Nanomaterials as nanocarriers: a critical assessment why these are multi-chore vanquisher in breast cancer treatment

Abstract

Breast cancer is a group of diseases with various subtypes and leads to high mortality throughout the globe. Various conventional techniques are in practice to cure breast cancer but these techniques are linked with various shortcomings. Mostly these treatments are not site directed and cause toxicity towards normal cells. In order to overcome these issues, we need smart system that can deliver anticancer drugs to specific sites. Targeted drug delivery can be achieved via passive or active drug delivery using nanocarriers. This mode of drug delivery is more effective against breast cancer and may help in the reduction of mortality rate. Potentially used nanocarriers for targeted drug delivery belong to organic and inorganic molecules. Various FDA approved nano products are in use to cure breast cancer. However, body’s defense system is main limitation for potential use of nano systems. However, this can be overcome by surface modification of nanocarriers. In this review, breast cancer and its types, targeted drug delivery and nanocarriers used to cure breast cancer are discussed. By progressing nanotechnology, we will be able to fight against this life threatening issue and serve the humanity, which is the basic aim of scientific knowledge.

Keywords:

• Nanocarriers
• FDA
• PEGylation
• targeted drug delivery
• passive/active drug delivery

Introduction

The utmost devastating disease related with progressive alterations or variations in the cellular, genetic and epigenetic physiognomies that leads to uncontrolled cell division, eventually causing the development of a malignant mass is known as cancer [1]. This heterogeneity and complexity encourage the fierce growth of cancer cells resulting insubstantial mortality and morbidity [2]. Owing to the growth and aging of global population and a greater adoption of cancer-causing behaviours, the worldwide burden of cancer endures to intensify largely; within economically developing countries [3]. Through multistep carcinogenesis process, cancer is commonly known to develop many cellular physiological patterns, for example apoptosis and cell signalling, creating unintelligible and complex disease [4]. Resulting malignant tumours (cancer) may occupy other adjacent organs, and beyond the location of its initiation (metastasis) posing the disease life-threatening [5]. Specificity in detecting precancerous conditions or early-stage cancer with a low rate of false positives, insufficient sensitivity, screening technologies, high cost and inability to determine tumour stage are the limitations of conventional cancer treatment practices [1]. This demands for a system which can overcome issues associated with conventional treatment. Nanotechnology offers ground to treat cancer where we direct targeted drug delivery to cancerous cells with the aid of nano-carriers.

Histo-pathological classification and subtypes of breast cancer (BC)

Breast cancer is a type of malicious tumour originates in the tissues of breast section, most probably from the interior lining of lobules or milk ducts. It is a heterogeneous disease; fifth most common cause of death [1]. Breast cancer may also occur in male but the preponderance occurs in women with probability one out of eight and about one dies in every 35 women [6,7]. Nevertheless, it remains sickly agreed that within the tumour microenvironment, how the alteration from wellbeing to malevolence changes the mechanical properties of cells [8,9]?

Breast cancer has many subtypes with diversified morphologies and clinical extrapolations. The initiation of micro-arrays has resulted in novel prototype breast cancer heterogeneity; on that basis inherent sub typing system using prognostic multi-gene classifiers has been formed. However, overlapping of gene panels to a higher degree, the gain of fresh data and perceptions cause advent of novel subtypes that obscure our insights to heterogeneity [10]. Abide molecular mechanisms understanding, carcinogenesis and advanced targeted therapies, breast cancer is uncontrolled [11]. Breast cancers are of numerous forms (Table 1; Figure 1) which can be started from different parts of the breast [5].

Figure 1. Morphology and medical illustration of the various types of breast cancer.

Table 1. Different types of breast cancer along with site of development and characteristics.

Type	Sub types	Sites of occurrence	Metastasis	Diagnosis	Treatment	References
Pre-invasive (Breast Cancer)	IDC	Ducts that carry milk to nipple	Yes	Early stage is possible	Local: surgery/radiation systemic: chemical/hormonal, therapies	[12]
	ILC	Milk glands (lobules)	Yes	Difficult to detect than IDC	Local: surgery/ radiation Systemic: chemical/hormonal, therapies	[12]
Invasive	EBC	Arises in the breast	May or may not	Detection is difficult in metastatic areas	Local: surgery/radiation and adjuvant systemic therapy	[13]
	LABC	In breast and is larger than 5cm	Yes	advanced breast cancer test	Combination of chemotherapy, surgery, radiotherapy, targeted and hormonal therapies.	[14]
	MBC	Arises in the breast	Yes	Difficult to diagnose	Chemotherapy, hormone therapy	[5]
	HRP	Breast	Yes	Immunohistochemical staining assay, or Immunohistochemistry (IHC).	Chemotherapy with targeted hormonal therapies	[15]
	HER2 P	Breast	Yes	IHC, FISH, SPoT-Light HER2 CISH and Inform HER2 Dual ISH test	Trastuzumab (Herceptin™) or lapatinib (Tykerb™), targeted therapy along with chemotherapy are in use.	[16]
	TN	Breast	Yes	mammograms, ultrasound, MRI, CAT scans, PET scans etc.	Surgery, radiation and chemotherapy.	[12]
Sarcomas and lymphomas	N.A	Muscle, fat or connective tissue	Yes	mammograms, MRI, CAT scans, ultrasound, PET scans etc.	Chemotherapy, radiotherapy and possibly surgery.	[17]
Paget’s Disease	N.A	Nipple and areola	Yes	Physical examination, mammogram, MRI, Ultrasound, Biopsy	Surgery, Mastectomy, radiation chemotherapy, hormone therapy.	[12]
Inflammatory	N.A	Breast or localized	Yes	Histologically	chemotherapy, surgery, radiation and possibly targeted therapy	[18]
Medullary	N.A	Breast ducts	Yes	Histologically	Surgery followed by chemotherapy	[12]
Mucinous	N.A	Milk duct	Less likely to spread	Physical examination, mammogram, MRI, Ultrasound, Biopsy	Lumpectomy, mastectomy, radiation, hormonal and chemotherapy.	[19]
Tubular	N.A	Breast's milk duct	Yes	Physical examination, mammogram, MRI, Ultrasound, Biopsy	Surgery followed by chemotherapy, surgery, radiation	[19]
Metaplastic (MBC)	N.A	Breast	Yes	Mammogram, Biopsy, ultrasound, FNA	Surgery followed by chemotherapy, surgery, radiation	[5]
Papillary breast cancer	N.A	Breast	Yes	Mammogram, biopsy, ultrasound, FNA	Surgery followed by chemotherapy, surgery, radiation	[20]

IDC: Invasive ductal carcinoma; ILC: Invasive lobular carcinoma; EBC: Early Breast Cancer; LABC: locally advanced breast cancer; MBC: Metastatic Breast Cancer; HRP: Hormone receptor positive; HER2 P: HER2 positive; TN: triple negative; IHC: immunohistochemistry; FISH: fluorescence in situ hybridization; SPoT-Light HER2 CISH: Subtraction probe technology chromogenic in situ hybridization; Inform HER2 Dual ISH test: inform dual in situ hybridization; FNA: fine needle aspiration.

Challenges in conventional treatments for BC

Accelerated partial breast irradiation has been scrutinized for the treatment of early-stage breast cancer as a therapeutic methodology to improve local control rates [7]. The restrictions of the existing cancer therapeutics are non-specific dispersion of drug, inadequate drug concentrations to target site, intolerable toxicity, partial ability to track and control the site-specific therapeutic reactions, adversative possessions and progression of drug resistance [21].

Therapeutic advantages of the nanocarriers for BC

Conventional treatments kill normal cells and are toxic to non-specific targets. Hence, it is more likely to develop such chemotherapeutic strategies that cause less or no toxicity to the patients and affect the cancerous cells passively or actively. Use of nanoparticles may confer targeted drug delivery to tumour cells. Concentration of drug in the cancer cells increases with the use of active or passive targeting. In light of above advantages, if development of nanoparticle therapies is in right direction, the outcomes can be improved in the patients of metastatic cancer. Though, drug resistance is primary hindrance to treat cancer [22]. The novel therapies, i.e. use of nanoparticles are being developed that are implemented to overcome the limitations associated with the chemotherapy.

Nanotechnology in targeted drug delivery

Nanotechnology has potential to revolutionize cancer diagnosis and therapy comprising non-invasive therapy, advanced imaging, monitoring response to therapy, improved nodal staging and treatment of metastatic disease [5]. Nanotechnology may modify pharmaco-kinetics and delivery refining effectiveness and lessening side effects [23,24]. The size and surface properties enrich drug portability, mobility, flexibility and thus enhance choosy internment in tumour tissue making them potentially operative tumour conveyance vectors [25]. Nanotechnology including metallic and semiconductor nanoparticles enlarges useful abilities for contemporaneous targeted drug delivery and imaging [26,27].

Targeted drug delivery

With the development in the imaging, delivery and the sensing techniques; the innovations in field of oncology has breakthrough in the treatment strategies [28]. Targeted drug delivery systems are considered for the bio distribution of specific drugs by macromolecular drug conjugates, chemically or genetically reformed proteins, particulate drug carriers and others [29,30]. Various targeting agents used are targeted drug delivery are shown in Figure 2. Passive and active approaches for drug delivery are currently in practice.

Figure 2. Overview of targeted drug delivery.

Passive drug delivery

In passive targeting, the specific features of the cancer cells are exploited that allows drug nanocarriers to accumulate in the tumour cells due to increased retention and permeability (Figure 3). Leaky vasculature of tumour tissues due to excessive angiogenesis, expresses the basis of passive targeting of the drugs. Brief accounts of these methods are as follows.

Figure 3. Passive and active drug delivery carried out by various methods.

Transdermal drug delivery

It is a striking substitute to the conventional drug delivery approaches of oral as well as intravenous systems of drug delivery. Stratum corneum is the only drawback of the complete targeting of transdermal drug that can be modified via application of ultrasound irradiation to the skin and increases permeability of drug [31].

Therapeutics through cytokines (TNF)

Various antitumour effects associate with natural killer cell and lymphocytes necrosis factors, including induction of necrosis and apoptosis, activation of the cells that are cytolytic and ICAM-1expression up regulation. In breast cancer patients, TNF production by monocytes has been found less impaired as compared to the normal persons. Many researches working on metastasis have revealed that interferon IFN-A is the most critical component that is involved in the regulation of the phagocytic response against the breast tumours and cancer. In tumour tissues, significant level of IL-10 mRNA has been observed. IL-10 has noteworthy activity against tumour. In vivo studies suggest that recombinant humanized IL-10 administration to animals significantly inhibits growth due to increase in CD4 positive cells which ultimately increase the Mig and IP-10 production. Both of these are the potent inhibitors of angiogenesis [32].

Anti-metastatic activity has also been demonstrated in IL-10 and it depends on natural killer cell activity. Expression of IL-10 also decreases expression of MHC class 1 in tumour cells which causes increased lyses of natural killers. IL-10 at higher concentration has significant anti-tumour activity. Another factor for the stimulation of natural killer cells is interleukin-12 that is produced by the macrophages and other monocytes, has suppression activity to control tumour size. It also tends to initiate cellular immunity and has significant effects on the natural killer cells and T cells. In recent years, a number of therapeutic strategies have been developed based on the principle of DC (dendritic cell). These cells are able to secrete the stimulator molecules, in addition to cytokines that are considered potent pro-inflammatory [33]. This is effective vaccine to induce cellular immunity. The over expression of IL-24 gene has inhibitory action on tumour growth. In vivo studies have shown that injection of interleukin induces apoptosis in tumour cells. The antitumour effects of the interleukin are mediated in p53-independent manner. The combination therapy of adenovirus vectors and the Herceptin have clear impact on breast cancer. For the gene therapy of cancer, IL-24 has considerable impact. It is under the clinical trials of phase II to determine the effects of the therapy in the cancer patients [34].

PEGylated nanoparticle development

Passive drug delivery systems pave way for the PEGylated nanoparticles; which due to their size and altered chemical structure can be directed to the site of tumour [35]. Long half-life, less immune reactions, good compatibility, ideal targeting, good penetration in the physiological barriers, self-regulation of drug and nearly no side effects are key features of nano vectors. To improve the circulation and selective targeting of drugs, the tools such as the immunolabelling and PEGylation are necessary. PEGylation shielding also enhances stability of drugs. In future, these approaches will be more likely to combine the particles in the hybrid based systems to lessen the limitations and synergistic efficacy [36].

Liposome-mediated drug delivery

Use of liposome assures the delivery of drugs by improving their solubility. In this way, they improve transfer of therapeutics in tumour cells, and also decrease drug toxicity. Among a lot of drug delivery methods, the liposome is in practice or some are in clinical trials after advancements in nanoparticle based delivery systems. While others are still in different stages of clinical development. Liposomes packed drugs are released steadily and have good compatibility. Liposome with the specific features has been developed that are capable to evade the RES system, and have enhanced binding specificity to the tumour cells. Certain studies have also shown promising results with ATP-mediated delivery of liposomes. Due to all these factors, the liposome is considered as the excellent vehicles for the transport of drugs in tumours [37].

Active drug delivery

Drawbacks and limited efficacy of passive drug targeting methods have urged scientists to move towards active drug delivery to the tumour site. This seems more promising due to ligand interaction with membrane expressed proteins that could effectively concentrate the given drug at the site of action (Figure 3). Many active drug targeting approaches have been used till now, account of which has been given below.

Formation of smart polymers

Targeted drug delivery via polymers that are sensitive to pH is under consideration. These are designed to deliver drugs to the cells by pH sensitization due to endosomal disruption after endocytosis. An improved efficacy in the delivery process is achieved by the formation of the polymers from different monomers that are made hydrophobic on changing the pKa values and adjusting them in the acidic range. Higher efficacy is achieved because this process mimics the common disruptive peptides behaviour [38].

Nanoshells as active targeting molecules

For the diagnosis and treatment of cancer, the nanoshells have been devised and are considered as promising candidates [39]. Most of the blood vessels in solid tumours have unique properties. These include angiogenesis, high vascular density and extravasations of macromolecules in plasma. The tendency of polymeric drugs to accumulate in the tumour increases due to diffusion of plasma contents facilitated by vascular epidermal growth factor (VEGF). More accumulation of nutrients and oxygen occur due to endothelial factors. These nutrients accumulate in the interstitial space so it allows the components in plasma to penetrate in walls of blood vessels. In this way tumour rapid growth sustain [40]. The applications of nanoshells are versatile but these are limited due to less penetration and tumour sites targeting. The gold nanoshells that lie in the near infrared region are able to heat up the tumours to extent that cause damage to the tumours irreversibly [41]. Bio-recognition sites that are capable to dock to the receptors on the cancer cells have also been included in the nanoshell treatment. These are combined to the endoscopic procedures that help to focus the Near Infrared (NIR) radiation at the increasing depths [42].

Use of transferrin targeted zoledronic acid (ZA) nanoparticles

Transferrin is used to complex with nanoparticles because transferrin receptors over express intra as well as extra cellularly [43]. Tumour has been treated with zoledronic acid and temozolomide. These are the cytotoxic agents that are used to inhibit abnormal proliferation of cell but the problems associated are cytotoxicity to normal cells. They accumulate in the bone marrow, not transported in effective concentration to inhibit cell growth and also cause haemolysis. Studies show that ZA increases apoptosis 1.27 times in U87MG cell lines according to control cells [44]. Recent research has reported that when transferrin is complexed with nanoparticles encapsulating ZA, it increases ability to target tumour cells. The intracellular concentrations are also reported to increase in the tumour cells which indicate increased uptake of the drug by tumour cells. In vivo and in vitro studies have shown that these particles do not cause haemolysis, nor accumulate in bone marrow [45]. Temozolomide is the cytostatic agent that tends to cause cytotoxicity in tumour cells. The cytotoxic effects of temozolomide are potentiated when it is administered along with the transferring targeted nanoparticles [46].

Antibody mediated targeted drug delivery

Among different types of the targeting agents, most common are antibodies, nucleic acids and the ligands of different receptors. Food and Drug Administration (FDA) has approved use of monoclonal antibody after clinical demonstration with the use of 17 antibodies. The use of monoclonal antibody rituximab was done in 1997 for the Hodgkin’s lymphoma. Another antibody, anti-HR antibody has also been approved for breast cancer treatment. Currently about 200 antibodies based delivery systems are under the clinical and preclinical trials. So, due to the advancement in the field of the antibody engineering, chimeric antibodies have been developed that are both human and animal origins [47]. The fragments as well as native form of the antibodies can also be used but the fact is that the use of whole antibody is more effective because binding sites of single antibody provides higher binding capacity and sensitivity of the drug delivery system. Whole antibodies usage also poses an additional advantage as they remain stable during the long-term storage. The use of antibody fragments does not offer stability but they reduce the chances of non-specific binding. Antibodies that are generated by this method bind different epitopes of the same target cells [48].

Hormonal therapy

The growth of the breast cells is regulated by oestrogen receptors. It is fact that when the ovaries of premenopausal females are removed, a regression of the tumours in breast is observed. Oestrogen produced by ovaries diffuses through plasma membrane of the cells where it interacts with ER (oestrogen receptors). On binding of oestrogen to ER, the dimerization of ER causes its translocation in to the nucleus. In nucleus, it binds to Oestrogen responsive element (ERE) that is present in the promoter region to activate downstream gene expression. Scientists have developed the modulators of the oestrogen receptor that act as antagonists through their AF2 domain. In females with ER positive status, a survival of 10-year has been reported. The annual rate of the breast cancer is observed to decrease to 31% by the tamoxifen therapy for continuous 5 years [49].

Immunotherapy

Up regulation of human epidermal growth factor is observed to about 25%in the tumours of breast because of abnormal amplification and over expression of the genes. This is the cause of less survival rates and shortened time. The first anti-kinase therapy was developed based on the genomic research and has been approved by FDA. This treatment is developed for the patients of invasive breast cancer in which Her2 over expresses. This antibody interacts with Her2 extracellular domain and inhibits the proliferation of tumours that are Her2 dependent and they block the formation of dimer [50].

In order to deliver drugs at specific sites of tumour cells, there is a prerequisite of an agent, which is capable to carry a drug and delivered to a destiny. An ideal system for this purpose comprises of nanocarriers, which are now actively used in medical sector.

Nanocarriers: new vehicles of drug delivery

Concept of nanocarriers arose from the observation made by Paul Ehrlich (1854–1915) that if an agent could selectively target a pathogen, then that toxic agent can be delivered with the agent of selectivity. Nanomaterials have been designed to function as a vector for drug delivery [51]. However, site specific targeting through nanomaterials is a pre-requisite to attain diagnostic or therapeutic effects [52]. Nanotechnology based carriers have been employed for high drug load and sustainable drug release [53], avoiding biological obstacles and targeted drug delivery with effective concentration, while sheathing the normal tissues from the toxic effects of these therapeutics [54]. Majority of organic [55] and inorganic [56] biomaterials have been discovered as a drug carrier (Figure 4).

Figure 4. Frequently used organic and inorganic nanocarriers in breast cancer.

Organic nanocarriers

Liposomes

Liposomes are aqueous compartment enclosed in spherical vesicles composed of single or multiple membranes of natural or synthetic lipid bilayers [57,58]. Drug can be stacked inside liposomes in watery medium that facilitates diverse medications to be completed [59]. Liposomes as a drug carrier have been used since 1960s [60] and in 1965 were considered as first nanoparticle to be employed in medication [61]. It can enhance drug accumulation in tumour cell while limiting their accumulation in normal tissue [62]. Different drugs i.e. doxorubicin [63], paclitaxel [64], daunorubicin, lurtotecan, annamycin, platinum compounds and genes such as the E1A gene [65], cisplatin [66] etc. have been encapsulated in liposomes. Drugs enclosed in liposomes can be released by altering pH at the target sites [67], induces mechanical stress [68], light [69], temperature [70], redox reactions [71] and by enzymatic reaction on the liposome [72].

Polymeric nanoparticles

These may be employed as the most operative nanocarriers for protracted drug delivery. Natural polymeric substances such as chitosan, heparin, dextran, gelatin, alginate and collagen as well as synthetic polymers as PEG, polyglutamic acid (PGA), polylactic acid (PLA), polycarprolactone (PCL), poly-d,l-lactide-co-glycolide (PLGA) and N-(2-hydroxypropyl)-methacrylamide copolymer (HPMA) have been comprehensively used owing to their biocompatibility, biodegradability, for the preparation of NPs and encapsulate drugs for therapy of cancer [73–76]. Improvement of polymeric nanoparticles encumbered with drugs is in practice since long. Langer and Folkman [77] recognized the first organized release of macromolecules by means of polymers. Couvreur developed polyalkyl cyanoacrylate-based nanoparticles releasing doxorubicin [78]. Langer et al. pronounced nanoparticles self-possessed of poly(lactic acid)/poly (lactic-co-glycolic acid) (PLA/PLGA) and Gref et al. demonstrated PEG block copolymer as “long mixing nanoparticles” due to their stealth properties [79]. The surface of nanoparticle is sterically alleviated by grafting, conjugating or adsorbing hydrophilic polymers such as PEG to its surface, which can also reduce hepatic uptake in addition to improve half-life [80].

Micelles

Micelles are self-assemblies of lipids or other amphiphilic molecules organized into nanoparticles [81]. Two or more polymeric chains with different hydrophilicity systematize into a core-shell assembly in an aqueous medium [82,83]. This leads to design appropriate for drug delivery. Drugs, proteins and nucleic acids can be loaded in the hydrophobic core although the hydrophilic shell is accountable for steric fortification of the nanoparticle [84]. Micelles are considered as an ideal drug delivery vehicles for hydrophobic drugs [85]. Drug released from micelles can be achieved by various means like erosion of biodegradable polymer, diffusion of the drug after polymer swelling or through the polymer matrix, varying external factors like pH and temperature or through surface modification with ligands; help in targeted drug delivery and decrease systemic toxicity and enhance specificities and effectiveness [86]. Drug delivery by micelle can be alienated into four assemblages; these are phospholipid micelles, pluronic micelles, poly (l-amino acid) micelles as well as polyester micelles that demonstrate a comparable molecular design which is not discussed here in detail.

Dendrimers

Dendrimers are well defined, regularly branched polymeric complexes surrounding an inner core and physio-chemically similar to macromolecules [87]. Regardless of their large molecular mass [88], they exhibit well-established architecture and functionalities [89]. Glyco, peptide and silicon based dendrimers have been achieved by functionalization of dendrimers [90]. Dendrimers with almost monodispersity in addition to suitable pharmacokinetic possessions are in practice for systemic drug delivery with dissociation of drugs [91]. The polyamidoamine (PAMAM) family of dendrimers is the most frequently studied dendrimers. Due to their biodegradable, biocompatible and fairly soluble nature in aqueous medium made them as a potent agent for drug delivery [92]. In addition, architecture and surface can be altered for intriguing applications including diagnosis and therapy [93]. For pharmaceutical applications, dendrimers are functionalized [PEGylation] most frequently [94]. Various anticancer drugs have been delivered to carcinogenic tissues through PEGylated dendrimers. Drugs release after attainment of target site by enzymatic action, pH changes, etc. [95]. Dendrimers associate with indomethacin [96], fluorouracil [97] and antisense oligonucleotides [98] have been inspected as delivery system. For active drug targeting, dendrimers have been functionalized with folate vector which enhances build-up of anticancer drug in the tumour tissue [99]. Functionalized dendrimers with RGD (arginine–glycine–aspartic acid) and neurotensin peptides got interest in recent research due to their greater stability and affinity to carcinogenic tissues [100].

Protein nanoparticles

Natural polymers such as albumin, heparin, gelatin and collagen, etc. have been widely used in encapsulation of anticancer drugs due to their biocompatibility, biodegradability and regulatory approval for cancer treatment [73]. Albumin is inert in the range of pH [4–9], solubilize in aqueous medium and thermodynamically stable even heated at about 60 °C up to 10 h. In addition, albumin has no immunogenicity and has a longer half-life [101]. Binding of albumin to the glycoprotein gp60 (albondin), surface receptors triggers binding of glycoprotein gp60 to the caveoline-1 (intracellular protein), results in the formation of caveolae (transcytotic vesicles) through membrane invagination. By this mechanism, transportation of albumin is regulated across endothelium into the extra vascular space. Active transportation of plasma proteins occurs in tissues with high metabolism like tumour and inflamed tissues [102]. Three main approaches are in use in drug delivery: (i) encapsulation of low-molecular-weight drugs to endogenous or exogenous albumin; (ii) binding of albumin with bioactive proteins and (iii) loading of drug into albumin NPs [92]. FDA has permitted albumin-bound paclitaxel (Abraxane, ABI-008, January 2005) for metastatic breast cancer treatment, as well as in numerous clinical trials in recent times in evolution for other types of cancer.

Organic materials as nanocarriers also severe some limitations like inadequate chemical and mechanic stability, swelling, liability to microbial attack, insufficient control in drug release [103] and quite expensive. In addition to these problems, polymer NPs also exhibit high polydispersity. During synthesis, particles with a wide size ranges and irregular morphologies limit homogeneous pharmacological properties. Dendrimer can overcome this limitation due to monodispersity and spherical design due to stepwise fabrication and purification [104]. Major shortcoming of dendrimers is high cost. Dendrimers can be quickly removed from the body during circulation in the body via defence mechanisms exhibited by the body remained a challenge.

Inorganic nanoparticles

Inorganic NPs are mostly metallic in nature while some are metalloids and have intriguing applications in many fields.

Gold NPs

Since 2500–2600 BC various compounds of gold are used as “Swarna Bhasma” by Chinese and Indian in medicines for variety of purposes [105]. Common usage of gold NPs are due to the obvious advantages associated with it like simple, cost effective and dependable methodologies, and various forms generation such as spheres [105], shells [106], rods [107] and cages [108]. AuNPs display strong surface plasmon resonance [109] and dielectric strength [110]. Possession of negative charge and robust binding aptitude of gold with chemical assemblies like thiols, disulfides, phosphine, as well as amines [111] are useful in modification and functionalization with various biological molecules [112]. Besides this, biocompatibility and non-toxicity [113] make them as an attractive tool for medicines especially in cancer therapy [114]. Use of gold NPs as a probe for hyperthermia by means of NIR [115] demonstrates photothermal therapy and treatment of cancer. Recent reports describe use of silica-gold nanoshell with NIR for in vitro and in vivo photothermal therapy of breast cancer [116]. Preliminary (phase I) test for dose intensification studies with use of a CYT-6091, i.e. PEGylated AuNPs with recombinant human tumour necrosis factor alpha have been approved [117] and AuNPs were absent in normal parenchyma of breast cancer patients [118]. Hyperthermia with NIR laser and AuNPs has recognized as an effective in vitro technique against breast cancer [119]. Functionalization of AuNPs with various therapeutic agents can help in drug delivery and controlled drug release in tumour site. So far, AuNPs have been functionalized with many materials, i.e. tumour necrosis factor, antisense DNA, small interfering RNA (siRNA), paclitaxel and plus docetaxel [120]. Lower pH within endosomes assists in the drug release [121] or photothermal therapy from NIR laser also aid in release of drug at target sites [122]. Mode of action of targeted gold mediated hyperthermia can be made easier. Gold NPs can be targeted by passive or active targeting the solid tumours due to their leaky vasculature through enhanced permeability and retention (EPR) [123]. Accumulation and binding of gold NPs first in tumours cells are irradiated with NIR which cause photothermal heating [124]. This procedure prevents side effects linked with conventional cancer treatments due to confined irradiation at the tumour site. Gold nanostars conjugated with trans-activator of transcription (TAT) and cell-penetrating peptide (CPP) showed better response to BT549 cell. CPP help in transportation of NPs across the plasma membrane and boost their delivery within the nucleus by macropinocytosis [112]. Bimetallic NPs of gold-silver functionalized with S2.2 aptamer targeted MUC1 receptors on MCF-7 breast cancer cells but limited binding is observed for HEPG2 or MCF-10 A liver and other breast cancer cells [125]. Another study demonstrated use of functionalized gold nanorods with AS1411 DNA aptamer, coated with mesoporous silica loaded with doxorubicin [DOX] to target breast cancer cells via light stimulated photothermal chemotherapy [126]. Almost 20% cytotoxicity was observed when these conjugated NPs were raised with the cells, representing leakage of more or less DOX . While irradiation with NIR provoked dehybridization of DNA aptamers which commanded in better DOX release expiring up to 90% MCF-7 cells [126]. Same were observed in various other methods such as pH dependent ligands to prompt DOX release commencing gold nanocages [127] or incorporation of gold nanoshells [128]. Thermal imaging of MDA-MB-231 breast cancer tumours in mice via nanomatryoshkas [gold–silica conjugate] are found enough for killing tumour cell after NIR [129]. Plasmonic gold vesicles loaded with chlorine e6 injected in athymic nude mice with breast cancer (MDA-MB-435) tumours and irradiated with laser NIR (671 nm, 2 W/cm², 6 min) resulted in increase of 10 °C in temperature prohibiting any tumour growth [130]. SK-BR-3 breast cancer cells when incubated with PEGylate AuNSs followed by 820-nm NIR laser resulted in limited survival of breast cancer cells in contrast to cells treated without AuNSs [116]. PEGylated AuNSs conjugated with a HER-2 antibody exhibited higher uptake by SK-BR-3 cells [119]. Use of PEGylated AuNPs loaded with trastuzumab against HER-2 overexpressing SK-BR-3 breast cancer cells with use of radiation [300 peak kV] leads in 5.1 times more breakage in double stranded DNA as compared to PEGylated AuNPs [131].

Iron oxide NPs

Magnetic NPs (MNPs) exists in two types, i.e. magnetite (Fe₃O₄) and maghemite (Fe₂O₃). Immense use of these MNPs in oncological studies are due to their tendency to target specific side by limiting systemic circulation, encapsulation of drugs, a slow rate of drug suspension during delivery and improved dissolution while reaching to the target sites, thus letting the usage of lower dosages of cytotoxic drugs and minimizing their side-effects [132–134]. Naked iron NPs can clump forming large clusters which increases particle size in turn reduces innate super paramagnetic character and stimulate opsonization [135]. Surface modifications can overcome clumping and minimizing opsonization. Various agents are in practice for surface modification of NPs like dextran, polyethylene glycol (PEG), poly(vinylpyrrolidone) (PVP), streptavidin, poly-l-lysine (PLL), polyethylene imide (PEI), etc. [136]. Drugs encapsulated in MNPs are mitoxantrone [137], tamoxifen [138], cefradine [139], doxorubicin [140], daunorubicin [141], cisplatin and gemcitabine [142], paclitaxel [143], adriamycin etc. [144]. NPs coated with water-dispersed oleic acid – pluronic resulted in sustained drug (doxorubicin) release and a concentration reliant on anti-proliferative significance experimented on breast and prostate cancer cell lines [145]. Hyperthermia produced by MNPs has been developed as an auspicious therapeutic method in cancer treatment. Iron NPs facilitate destruction of tumour cells by production of effective heat when exposed to an oscillating external magnetic field [146]. In comparison to the conventional hyperthermic techniques, magnetic hyperthermia offers minimal invasive means to carry a therapeutic dose of heat precisely to cancer sites [147]. Hyeon group described the production of uniform-sized ferromagnetic iron oxide nanocubes (FIONs) [148] and have been effectively applied for MRI-based tracing of transplanted pancreatic islets at the single-cell level [149]. Functionalization with trastuzumab targeted HER2 to form tumour-specific radiological nanoprobes have also been used to detect breast xenografts over expressing HER2 receptors [150]. All of the studies discussed above state that iron NPs can be used as a potential carrier or vector for drug delivery and these give new grounds towards cancer treatment.

Titanium dioxide

Titanium dioxide nanoparticles (TiO₂ NPs) belongs to semiconductor have been extensively used in biomedical applications such as drug delivery and cancer therapy [151] due to inert, strong oxidizing potential, photoreactivity, eco-friendly, stable, cost efficient and biocompatibility with low or no toxicity [152]. Among rutile, anatase and brookite crystallograph of TiO₂, anatase shows enhanced biocompatibility while other have some toxicity [153]. Adriamycin halts the growth of tumour cells and has been used since 1970s to cure a wide variety of tumours [154]. Titanium is a second metal in clinical trials that uses Ti (IV) which binds with DNA through covalent bonds [155]. Budotitane, is a titanium based inorganic complex proved as anti-tumour agent but instability attributes to Ti (IV) species [156]. Recently, titanium salan complexes belong to titanium (IV) complexes, proved to have higher stability in solution with enhanced anti-tumour activity [157]. Scientist has developed a conjugation of doxorubicin and TiO₂ NPs. These nanocomposites have enhanced accumulation of DOX in tumour cells led to increase anticancer potential by inducing apoptosis in a caspase-dependent manner [158]. All of the above findings speculate that TiO₂ NPs act as potential agent against many cancers especially breast cancers.

Platinum NPs

Use of platinum in Pharmaceutical industries is not well recognized rather their compounds are famous for anticancer potential [159]. Almost 50% of chemotherapeutic techniques comprise of platinum compounds [160]. In recent years, platinum based products are in clinical use due to their widespread applications against various tumours [54]. Common use of platinum NPs in medical sector are as a composite material, i.e. Yolk-shell nanoparticles [FePt@CoS2] being more well-organized in obliteration of HeLa cells associated to cis-platin [161]. Platinum conjugated with multi-walled carbon nanotubes [MWCNTs] displays sensitivity of catalytic exposure of the DNA [162]. FePt NPs linked with luteinizing hormone-releasing peptide (LHRH) hinders tumour growth in a pH-dependent manner [163]. Au-Fe₃O₄ NPs with dumbbell morphology lodge platinum based anticancer drugs through herceptin antibody to embattle distribution of platin complexes to breast cancer cells [SK-BR-3] [164]. Cisplatin an anti-tumour drug, induces apoptosis through the binding of DNA [165]. FDA has approved drug “Oxaliplatin” that exhibit similar therapeutic results as cisplatin, with no expressive acquisition of multidrug resistance due to immunogenic response dependent of the toll-like receptors [166]. Satraplatin, being more lipophilic has enhanced anticancer pharmacokinetic properties, is in advanced clinical trial phases. Another advantage of Satraplatin is the production of adducts which are not identified by DNA mismatch repair mechanism, which lower the drug resistance [167].

Cerium oxide NPs

Cerium belongs to lanthanide series discovered in 1803 and thereafter used in medicine [168,169]. Cerium oxide NPs [CeO₂ NPs], also known as nanoceria, have intriguing applications in biomedicine due to antioxidant potential [170]. Nanoceria have gained remarkable attention due to oxidation state from Ce³⁺ to Ce⁴⁺ [171]. CeO₂ NPs have emerged as an antioxidant and anti-inflammatory agent [172] can also induce lipid peroxidation, lung damage, generation of reactive oxygen species, autophagy and shelter normal cells against radiation induced injuries [173,174]. This prevents the subsequent production of ROS which induces apoptosis in normal cells [175]. CeONPs also exhibit distinctive cytotoxicity to cancer cells. Hence, CeONPs have wide prospective as a therapeutic mediator for the management of cancer, as well as additional diseases in which ROS are involved [176]. CeONPs can be used as a nanocarriers for transporting anticancer drugs with less side effects [171–177].

Nickel NPs

Nickel nanoparticle synthesized from different routes are broadly used in catalysis and sensing [178]. Current studies highlight potential use of Ni NPs in biomedicines, comprising cancer diagnosis as well as therapy. Ni nanowire induces ROS which results in apoptosis in human pancreatic adenocarcinoma cancer cells [179], and MCF-7 cells of human breast cancer. Caspase-3 enzyme activation and enhancement of mRNA level is observed after exposure to NPs [180]. Ni NPs conjugated with daunorubicin showed effective cytotoxicity against leukaemia cancer cells [141,181]. Verbascoside; an anticancer drug associated with Ni NPs induces apoptosis in K562 cells averting tumour growth in model organism [182]. MCF-7 human breast cancer cells also showed cytotoxicity after 24 h treatment with Ni NPs [183].

ZnO NPs

Zinc is an essential trace element required to body for more than 300 cellular processes therefore used in numerous biological applications [184,185]. Cytotoxicity of ZnO NPs can be improved further by reduction of size [186]. Researchers have revealed that ZnO NPs show cytotoxic activity against carcinogenic cells with negligible effects on normal cells [187]. These outcomes propose that if selective targeting of cancer cells is done with ZnO NP; it can be used as a potential agent in cancer treatment. Eukaryotic plasma membranes are usually negatively charged [188] while cancerous cells have over expressed negatively charged phospholipids bilayer with respect to normal cells [189] and probably these charged membranes interact with positively charged NPs. One probable way to develop a targeted killing of cancerous cells is to modify/functionalize ZnO NPs with various substances such as polyacrylic acid [PAA], or dextran carboxyl [–COOH], or amine [NH2] groups [190]. ZnO nanocomplex with liposomes facilitates daunorubicin release in response to pH change [191]. The well-studied action of ZnO NPs is due to the production of ROS [192]. ROS act as second messengers and enhance cellular pathways [193] while higher level of ROS activates apoptotic pathways [194] and results in significant cytotoxicity [194]. Superior cancer cell cytotoxicity of ZnO NPs is most probably related to the proliferative cell potential [194]. While another study confirmed higher vulnerability of cancerous T cells towards the ZnO NPs [195].

Cobalt [Co] NPs

NPs of cobalt may be fabricated as cobalt oxide, conjugated with organometallic compounds or biological polymers [196]. Anticancer activity of cobalt oxide NPs can be enhanced through surface modification of these NPs [197,198]. In biomedicines, cobalt is recognized as contrast agent via magnetic resonance imaging [MRI], in conjugation with gold, iron, graphite and platinum [199]. It has also been inspected for cancer treatment especially breast cancer MCF-7 cell line [200]. In addition, eco-friendly nature also marks them as an appropriate nominee for biomedical applications [201].

Copper oxide NPs

Copper is an intriguing element because of its unique electronic configuration and its role as a co-factor for redox reaction in enzymes cycling and induces cellular stresses [202]. Due to this reason, various copper compounds have been scrutinized for anticancer activity [203]. Anticancer potential of copper compounds are due to their selective permeability to cross cancer plasma membrane [204]. Cu²⁺ has potential to interact with single stranded DNA due to cross linking with adjacent phosphate groups [204]. Although there is still absence of adequate data regarding mode of action of CuO NPs [205], different pathways have been proposed which utilizes involvement of ROS species [206]. Toxicity exhibited by CuO NPs are also due to the production of ROS [207]. In general, CuO NPs induced cellular stress results in apoptosis which act as a basic indicator for researcher to study the therapeutic prospective of CuO NPs [208]. These NPs participate in inhibition of in vitro growth and autophagostic mechanism in MCF-7 cells, demonstrating that CuO NPs in conjugation with autophagy inhibitor are vital in induction of apoptosis in breast cancer cells [209]. MCF-7 cells are usually recognized as resistant to chemical treatments such as adriamycin and paclitaxel [210] and have the possibility to develop responses to cellular stress, such as the MEK5-BMK/Erk5, which may subsidize anti-apoptotic signalling [211]. Regardless of the fact that ROS and cancer are related in a contradictory way; ROS and oxidative stress induce carcinogenesis, but enhance level of ROS induces cell death [212,213].

Silver nanoparticles

Silver NPs have been used in medical sector since long especially well known for antibacterial activity. AgNPs also exhibit in vitro antitumour, antiproliferative and antiangiogenic properties by ROS mediated apoptotic pathway [214]. AgNPs show potential cytotoxicity in breast cancer cells MDA-MB-231, MCF-7 via preventing cell growth by activating production of ROS and caspases-3 which lead to cell death through concentration dependent activation of LDH [215,216]; by disturbing membrane structure, activating different genes involved in apoptosis lead to cell death [217]. AgNPs activates production of ROS and JNK pathway responsible to mitochondrial mediated apoptosis that results in cell death in NIH3T3 cells [218,219]. Various studies highlighted cytotoxicity induced by AgNPs in phagocytosing cells both in mouse peritoneal macrophages and human monocytes [219] due to damages in DNA by generation of ROS [220], increased caspase-3 activity [221]. These findings suggest that AgNPs can be used as a possible alternative agent for human breast cancer therapy by constraining the development of the tumour cells and offers a novel technique to advance molecule for cancer therapy.

Arsenic trioxide

Arsenic trioxide [As₂O₃] is being employed in medicines for more than 2400 years against cancer and infectious diseases [222]. As₂O₃ is recognized as a highly reactive molecule and potentially linked with thiol moieties of many proteins [223]. This property of As₂O₃ has made it an effective candidate against acute promyelocytic leukaemia [APL] [223]. Recent research reveals that As₂O₃ suppress cell growth and induces apoptosis to breast cancer [224] through inhibition of oestrogen receptor [225]; directive of p53 tumour suppressor protein and down instruction of Bcl-2 protein [226]; introduction of p21 as well as p27 tumour suppressor proteins [227]; induces demethylation and apoptosis [228]; down-regulation of Notch-1 [229] and others [230,231].

Nanocarriers approved by FDA and in clinical trials currently

Scientists are trying to explore new drug candidates to overcome drug resistance offered by conventional pharmaceutics. Nanotechnology based products are being actively used against breast cancer which provide an effective and efficient tool and aid in the reduction of mortality rate caused by this devastating disease. Recently, there are number of nanotechnology based products that have been approved by FDA to be applied for breast cancer and some are in clinical trials too be rigorously tested either can be applicable for breast cancer or not (Tables 2–4).

Table 2. Nanotechnology based FDA approved products against breast cancer.

Nano carrier	Active agent	Drug	Mode of action	Company	Admin.route
Liposomes	Doxorubicin	Doxil/ Caelyx	Produces EPR effect through passive targeting.	Orthobiotech, Schering-Plough	Intravenous [IV]
	Doxorubicin	Myocet	Targeted MPS; carry slow drug release into blood similar to prolonged infusion	Elan Pharmaceuticals/Sopherion Therapeutics	IV
	Doxorubicin	Lipodox	Penetrate the cells, binds with chromatin &hindered DNA synthesis.	Sun Pharma	IV
	Paclitaxel	Taxol^®	Microtubule-stabilizing drug. Block cell in the G2/M phase of cell cycle.	Bristol-Myers Squibb Co.	IV
Micelles	Paclitaxel	Genexol-PM Cynviloq IG-001	Drug binds specifically to the beta- tubuline and then enhances the polymerization of tubuline to stable microtubules.	Samyang	IV
Protein Nps	Paclitaxel	Abraxane	Produces EPR effect through passive targeting.	Abraxis Bioscience, Astrazeneca	IV
	Trastuzumab emtansine	Kadcyla	Trastuzumab inhibit cancer growth by binding withHER2/neu receptor while mertansine on entering on cells and kill them by binding to tubulin.	Roche and ImmunoGen	IV
NP delivery	Paclitaxel	Nanoxel	Act as an anti-microtubule. Prevent growth and spread of cancer cells.	Dabur Pharma	IV

Table 3. Nanotechnology based products in clinical trials against breast cancer.

Nano carrier	Active agent	Drug	Mode of action	Current Status	Company	Admin. route	References
Liposomes	Paclitaxel	LEP-ETU	Hinder or block cell cycle and destroy cancerous cells	Phase II	Neopharma	IV	[232]
	Taxotere	LE-DT [Docetaxel]	Anti-microtubule agent, prevents cell division by promoting the assembly and stabilization of microtubules	Phase I	Neo-Pharm. Inc. [NEOL]	IV	[233]
	Cisplatin	Lipoplatin	Not known	Phase III	Regulon	IV	[234]
	Irinotecan [PEGylated]	MM-398	Irinotecan linked reversibly with topoisomerase 1-DNA & inhibit re-ligation of the single-strand breaks, result in cell death via damage of ds DNA	Phase III	Nektar Therapeutics	IV	[235]
	Paclitaxel	EndoTAG-I	Targets the vascular endothelial cells and lead to cell damage and death	Phase II	Medigene/SynCore Biotechnology	IV	[236]
	Mitoxantrone	[LEM-ETU]	Stop nucleic acid synthesis &intercalates with DNA in vitro, exact mechanism of action is under research	Phase II	Taj Pharmaceuticals Ltd.	IV	[237]
	Doxorubicin	Thermodox®	Temperature-triggered doxorubicin release	Phase III	Celsion	IV	[238]
	Doxorubicin	MM-302 HER2-targeted liposomal	Binds specifically to tumour cells [overexpress HER2] and undergoes receptor-mediated endocytosis, releasing doxorubicin inside the cell.	Phase II	Merrimack Pharmaceuticals	IV	[239]
	Vinorelbine	Vinorelbine [INX-0125]	Mitosis inhibitors; Tubulin polymerization inhibitors	Phase II	TLC	IV	[240]
Polymeric NPs	Paclitaxel	Genexol [PEG-poly[lactic acid]	Passive targeting via EPR effect	Phase 3	Samyang Biopharmaceuticals Corporation	IV Infusion	[241]
	Annamycin	Annamycin [Liposomeannamycin]	N. A	I/II		IV	[242]
	Doxorubicin, Paclitaxel, platinum baseddrugs, Docetaxel	Polymeric nanoparticles [50–200]	N. A	Phases III			[243]
	Oxaliplatin*	Oxaliplatin vectorized in chitosan NPs	pH dependent behaviour	Pre-clinical [In vitro studies]	DR Reddy's	IV	[244]
Micelles	Paclitaxel	NK105	N.A	Phase 3	Nippon Kayaku	IV	[245]
Gold NPs	rhTNF	CYT-6091	N.A	Phase II	Cytimmune	IV	[117]
		Silica-Gold Shell	Photothermal				[116]
Arsenic Trioxide	As2O3	Trisenox®	Exact mechanism is not known	Pilot phase II	University of Texas Medical Branch, Galveston	IV	[246]

rhTNF: Recombinant human tumour necrosis factor alpha.

Table 4. Nanotechnology based inorganic nanocarriers used in research against breast cancer.

Nanomaterials	Morphology	Modification	Drug loaded	Cell line	Response	References
Gold NPs	Nanostars	TAT cell-penetrating peptide	N.A	BT549	Killing of cancerous cell while not effecting normal cells	[112]
	Nanorods	AS1411 DNA aptamer	Doxorubicin	MCF-7	90% cells death was observed	[125]
	N.A	PEGylate	N.A	SK-BR-3	Cell death	[115]
	N.A	PEGylated	HER-2 antibody	SK-BR-3	Higher cytotoxic towards cancerous cells	[118]
	N.A	PEGylated	Trastuzumab	SK-BR-3	Breakage in double stranded DNA	[130]
MNPs	N.A	N.A	Trastuzumab targeted HER2	HER2 receptors	Radiological nanoprobes used to detect breast xenografts	[148]
MNPs	N.A	Oleic acid – Pluronic	Doxorubicin		Antiproliferative effect	[144]
TiO2 NPs	N.A	N.A	Doxorubicin	Tumour cells	Increased anticancer potential	[157]
Budotitane						[155]
Titanium salan						[156]
FePt@CoS2	Yolk-shell NPs	N.A	N.A	HeLa cells	IC50 = 35.5 ± 4.7 ng Pt/ml	[54]
Au-Fe3O4 NPs	Dumbbell	Herceptin antibody	Platinum based	[SK-BR-3]		[179]
Ni NPs	N.A	N.A	N.A	MCF7	ROS induced cytotoxicity	[200]
Cobalt NPs	N.A	N.A	Cobalt ferrites NPs	MCF7	Apoptosis	[200]
CuO NPs	N.A	N.A	N.A	MCF7	Apoptosis in breast cancer cells	[208]
AgNPs	N.A	N.A	N.A	MDA-MB-231	ROS and caspases-3 through activation of LDH	[214]
As2O3	N.A	N.A	N.A	MCF-7 and T47D	Inhibition of oestrogen receptor	[221]
As2O3	N.A	N.A	N.A	MCF7cells	Apoptosis via activation of caspase-3 and the reduction in expression of HERG	[222]
Bimetallic NPs [gold-silver]	N.A	S2.2 aptamer	N.A	MCF-7	97% cell death observed	[124]

Fate of metallic NPs in clinical treatment of breast cancer

Traditional treatment to cure cancer are toxic for normal cells which results in severe side effects in patient’s even damages their immune system due to non-targeted drug delivery. On the other way round, nanotechnology offers targeted drug delivery by limiting side effects linked with conventional techniques. Various products are in clinical trials which have been proved to be most effective than other medications because of smaller particle size. Lot of FDA approved organic nanocarriers are in practice for breast cancer while inorganic nanocarriers are being actively explored for anticancer activity. Various metallic based NPs are in progress which show superior anticancer potential in breast cancer (Table 4). Abraxane is among the most obvious product of nanotechnology towards the treatment of breast cancer along with many more. In case of inorganic nanocarriers gold, iron, platinum, arsenic trioxide etc. show enhanced anticancer activity and are in rigorous clinical phase to evaluate their superior effects in contrast to other drugs. Some of them are CYT-6091, Oxaliplatin, Trisenox^® etc. are FDA approved inorganic nanocarriers. Obvious advantages offered by nanotechnology over conventional anticancer agents attribute due to the ability of NPs to cross the fine capillaries, easiest penetration within cells and tissue to reach at the targeted place, sustained drug release and reduced toxicity. In spite of these characteristics nanotechnological products are still not be able to replace conventional techniques used against breast cancer and are used with adjuvant conventional treatments.

Conclusion

Uncontrolled cell division results in a group of pathologies known as cancer. Among various types of cancer; breast cancer (BC) with various phenotypes has become problematic for humanity since a long ago due to association of high mortality rate. Many conventional techniques have been available to cure cancer like surgery, hormonal therapy, radiation and chemical treatment. All such treatments are quite painful and associate with severe side effects. For example, in surgery in some cases, whole of the breast of the patient is removed that bring serious social issues for the female patient. Besides this, conventional therapies also face major limitations since form the detection to the treatment of BC because of non-specific targeting and drug resistance. These limitations demand an urgent need to develop a novel and targeted method that can deliberately overcome human sufferings associated with BC. Recently nanotechnological based products offer many advantages to be employed as a powerful tool against BC. Various organic and inorganic based nanocarriers are in practice and some are in clinical phases with outstanding results against BC due to their specific targeting. From above all it is concluded that nanotechnological based nanocarriers like liposomes, micelles, gold, iron, platinum etc. will be specifically delivered by taking advantage of active and passive drug targeting and useful to cure BC. By this way, we can omit the need of conventional therapies although plenty of research work is needed to translate potentials of nanotechnology in medicines to bring a breakthrough in cancer technology. However, issues linked with nanotechnology are like problematic control in liquid and dry forms, limited drug loading, burst release and toxicity. So, in order to translate the potential advantages offered by nanotechnology, more research is needed to rigorously analyze the toxicity associated with NPs and systemic studies to evaluate the mechanism of action etc. It establishes new grounds for enlists to bring these NPs to demolish the roots of breast cancer and overcome the sufferings.

Disclosure Statement

No potential conflict of interest was reported by the authors.