastuzumab and platinum complex showed target-specific delivery of platinum compounds to HER-2-positive SK-BR-3 cells. That cisplatin was released at lower pH levels led the investigators to suggest that the intracellular release of cisplatin (and hence its cytotoxicity) was stimulated by the lower pH in endosomes after uptake of the conjugates (Xu et al. 2009). The lower pH levels in cellular endosomes could also facilitate the release of drugs from chloroquine-conjugated AuNPs, which also have antitumor activity in breast cancer, and lead to increased cytotoxicity in MCF-7 cells (Joshi et al. 2012).

AuNPs and ovarian cancer

Ovarian cancer is the fifth most prevalent cancer among women. There are no early symptoms for ovarian cancer, which hinders detection until it reaches advanced stages (Chauhan et al. 2009). In fact, of the top ten cancer types afflicting American women in 2008, ovarian cancer had the highest death incidence ratio, even exceeding that of lung cancer (Greenlee et al. 2000).

Some of the greatest challenges in the diagnosis and treatment of ovarian cancer stem from its heterogeneous nature. The term “ovarian cancer” refers not to a single disease, but to a various group of malignancies disturbing the ovary. On the other hand, ovarian tumors may expand from one of three cell types: epithelial cells, sex cord-stromal cells (including granulosa, theca, and hilus cells), or germ cells (oocytes) (Chen et al. 2003).

Importantly, ovarian cancer patients are often initially responsive to these therapeutic modalities but eventually become resistant to therapy. Therefore, drug resistance remains the major obstacle in the treatment of ovarian cancer. One way to improve the efficacy and specificity of chemotherapeutic agents is through nanotechnology-based formulations (encapsulated, conjugated, or entrapped/loaded forms in nanocarriers or drug delivery vehicles/vectors). Nanotechnology-mediated therapies promote a controlled delivery of chemotherapeutic drug (s) in a targeted way, which directly acts on the cancer site for prolonged periods of time, with minimal or no organ toxicity normally seen (Yallapu et al. 2010).

In cancer treatments, NPs can rely more on the enhanced permeability and retention effect caused by leaky tumor vasculatures for better drug accumulation at the tumor sites (Agarwal and Kaye 2003).

Ovarian cancer is the fifth most prevalent of the gynecologic malignancies among women in the Western world, with a lifetime risk of 1.4 to 1.8%. There are no early symptoms for ovarian cancer, which hinders detection until it reaches advanced stages. Primary management consists of an extensive surgery, in combination with chemotherapy post-surgery (Agarwal and Kaye 2003, Herzog and Pothuri 2006).

Over the past decade, nanotechnology has received considerable attention for cancer therapy (Arvizo et al. 2010). At the molecular level, treatment with AuNPs has been seen to alter the profiles of a series of secretory cytokines (Qiao et al. 2011).

Cisplatin and carboplatin (CBP) have been the most effective chemotherapeutic regimens for more than two decades (McGuire and Ozols 1998).

Cisplatin retains its cytotoxicity in the nanoconjugated form. Fascinatingly, nanoconjugation in the form of Au–PSH–CP–FA protects the cytotoxic effect of CP to normal cells while enhancing cytotoxic effects on tumor cells (Patra et al. 2010).

Cisplatin treatment has been found to upregulate the expression of several stem cell markers such as ALDH1, CD24, CD44, CD133, EpCAM, Nanog, Oct-4, and Sox2, and increase the side population (SP) simultaneously. In addition, pretreatment with AuNPs also prevented cisplatin-induced acquired ‘stemness’ and enrichment of SP cells.

Progress in nanomedicine has led to the development of molecular targeted NP therapeutic carriers. These NP drug carriers can be targeted against cancer cells using cancer cell surface markers to directly deliver therapeutics to cancer cells (Wang et al. 2008) . Another exciting aspect of the behavior of AuNPs is their unequal cytotoxicity toward cancer cells. Metallic materials may arrest cells at the G2/M phase, the most radiosensitive phase of the cell cycle, and thus unreasonably increase the sensitivity of cancer cells toward radiation (Turner et al. 2005). On the other hand, Glu–AuNPs trigger activation of the CDK kinases, leading cancer cells to gather in the G2/M phase. Consequently, after treatment with Glu–AuNPs, cancer cells were found to be more sensitive to radiotherapy (Ojeda et al. 1994).

It is well recognized that the FRs are overexpressed in a number of malignant cells such as ovarian, kidney, lung, breast, endometrial, colorectal, brain, etc., compared to their normal complement (Patra et al. 2010, Torchilin 2007).

AuNPs were found to inhibit the expression of stem cell markers and reduce the pool of SP cells. Exploring the signaling that regulates AuNP-mediated inhibition of stemness will help to identify key players involved in the cisplatin resistance and develop AuNP-based combination therapy (Xiong et al. 2014).

Inhibition of Akt/NF-κB signaling by AuNPs provides an inorganic nanomaterial-based therapeutic approach for sensitizing cells to cisplatin by decreasing EMT and stemness, and thus may play an important role in therapeutic management of ovarian cancer (Xiong et al. 2014).

Conclusions

NPs possess great potential for future clinical applications in imaging, diagnosis, and therapeutics. Further clinical investigations will determine the translation of AuNPs toward clinical applications. AuNPs show promise for both the imaging and treatment of breast and ovarian cancers. They possess characteristics which could improve ovarian cancer therapy.

Authors’ contributions

LK and TK conceived of the study and participated in its design and coordination. AA participated in the sequence alignment and drafted the manuscript. All authors read and approved the final manuscript.

Acknowledgments

The authors thank the Department of Medical Nanotechnology, Faculty of Advanced Medical Science of Tabriz University, for all support provided. This work is funded by a 2014 grant by the Drug Applied Research Center, Tabriz University of Medical Sciences.

Declaration of interest

The authors have no declaration of interest. The authors alone are responsible for the content and writing of the paper.