Introduction

Cancer is one of the leading causes of death worldwide and is defined as a disease that begins when cells grow uncontrollably and crowd out normal cells. Cancer can develop anywhere in the body, such as in the lungs, breasts, or liver. The World Health Organization predicted that the burden of cancer will increase to 23.6 million new cases annually by 2030 (World Health Organization 2014). Thus, cancer treatment has become a prominent issue over the past several decades. For women, breast cancer is one of the most commonly diagnosed cancers globally. In 2018, approximately 266,120 new cases of invasive breast cancer were estimated in women constituting 30% of all cancer cases (878,980 total cases); in addition, 40,920 of these breast cancer cases were estimated to be fatal (American Cancer Society 2018). Breast cancer is usually classified on the basis of the type of receptor overexpression present on the cancer cell membrane (Fig. 1), including progesterone (PR) and estrogen (ER) hormone receptors and HER2 receptors, with HER2 being a member of the human epidermal growth factor receptor family. Breast cancers that present the overexpression of these receptors are called either PR− , ER− , or HER2-positive, depending on the type of receptor overexpression. Patients that show PR− , ER− , HER2-positive breast cancer cells are said to have triple-positive breast cancer. In addition, triple-negative breast cancer group exists that is composed of breast cancers that are neither PR/ER-positive nor HER2-positive. It has been reported that the primary cause of deaths due to breast cancer is the result of its potential metastasis to distant organs such as the liver, lungs, lymph nodes, bones, and brain (Carty et al. 1995; Grobmyer et al. 2012).

Fig. 1
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Receptor-based breast cancer classification

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Currently, surgery (in which whole breast is removed, called a mastectomy, or in which only the tumor and surrounding tissues are removed, called a breast-conserving lumpectomy), chemotherapy (in which drugs are used to kill cancer cells), and radiotherapy (in which high-energy waves are used to kill cancer cells) are the three main cancer treatment strategies (Shewach and Kuchta 2009). Among them, chemotherapy is more popularly used for treating most types of cancer. Chemotherapy can kill many cancer cells throughout the body, eradicate microscopic disease at the edges of tumors that may not be seen by a surgeon, and be used in combination with other therapies.

Many anticancer drugs such as tamoxifen, paclitaxel, docetaxel, doxorubicin, and methotrexate have been approved for the treatment of breast cancer (Colleoni et al. 2002; Patt et al. 2006; Gradishar 2012; Jordan 2014; Gabizon et al. 2016). However, the poor aqueous solubility and permeability of these drugs have resulted in low bioavailability and decreased treatment efficiency. Thus, the controlled release and tumor-targeted delivery of these anticancer drugs via the use of nanoparticles represent two important strategies to improve therapeutic efficacy and reduce the side effects of cancer treatments.

Nanotechnology has been widely used over the last decades and nanoparticle drug delivery is considered a promising tool for cancer treatments due to the high loading capacity, reduced toxicity, stability, efficacy, specificity, and tolerability of drug-loaded nanoparticles compared to conventional chemotherapy drugs. Anticancer drug loaded nanoparticles can be used to actively or passively deliver drugs to tumors during breast cancer treatments (Singh et al. 2017). The advantages to using nanoparticles are not only due to their ability to be created in a range of small sizes but also to their capacity to be made from various substances, such as lipids (e.g., solid lipid nanoparticles, liposomes), polymers (e.g., polymeric nanoparticles), and inorganic materials (e.g., gold nanoparticles). Among the various types of nanoparticles, liposomes, micelles, polymeric nanoparticles, solid lipid nanoparticles, and gold nanoparticles are popularly used in the treatment of breast cancer. Thus, this review focuses on these nanoparticle types and discusses recent advances in the treatment of breast cancer.

Nanoparticle types and the treatment of breast cancer

To date, nanotechnology has rapidly developed to produce some of the most important cancer treatment strategies. Among the various nanoparticle types, the most popular nanoparticles used in breast cancer treatments are liposomes, micelles, polymeric nanoparticles, solid lipid nanoparticles, and gold nanoparticles (Fig. 2).

Fig. 2
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Nanoparticle types commonly used in the treatment of breast cancer

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Liposomes

Liposomes were first developed in 1964 by Bangham and Horne (1964) and are spherical vesicles ranging in size from ~ 50 to 200 nm comprised of aqueous material contained by a phospholipid outer layer (Singh et al. 2017). Liposomes are used in the targeted drug delivery of both hydrophilic and hydrophobic drugs due to their phospholipid layers, which are composed of biocompatible, biodegradable, and non-immunogenic materials. Given their small particle size, liposomes easily pass through vascular pores to accumulate in tumors. In addition, it was reported when P-glycoprotein (P-gp) was inhibited by anionic membrane lipids and liposomes were loaded with rhodamine 123 to be used as a P-gp substrate, rhodamine retention in MCF-7/P-gp cells increased, suggesting P-gp is functional in transfer of its substrate (Kang et al. 2009). The representative examples of liposomes used for anticancer drug delivery to breast cancer cells are presented in Table 1. In 1965, a liposomal formulation of doxorubicin (Doxil®) was first approved by FDA for ovarian cancer, AIDS-related Kaposi’s sarcoma, and multiple myeloma (U.S. Food and Drug Administration 1995) and was recently approved for breast cancer (Gabizon et al. 2016). A paclitaxel-nanoliposome formulation was prepared using phosphatidylcholine and cholesterol, and the cytotoxicity of this liposome was evaluated in MCF-7 breast cancer cells (Esfahani et al. 2013). The results showed that the paclitaxel-liposomal formulation significantly destroyed a greater number of cancer cells compared to the free drug. Anders et al. studied the pharmacokinetics and efficacy of PEGylated liposomal doxorubicin (PLD) in an intracranial breast cancer model, and the results showed that the area under the curve (AUC) in the group treated with PLD was 1500-fold higher compared to the group treated with non-liposomal doxorubicin (Anders et al. 2013). In addition, PLD was detected in the plasma for a longer time (96 h) than non-liposomal doxorubicin (24 h). In another study by Jeong et al., pH-sensitive polymer-liposome complexes were prepared by using Pluronic P104-based multiblock copolymer as a pH-sensitive polymer to explore its potential in anticancer therapies in combination with doxorubicin and siRNA (Jeong et al. 2014). The results indicated that the cellular uptake of the pH-sensitive liposome in MCF-7 and MDA-MB-231 breast cancer cells was higher than with free doxorubicin. In addition, the in vitro cytotoxicity of doxorubicin in pH-sensitive liposomes delivered to cells was higher than that of free doxorubicin.

Table 1 Anticancer drug delivery by liposomes to breast cancer cells
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Liposomes have been also developed by combining two anticancer drugs to obtain synergistic anticancer effects. For instance, Eloy et al. developed co-loaded liposomes with paclitaxel and rapamycin, and evaluated their performance in breast cancer therapies in vitro and in vivo (Eloy et al. 2016). Soy phosphatidylcholine (SPC), cholesterol (Chol), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethyleneglycol)-2000] (DSPE-PEG2000) were used in the preparation of the co-loaded liposomes. The SPC/Chol/DSPE-PEG2000 liposome was successful in co-encapsulating paclitaxel and rapamycin. Liposomes were more cytotoxic (approximately twofold at lowest concentration) to 4T1 breast cancer cell lines than the free drug in vitro.

Micelles

Micelles present particle sizes that range from 10 to 100 nm are formed by the self-assembly of amphiphilic molecules comprised of hydrophilic heads and hydrophobic tails. The advantages associated with micelles include prolonged blood circulation times, low toxicity, and enhanced tumor accumulation; furthermore, they are commonly used for the delivery of anticancer drugs with poorly water solubility (Zhang et al. 2014). Pluronic block copolymers, a triblock copolymer of poly(ethylene oxide) and poly(propylene oxide), are widely used in the preparation of drug delivery micelles. As shown in Table 2, many anticancer drugs have been encapsulated in micelles for delivery to breast cancer cells. Batrakova et al. demonstrated that the exposure of cells to Pluronic P85 resulted in a substantial decrease in ATP level selectivity in multidrug-resistant (MDR) cells for the first time (Batrakova et al. 2001). In another study, teniposide-loaded polymeric micelles were prepared for breast cancer therapy, using monomethoxy-poly(ethylene glycol)-poly(ε-caprolactone-co-d,l-lactide) (MPEG-PCLA) copolymers with a thin-film hydration method to improve hydrophilicity and reduce systemic toxicity. The results showed that the half-life of the micelle formulation was improved compared to the control drug. In addition, the cellular uptake and the distribution of micelles in MCF-7 breast cancer cells and in the tumor itself were increased when compared to the commercial drug. Besides, micelles proved safe with the maximum tolerated dose (50 mg/kg), which was 2.5-fold higher than the commercial drug (20 mg/kg) (Chu et al. 2016). Zhang et al. developed a novel super-antiresistant paclitaxel micelle formulation for oral administration and evaluated its ability to combat breast cancer (Zhang et al. 2017). As a result, super-antiresistant micelles showed higher cellular uptake efficiency, cytotoxicity, and antimitotic effects in MCF-7/ADR cells with compared to the control drug. In vivo, micelles significantly improved bioavailability after oral administration and inhibited tumor growth in multidrug-resistant xenografted MCF-7/ADR nude mice. In a study by Mishra and Dey, doxorubicin and docetaxel were co-loaded in the micelle using a poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) copolymer for the treatment of breast cancer with synergistic anti-tumor effects (Mishra and Dey 2018). The in vitro cytotoxicity result showed a distinct synergistic effect of drug-loaded micelles on the viability of MCF-7 cells. Only 33% of MCF-7 breast cancer cells were viable after 48 h of treatment with doxorubicin-docetaxel-PEG-PLA micelle nanoparticles.

Table 2 Anticancer drug delivery by micelles to breast cancer cells
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Polymeric nanoparticles

Polymeric nanoparticles are solid colloidal systems with particle sizes less than 200 nm, in which anticancer drugs are dissolved, entrapped, encapsulated, or adsorbed into the composition of the polymer matrix (Joshi et al. 2015; Singh et al. 2017). The polymers used in the preparation of nanoparticles can be natural (e.g., chitosan, cellulose, alginate, and gelatin) or synthetic polymers [e.g., (poly-ε-caprolactone (PCL), polylactide (PLA), and poly(lactic-co-glycolic acid) (PLGA)]. The polymeric nanoparticles for anticancer drug delivery to breast cancer cells are shown in Table 3. To enhance the solubility and bioavailability of psoralen, which is a promising anticancer drug that is limited by its poor aqueous solubility and bioavailability, Du et al. used a combination of Tween 80 and soy lecithin in the preparation of polymeric nanoparticles. The effect of nanoparticle on breast cancer MCF-7 cells was also investigated (Du et al. 2019). In vivo results showed significantly lower tumor weights and tumor volumes in the BALB/c mice treated with psoralen-polymeric nanoparticles compared with mice in the control group. In another study, Shenoy and Amiji used poly(ethylene oxide)-modified poly(ε-caprolactone) (PEO-PCL) in the preparation of tamoxifen nanoparticles and the in vivo biodistribution was evaluated in Nu/Nu athymic mice bearing a human breast carcinoma xenograft, MDA-MB-231 using tritiated [3H]-tamoxifen as radio-marker for quantification (Shenoy and Amiji 2005). Polymeric nanoparticles containing tamoxifen showed significantly greater accumulation in tumors and in systemic circulation compared to the control group; below 5% of control drug and over 15% of nanoparticles were accumulated in tumor and systemic circulation after 1 h, respectively. In a study by Jadon and Sharma, PLGA and DSPE-polyethylene glycol 2000 (PEG2000)-NH2 were used in the preparation of docetaxel nanoparticles for breast cancer therapies (Jadon and Sharma 2019). The cytotoxicity of docetaxel lipid hybrid nanoparticles in MDA-MB-231 breast cancer cells was significantly higher than that of the drug alone. In addition, the cellular uptake efficiency of docetaxel lipid hybrid nanoparticles (45–48%) was improved compared to the free drug (37–39%). The onset of early apoptosis in MDA-MB-231 breast cancer cells after treatment with docetaxel nanoparticles (11.3%) was 3.5-fold higher than that of the free drug (3.2%). In addition, the residual tumor burden for docetaxel nanoparticles (31.9%) after 3 weeks of treatment was lower than that for the free drug (69.9%). This result was correlated with in vitro cytotoxicity and cellular uptake results.

Table 3 Anticancer drug delivery by polymeric nanoparticles to breast cancer cells
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Solid lipid nanoparticles (SLNs)

SLNs were introduced as a novel drug carrier system for oral delivery (Mehnert and Mäder 2001). Over the years, SLNs have attracted special interest in cancer treatments. In particular, SLNs have several advantages, including a good release profile, biocompatibility, high drug content capacity, and high physical stability. SLNs is one of the novel potential colloidal carrier systems. By incorporating between colloidal nanoparticles and anticancer agents, resistances to drug action can overcome, the concentration of cancer drug in cancer cells including breast cancer cells can increase. Besides, the antitumor activity can enhance and their toxicity towards normal cells can reduce. They can be endocytosed/phagocytosed by cells, with resulting cell internalization of the encapsulated drug (Güney and Kutlu 2011). Therefore, SLNs are usually used to overcome the limitations associated with other formulations such as liposomes or polymeric nanoparticles. The applications of SLNs for anticancer drug delivery to breast cancer cells are listed in Table 4.

Table 4 Anticancer drug delivery by solid lipid nanoparticles (SLNs) for to breast cancer cells
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Guney Eskiler et al. prepared tamoxifen-SLNs using stearic acid and Tween 80 and evaluated the SLNs in MCF-7 Tam-resistant breast cancer cells (MCF-7-TamR) (Guney Eskiler et al. 2018). The cytotoxicity results showed that tamoxifen-SLNs significantly enhanced the efficacy of tamoxifen and reversed acquired tamoxifen resistance by inducing apoptosis and altering the expression levels of specific miRNAs and the related apoptosis-associated target genes in both MCF-7 and MCF-7-TamR cells without damaging the MCF-10A control cells. In another study, Xu et al. used egg L-α-phosphatidylcholine (PC) and DSPE–methyl(polyethylene glycol)-2000 (mPEG2000) for the preparation of paclitaxel-SLNs and evaluated their performance in the drug-sensitive human breast cancer cell line MCF-7 and its MDR variant MCF-7/ADR (Xu et al. 2018). Paclitaxel-SLNs showed remarkably enhanced anticancer activity in the MCF-7/ADR cell lin compared to the control. In addition, the cellular uptake of paclitaxel-SLNs in MCF-7/ADR cells was also greater than that of the control. Quereshi et al. also developed docetaxel-loaded SLNs to improve the solubility and pharmacokinetics of docetaxel, and evaluated the in vitro cytotoxicity in MCF-7 breast cancer cells (Qureshi et al. 2017). The AUC of docetaxel-SLNs increased 3.7-fold in comparison with that of docetaxel-loaded micelles (commercial formulation, Taxotere®). In vitro cytotoxicity results showed that the half-maximal inhibitory concentration (IC50) of docetaxel-SLNs (2.50 ± 0.14 µg/mL) for MCF-7 breast cancer cells was significantly lower (1.9-fols) than that of the commercial formulation (4.81 ± 0.15 µg/mL).

The addition of 2-hydroxypropyl-β-cyclodextrin in SLNs improved the bioavailability, cellular uptake, and anticancer activity of paclitaxel in MCF-7 breast cancer cells via modification of paclitaxel-SLNs (Cho et al. 2015). Moreover, hyaluronic acid (HA)-coated docetaxel-SLNs were developed to overcome drug-resistance in tumor cells (Lee et al. 2019). Docetaxel-loaded HA-SLNs were shown to be effective in overcoming drug resistance in tumor cells and a considerable amount of CD44 expression was detected in MCF-7/ADR cells. Additionally, the in vitro cytotoxicity and cellular uptake of docetaxel-loaded HA-SLNs in MCF-7/ADR cells were higher than those of other cells. Kang et al. prepared doxorubicin-loaded SLNs to overcome multidrug resistance in cancer therapy (Kang et al. 2010). In the preparation, doxorubicin-loaded SLNs were prepared by solvent emulsification-diffusion method in which glyceryl caprate (Capmul®MCM C10) was used as lipid core and curdlan was used as the shell material. Dimethyl sulfoxide (DMSO) was used to dissolve both lipid and drug, Solutol®HS15 was used as a surfactant (Subedi et al. 2009). As the result, doxorubicin decreased the percentage of cell viability in MCF-7/ADR cells; after treating with doxorubicin and doxorubicin-loaded SLNs (30 µM), the percentage of cell viability decrease from approximately 90% (doxorubicin) to approximately 10% (doxorubicin-loaded SLNs).

Gold nanoparticles

Gold nanoparticles are inert and non-toxic, contain a gold core, and are below 150 nm in size (Manju and Sreenivasan 2010). Gold nanoparticles have recently emerged as attractive candidates to deliver anticancer drugs due to their biocompatibility (Singh et al. 2017). Besides, there are several advantages associated with gold nanoparticles such as radiosensitization, photothermal therapy, etc. (Arvizo et al. 2010). The study by García Calavia et al. showed that phthalocyanine functionalized gold nanoparticles can be stabilized and dispersed in aqueous solutions using a lactose derivative. Gold nanoparticles were prepared and functionalized with a mixed monolayer of a zinc phthalocyanine and a lactose derivative (García Calavia et al. 2018). The functionalization of the phthalocyanine-gold nanoparticles with lactose led to the production of water-dispersible nanoparticles that can generate singlet oxygen and effect cell death upon irradiation. The targeting ability of lactose of the lactose-phthalocyanine functionalized gold nanoparticles has studied in vitro towards the galectin-1 receptor on the surface of MDA-MB-231 and SK-BR-3 breast cancer cells. The results showed the exciting potential of lactose as a specific targeting agent for galactose-binding receptors overexpressed on breast cancer cells. It has been reported that gold nanoparticles can conjugate with antibodies specific to antigens that are overexpressed on tumor cells (Lim et al. 2011). Examples of gold nanoparticles used for anticancer drug delivery to breast cancer cells are summarized in Table 5.

Table 5 Anticancer drug delivery by gold nanoparticles to breast cancer cells
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As reported by Lee et al., antibody-conjugated gold nanoparticles were used for the surface-enhanced Raman spectroscopy imaging of tumor biomarkers that are overexpressed in MCF-7 breast cancer cells (Lee et al. 2009). Chloroquine gold nanoparticles were prepared, and their anticancer activity in MCF-7 breast cancer cells was explored (Joshi et al. 2012); interesting anticancer properties were found in vitro. The release of chloroquine from gold nanoparticles at a lower pH suggested that the lysosomal/endosomal uptake of chloroquine and the cytotoxicity of chloroquine nanoparticles in MCF-7 breast cancer cells was concentration-dependent (Joshi et al. 2012). In another study, docetaxel gold nanoparticles were prepared and evaluated in cancer cells (François et al. 2011), and the efficiency of docetaxel gold nanoparticle against MCF-7 breast cancer cells was 2.5-fold higher than that of docetaxel alone (François et al. 2011). Inulin-coated gold nanoparticles were also prepared for the selective delivery of doxorubicin to breast cancer cells (Licciardi et al. 2016). The anticancer activity toward MCF-7 breast cancer cells increased and inulin-coated gold nanoparticles preferentially accumulated in cancer cells rather than normal cells.

Recent advances in nanoparticles for the treatment of breast cancer

Nanoparticles have considerable potential for drug delivery and are widely used in the treatment of cancer. Nanoparticles have shown several advantages, such as good stability, high encapsulation, and the ability to incorporate both hydrophilic and hydrophobic drugs. However, nanoparticles have also shown some potential risks (Table 6). For example, nanoparticles with small particle size can easily pass through membranes, access many areas of the body, interact with cells in an unfavorable manner, and potentially cause intrinsic toxicity in many normal cells. In addition, materials can limit the preparation of nanoparticles. For instance, PLGA is a safe material with low toxicity, but it degrades quickly and does not circulate in tissues long enough for sustained drug/gene delivery resulting in decreased treatment efficiency (Jain et al. 2011; Nguyen 2011). Therefore, the disadvantage of PLGA can be overcame by changing the poly-lactic/glycolic acid ratio (Makadia and Siegel 2011). For example, with the ratio of 50:50 (PLA/PGA), PLGA exhibited a faster degradation than PLGA with a ratio 65:35 (PLA/PGA) due to preferential degradation of glycolic acid proportion assigned by higher hydrophilicity. Subsequently PLGA 65:35 (PLA/PGA) shows faster degradation than PLGA 75:25 (PLA/PGA) and PLGA 75:25 (PLA/PGA) than PLGA 85:15 (PLA/PGA). Therefore, the absolute value of the degradation rate depends on the ratio of glycolic acid. The amount of glycolic acid is a critical parameter in tuning the hydrophilicity of the matrix and thus the degradation and drug release rate (Park 1995; Lu et al. 1999, 2000). On the other hand, inorganic materials, such as carbon nanotubes, are durable and can persist in the body for weeks, months, or even years, making them potentially toxic and limiting their use for repeated treatments. In addition, some cancer cells can develop a resistance to the drug over the course of treatment, rendering the drug released from the nanoparticle ineffective (Nguyen 2011).

Table 6 Advantages and disadvantages of liposomes, micelles, polymeric nanoparticles, solid lipid nanoparticles, and gold nanoparticles
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In recent years, the surfaces of nanoparticles have been modified using active targeting ligands to improve the distribution of anticancer drugs to target cells (Sohn et al. 2017; Choi and Park 2017). For example, a docetaxel liposome was prepared using d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and further conjugated to trastuzumab for cellular uptake intended to produce cytotoxicity in SK-BR-3 cells, while in vivo pharmacokinetics were also investigated in rats (Raju et al. 2013). The IC50 value of a marketed preparation of docetaxel, TPGS liposomes, and trastuzumab-conjugated TPGS liposomes after a 24 h incubation with SK-BR-3 cells was 20.23 ± 1.95, 3.74 ± 0.98, and 0.08 ± 0.4 µg/mL, respectively. In addition, the half-life of trastuzumab-conjugated TPGS liposomes was tenfold higher compared to docetaxel alone in the pharmacokinetic study. In another study, PLA-TPGS was used as a polymer in the preparation of emtansine nanoparticle that were subsequently conjugated with trastuzumab for the treatment of HER2-positive breast cancer (Rong et al. 2017). The toxicity of emtansine nanoparticle-trastuzumab in breast cancer cells was higher that than of emtansine and trastuzumab alone. In vivo, the nanoparticle showed fewer toxic effects and inhibited tumor growth by 88% compared to the non-targeting group after administration in MDA-MB-453 xenograft-bearing mice. To modify the surface of the docetaxel-PLGA nanoparticles with Herceptin® (HCT), different methods such as adsorption, bio-conjugation, and charged adsorption were applied to enhance internalization and cytotoxicity in BT-474, SK-BR-3, and MCF-7 breast cancer cells (Choi et al. 2018a). The cellular uptake of HCT-bioconjugated nanoparticles in BT-474, SK-BR-3, and MCF-7 breast cancer cells was 5.0-, 4.4-, and 4.6-fold higher than that of the nanoparticles, respectively. In addition, the cytotoxicity of HCT-bioconjugated DTX-nanoparticles in BT-474, SK-BR-3, and MCF-7 breast cancer cells was higher compared to other formulations. Moreover, tumor-targeting gold nanorod (AuNR)-photosensitizer conjugates were designed using glutathione-sensitive linkages for effective photodynamic (PDT)/photothermal (PTT) therapies to improve active tumor-targeting activity and stability and in vitro cytotoxicity and cellular localization were also investigated in MCF-7 breast cancer cells (Choi et al. 2018b). The AuNR-photosensitizer conjugates presented good stability and biocompatibility. In addition, more than 99% of MCF-7 breast cancer cells showed AuNR-photosensitizer conjugate uptake in vitro.

Conclusions

Currently, nanoparticle research for the treatment of breast cancer has increased rapidly and has been primarily focused on using targeting ligands to achieve high accumulation with tumors. One of the most common cell surface receptors on breast cancer cells, is HER2 and this receptor is used as an effective target for traditional anticancer drugs, such as paclitaxel, docetaxel, and doxorubicin. By using targeting ligands in the preparation of nanoparticles, treatment efficiency is increased and toxicity is avoided in normal cells compared to nanoparticles without targeting ligands. Therefore, nanoparticles are a promising tool for the treatment of breast cancer and other cancers in the future.