Nanobiotechnological Approaches to Overcome Drug Resistance in ...

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Nanobiotechnological Approaches to Overcome Drug Resistance in Breast Cancer Peyman Ranji, Zahra Heydari and Ali Mohammad Alizadeh* Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran Abstract: Drug resistance primarily appears where there is altered drug metabolism or target modification. It is a major challenge in cancer therapy which affects treatment process, and limits chemotherapeutics. Recently, nanotechnological approaches were shown to be capable of lowering drug side effects and protecting from enzymatic degradation. Therefore, patient’s compliance and survival rate have dramatically increased. This review elaborates on the structures and functions of the factors involved in cancer drug resistance together with nanobiotechnological approaches for overcoming the obstacles in breast cancer research and therapy. The present paper provides information and suggestions to both basic and clinical researchers to develop new nanobiotechnological methods to improve breast cancer modalities especially in drug resistance.

A.M. Alizadeh

Keywords: Breast cancer, drug resistance, nanotechnology, review. INTRODUCTION Cancer, medically known as malignant neoplasm, is a broad spectrum disease presenting with unregulated cell growth. It is responsible for about 13% of worldwide deaths [1]. In spite of low incidence of cancer death rate in developed countries like the US, number of cases and deaths are projected to be doubled in the next 20-40 years [1-3]. Globally, more than 1 million women are annually diagnosed with breast cancer, accounting for one-tenth of new cancer cases [4, 5]. Tumor pathogenesis and progression are the major issues in cancer biology helping to find new therapeutic and preventive modalities [1]. Surgery, chemotherapy, radiotherapy and palliative interventions are the primary treatment options. Chemotherapy and/or cytotoxic drugs are commonly applied in many cancer types [6, 7]. However, both primary and acquired drug resistance forms are limiting factors in the current chemotherapeutics [8, 9]. Drug resistance related factors basically categorize into kinetic, biochemical and pharmacologic ones [10]. Kinetic resistance is a particular problem found in many different cell phases of human tumors. Generally, certain cells commonly lie in the plateau phase while a small fraction of them are usually in the growth phase [10]. Biochemical resistance is the tumor failure to convert drug to its activated or inactivated form. Biochemical resistant cells can decrease drug uptake or intracellular activity, increase drug efflux or inactivation, and change the level or the structure of its intracellular target [10]. Pharmaceutical resistance, however, is inadequate drug levels in blood that originates from poor tumor blood supply, and/or erratic absorption, both are capable to increase drug excretion or catabolism (Fig. 1) [10, 11]. Moreover, there are some drug resistance sources in breast cancer which are cell originated *Address correspondence to this author at the Cancer Research Center, Tehran University of Medical Science, Tehran, Iran, P.O: 1419733141; Tel/Fax: +98-21-61192501; E-mail: [email protected] 1873-5576/15 $58.00+.00

including adenosine triphosphate (ATP)-binding cassette (ABC), permeability glycoprotein (P-gp), microtubules (MTs) alteration, topoisomerase (Topo), P53, breast cancer type 1 (BRAC1), and human epidermal growth factor receptor 2 (HER2) [10, 11]. In this regard, P-gp over expression can lead to drug resistance via drug efflux. HER2 over expression can also increase the activity of metastasis pathway-related factors and drug resistance in breast cancer. Moreover, altered MTs and topoisomerases can decrease their drug binding. P53 gene mutation is currently the most common factor that promotes various oncogenic pathways and prevents cell death. Furthermore, BRAC1 mutation can also repair drug-induced DNA damage and subsequently stop drug resistance (Fig. 2) [11]. Thus, several strategies such as novel anti-neoplastic agents, combination therapies and sophisticated nanotechnology approaches have been taken to combat drug resistance with different targets. Nanotechnology application plays a pivotal role in diagnosis, prognosis and cancer treatment management [12, 13]. Using nanoparticles (NPs) has gained immense popularity during last decade due to their potential therapeutic effects. NPs-encapsulated drugs are able to protect drugs from enzymatic degradation, control their release, prolong their blood level, change their pharmacokinetics and decrease their toxicity via limiting non-specific uptake [14, 15]. NPs such as liposomes, micelles, chitosan, cyclodextrins, carbon, gold, silica and solid lipids are emerging as useful alternatives, and have been shown to overcome breast cancer resistance (Table 1). In preclinical studies, gold, carbon and silica have been reported to be promising carriers mainly due to their capability to enhance drug permeability and retention in breast tumors [16, 17]. Additionally, targeted therapies against breast cancers using NPs such as liposomes are now being developed at a fast pace due to advanced understanding of cancer biology. They have already entered clinical trials and are expected to become attractive treatment options for breast malignancies [18-20]. This review discusses the © 2015 Bentham Science Publishers

Nanobiotechnology and Cancer Drug Resistance

Biochemical resistance ¾ Increased drug efflux

Current Cancer Drug Targets, 2015, Vol. 15, No. 7

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Cell kinetic drug resistance Tumor in plateau growth phase

¾ Decreased drug uptake ¾ Sequestration of drugs ¾ Alterations in drug targets ¾ Activation of detoxifying systems ¾ Increased repair of drug-induced

Cancer drug resistance

DNA damage ¾ Blocked apoptosis ¾ Disruption in signaling pathways ¾ Alterations of factors involved in cell cycle regulation ¾ Poor absorption ¾ Excessive metabolism ¾ Poor penetration to certain sites ¾ Blood supply of tumor ¾ Drug diffusion

Pharmacokinetic drug resistance Fig. (1). Important basic factors in cancer drug resistance. There are three basic categories of important factors in drug resistance including cell kinetic, pharmacokinetic and biochemical drug resistance. Each of the mentioned factors with different mechanisms can cause drug resistance in cancer (see the text for more information).

beneficial effects of nanotechnology approaches including P-gp, altered MTs, Topo, P53, BRAC1 and HER2 to overcome drug resistance in breast cancer. ABC PROTEINS ABC proteins are a family of transporters involved with drug resistance through an ATP-dependent drug efflux pumps with considerable clinical importance [21, 22]. They present in all living species with a relatively conserved structure [23]. Two ABC members are important in breast cancer; P-gp and MPR1. The latter is the most typical efflux pump in cell membrane, generally composed of four structural domains, two in membrane and two in cytoplasm [24, 25]. Cytoplasmic domains, named nucleotide binding domains, play a pivotal role in ATP hydrolysis to obtain the energy necessary for transporting cell nutrients [26]. Mutagenic P-gp has a molecular weight of 170 kDa made from ABCB1 (MDR1) gene amplification [21, 25]. On the other hand, ABCC1 (MRP1, 190-kDa) protein is quite widespread in normal tissues, and is both structurally and functionally similar to P-gp, with divergent cytoplasmic domains. MRP family has a five domain structure with an extracytosolic NH2 terminus and a third NH2-proximal domain spanning with transmembrane segments [27, 28]. In addition, MRPs are the organic anion transporters capable of mediating drug efflux mainly through glutathione, glucuronate or sulfate drug conjugation [29, 30].

P-gp and MRP1 overexpressions are linked to multidrug resistance (MDR) in mammalian cell lines and human cancers [31]. In human, they can detect and bind to a large variety of hydrophobic natural-product drugs entering the plasma membrane [32, 33] including doxorubicin, daunorubicin, vinblastine, vincristine and taxol [33, 34]. Drug binding causes ATP hydrolysis and P-gp’s conformational change followed by extracellular drug release [33, 35]. Hydrolysis of an extra ATP molecule is needed for transporter restoration and further drug binding cycle and release [33, 36, 37]. Previous studies indicated that almost 40% of all breast tumors expressed ABCB1/MDR1 coded Pgp. Additionally, expression of this gene has shown to be a prognostic tool for anticancer drug cell resistance [38-40]. Therefore, all three generations of P-gp inhibitors are theoretically able to overcome P-gp's drug resistance based on their specificity, affinity and toxicity. First generation of P-gp inhibitors is pharmacologically active and includes verapamil, cyclosporine A, reserpine, quinidine and yohimbine. They all have clinical use for specific modalities with inhibitory roles on P-gp [41-43]. Dexverapamil, dexniguldipine and valspodar, classified into second generation of P-gp inhibitors, have a great P-gp affinity with no pharmacological activities. The third generation of P-gp inhibitors including cyclopropyldibenzosuberane, zosuquidar and laniquidar, is all under clinical development for higher specificity and lower toxicity [43-46].

546


BRAC1, 2 Topoisomerases BRCA1,2 second mutation

Increase repair of drug-induced DNA damage

Topoisomerase alteration expression

Decrease drug binding to topoisomerase

Ranji et al.

HER2

P53

Microtubule

HER2 over expression

TP53 mutation

Mutations in the drug binding sites

Over-activate Src, STAT, PI3K, and MAPK pathways

Promote various oncogenic pathways

Increase metastasis

Prevent cell death

Decrease drug binding to MTs

P-gp P-gp overexpression

Release drug outside

Drug resistance Fig. (2). Key drug resistance mechanisms in breast cancer. There are some considerable cellular drug resistance factors in breast cancer including permeability glycoprotein (P-gp), microtubules (MTs) alteration, topoisomerase, P53, breast cancer type 1 (BRAC1), and human epidermal growth factor receptor 2 (HER2). This figure mentions to the reasons of these factors in drug resistance (see the text for more information).

In recent years, MDR nanotechnology has shown a great promise in drug resistance studies in preclinical and clinical nanomedicine (Table 2). Although, the efficacy of this method has been confirmed in in vitro and in vivo studies, the exact mechanisms are still under a cloud of ambiguity [47]. Guo et al. (2013) used Chitosan-g- D-α-Tocopheryl polyethylene glycol succinate-carbon tube (TPGS-CT) to overcome P-gp drug resistance and provide better drug delivery [48]. They made DOX-loaded carbon tube (CT) using a modified solvent extraction/evaporation method and combined it with ionic cross-linking to form a uniform particle size of 140-180 nm and obtained ~40% DOX loading efficiency. These drug-loaded CT nanoparticles have shown to have a pH-responsive release behavior, quick DOX release under low pH levels, and high liver and breast cell line cytotoxicity [48]. The authors attributed drug-loaded CT nanoparticle properties to P-gp block and ATP downregulation. Furthermore, in drug-resistant cells, CT NPs significantly improved DOX cytotoxicity, and increased TPGS cell apoptosis [48]. These results show that CT NPs may be the appropriate nanocarriers for anticancer drug delivery especially in drug-resistant cancer cells [48]. Jiang and colleagues (2010) presented the arginine-glycineaspartic acid (RGD) peptide-modified liposomes containing tumor targeted drugs using tumor integrin receptors binding [49]. They also employed P-gp RGD-modified liposomes to small interference RNA (siRNA) or DOX in a xenograft animal model of the drug-resistant MCF7 cells. The

outcomes confirm effective tumor growth inhibition of siRNA or DOX RGD-modified liposomes [49]. Moreover, Green and colleagues (2011) used 40 mg/m2 pegylated liposomal doxorubicin (PLD) every 28 days in twenty-five cases of women aged 65 in their clinical trial [50] and measured time to treatment failure (TTF), response rate, time to progression (TTP) and overall survival (OS). Administration of 7.4 cycles PLD resulted in TTF and OS of 5.5 and 20.6 months, respectively. They also showed that PLD at 40 mg/m2 is the safe and effective treatment for elderly women with breast cancer [50]. In summary, sequential treatment of P-gp gene silencing with RGDmodified liposome and PLD delivery system can be a promising clinical treatment for drug-resistant tumors. In summary, advanced nanotechnology methods have improved the therapeutic effects via modifying pharmacokinetics, toxicity and non-specific cytotoxic drug uptake [51]. For example, DOX-loaded solid lipid nanoparticles (SLNs), and paclitaxel-loaded SLNs have shown to increase cytotoxic drug uptake [52, 53]. Furthermore, TPGS and polylactide-surfactant block copolymer poly (l-lactide)vitamin E TPGS (PLA-TPGS) increased intracellular accumulation and therapeutic efficacy of DOX in MCF7 cells [54, 55]. Other nanoparticles such as hollow mesoporous silica (HMSNs), poly-butyl cyanoacrylate (PBCA-NPs), pluronic P123/F127 copolymers and polyester-based hyperbranched dendritic-linear (HBDL)-based NPs used in breast cancer cell lines with good efficacy [56-58]. Collected


Table 1.


547

Nanoparticle types used to overcome drug resistance in breast cancer. Nanoparticles

Form

Size (nm)

Methods

Results

Refs.

-Increased cellular uptake & therapeutic efficacy - Enhanced anti-tumor & antiangiogenesis effects, improved survival rate -Improved treatment and reduce short term side effect

[58, 146] [49] [110, 111]

Liposome

Globular

25-205

In vitro In vivo Clinical trial

Micelle

Spherical

10-100

In vitro

-Improved drug solubility, stability, freeze-drying properties, & anticancer activity

[108, 132]

Cyclodextrin

Cyclic

150-500

In vitro

-Increased cellular uptake of drug

[53]

Chitosan

Linear polysaccharide composed

100-250

In vitro

- Enhancement of apoptosis and cytotoxicity -Increased anti-tumor effects

[48, 56, 112]

-Appropriate combined therapeutic and diagnostic - Increased successful accumulation of drug into tumor

[93, 116] [117]

-Enhanced efficacy and cellular uptake of drug

[52, 53]

Gold

Globular

200-250

In vitro In vivo

Solid lipid

Spherical

50-1000

In vitro

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Ranji et al.

Table 1. contd….

Nanoparticles

Form

Silica

Mesoporous

Carbon

tubular cylinders (Nanotube)

Size (nm)

Methods

Results

Refs.

50-200

In vitro In vivo

-Enhanced uptake of intracellular drug -Demonstrated higher cytotoxicity & synergic anti-cancer activity -Reduced the systemic toxicity & improved survival rate

[57, 91, 133] [131] [133]

1-50

In vitro In vivo

-Induced drug accumulation -Arrested G2/M phase & induce cell death -Induction of apoptosis in without obvious toxic effects

[78, 107] [78]

See the text for abbreviation definitions.

data from in vivo studies indicated that polymer-blend nanoparticle and EGFR-targeted polymer blend nanocarriers beside RGD peptide-modified liposomes reduced tumor growth, and induced apoptosis in animal models [49, 59, 60]. Among above mentioned clinical trial studies, pegylated liposomal doxorubicin (PLD) reduced drug side effects and improved treatment in phase III and IV (Table 2) [50, 61]. The collected data show that nanotechnological approaches mostly used to overcome P-gp induced drug resistance are comparable with other drug resistance agents. We expect early use of pegylated liposome in phase I and II clinical trial in ensuing studies. MICROTUBULES AND MICROTUBULE-ASSOCIATED PROTEINS Microtubules are cytoskeleton-derived components with α- and β-tubulin noncovalent polymers that divided into six isotypes [62]. Post-translational modifications of tubulin including phosphorylation, acetylation, detyrosylation and glutamylation may affect the tubulin dimer polymerization [63]. In order to assemble into microtubules, hydrolyzed β-tubulin subunit must bind to GTP. GTP binding site in α-tubulin is stable, but in β -tubulin, it is hydrolyzed to GDP after polymerization [64]. GTP-capped microtubule is stable and grows, whereas a microtubule capped with GDP-bound β-tubulin at the (+) end is unstable and depolymerizes rapidly [64, 65]. Therefore, MT growth and shortening involve the association and the dissociation of GTP-bound subunits. MTs have important cellular functions such as mitosis, organelle movement, vesiclular and protein development, cell shape and signaling pathway maintenance and cellular growth [66, 67]. MT inhibitors can be classified into two groups; stabilizing and destabilizing agents. MTstabilizing agents such as taxanes and epothilone, mainly act via polymerization stimulation while their destabilizing

agents such as vinca alkaloids work as MT polymerization inhibitors[64]. Alteration in microtubule dynamics, mutations in the drug-binding sites and overexpression of β3-tubulin are among the most important drug resistance mechanisms in cancer chemotherapy [68]. Paclitaxel, for example, can bind to tubulin β-subunit and improve microtubule polymerization and stability, mitotic arrest and apoptosis in cycling cancer cells. In addition, overexpression of β3-tubulin can decrease paclitaxel β tubulin binding [69]. Therefore, in clinical studies, β3-tubulin overexpression can be a potential biomarker for paclitaxel resistance in patients with advanced breast cancer. Furthermore, overexpression of β -tubulin (types I–IV) may be a mechanism of docetaxel resistance. Other studies also demonstrated that tubulin reduction may be associated with taxane resistance [70]. Besides MTs, microtubule-associated proteins (MAPs) like MAP1A, MAP1B, MAP2, MAP4 and tau proteins are able to bind to microtubules, and regulate their dynamic behavior [71]. MAP2 and tau proteins can both stabilize microtubule structure and reduce its space arrangement. Nonetheless, MAP4 is only able to stabilize microtubule structure while MAP1 can solely reduce its space arrangement [71, 72]. Post-translational modification such as phosphorylation regulates these MAPs. In general, MAPs phosphorylation leads to their separation from tubulin, resulting in microtubule instability [73]. Improper expression of MAPs correlates to resistance of a wide range of malignancies to microtubule targeting agent. In addition, tubulin alterations affect microtubule dynamic changes [74]. Tau protein expression has also been demonstrated to change antimicrotubule agent responses. Low expression of tau proteins was shown to increase sensitivity to paclitaxel and Ixabepilone [75, 76]. Moreover, high tau protein expression in ER-positive breast cancer cells indicates taxane-containing


Table 2.


549

Various approaches to overcoming drug resistance due to P-gp and ABCC1 on breast cancer. Drugs

Nanotechnology Applied

Study Type

Models

Endpoints

Refs.

Doxorubicin (DOX) Antisense oligonucleotides

Liposomal drug delivery system (LDDS)

In vitro

MCF-7/ADR

- Increased anti-cancer properties of drug - Suppressed multidrug resistance

[147]

DOX

Solid lipid nanoparticles (SLNs)

In vitro

MDA435/LCC6/MDR1

-Enhanced efficacy and drug delivery

[52]

DOX

Polylactide-surfactant block copolymer poly(l-lactide)vitamin E TPGS (PLA-TPGS)

In vitro

MCF-7/ADR cells

- Enhanced nuclear accumulation & cytotoxicity of drug.

[55]

DOX

Hollow mesoporous silica nanoparticles (HMSNs)

In vitro

MCF-7/ADR cells

-Enhanced uptake of intracellular drug

[57]

DOX

D-alpha-tocopherylpoly (ethylene glycol) 1000 succinate & Photosensitizer NPs

In vitro

MCF-7

-Increased intracellular accumulation and therapeutic efficacy of drug

[54]

DOX Curcumin (CUR)

Poly (butyl-cyanoacrylate) NPs

In vitro

MCF-7/ADR cell lines

-Increased cytotoxicity of drugs

[56]

PTX Rhodamine 123 rhodamine 6G DOX

Pluronic P123/F127 copolymers

In vitro

MCF-7 cells

-Promising drug delivery system for overcoming MDR

[58]

DOX

Copolymer chitosan-TPGS

In vitro

Breast adenocarcinoma cells (MCF-7)

- Enhancement of apoptosis and cytotoxicity

[48]

Paclitaxel (PTX)

Solid lipid NPs (SLNs) modified with 2-hydroxypropyl-βcyclodextrin

In vitro

MCF-7/ADR cells

-Increased cellular uptake of drug

[53]

C6-ceramide (CER) PTX

Polymer-blendnanoparticle

In vivo

Orthotopic MCF7 human breast xenograft

-Reduced final tumor volume Enhancement of apoptosis

[60]

DOX siRNA

RGD peptide (arginine-glycineaspartic acid)-modified liposomes

In vivo

Mouse model of drugresistant MCF7/A tumor

-Inhibition of tumor growth Demonstration promising clinical treatment

[49]

PTX lonidamine

EGFR-targeted, polymer blend NPs

In vivo

Orthotopic model of MDR breast cancer xenograft

-Decreased tumor density and toxicity of drug

[59]

Verapamil (VER)

Phase III

Breast carcinoma Patients with acquired anthracycline resistance

-Increased patients survival

[148]

Elacridar (GF120918) Toptecan

Phase I

16 Patients with histologic proof of breast cancer

-Increase of oral topotecan bioavailability

[149]

VX-710 (biricodar) PTX

Phase II

Metastatic breast cancer patients

-Improvement of quality of life Increased the survival

[146]

Phase III

Metastatic breast cancer Women (n = 509)

-Reduced cardio-toxicity, myelosuppression, vomiting, alopecia & short term side effects

[150]

Docetaxel Zosuquidar (LY335979), a difluorocyclopropyl quinoline

Phase I

Locally advanced or metastatic breast cancer patients

-Demonstrated controllable selective dose with acceptable toxicity

[151]

Taxane Tariquidar (anthranilic acid derivative)

Phase II

Patients with stage III– IV breast (n = 17)

- Increased sensitivity to anthracycline or taxane chemotherapy

[45]

DOX

Pegylated liposomal (PL)

550


Ranji et al.

Table 2. contd….

Drugs

Nanotechnology Applied

Vinorelbine Tariquidar

DOX

Pegylated liposomal

Study Type

Models

Endpoints

Refs.

Phase I

Patient with chemotherapy resistant, advance breast carcinoma (n = 26)

-Increased drug exposure in drug-resistant cancers

[152]

Phase IV

Women > 65 years with breast cancer (n = 25)

-Improved treatment

[50]

ABCC1 modulator Tetrahydrocurcu -min (THC)

In vitro

Human breast cancer MCF-7 MDR

-Inhibited function of P-gp & MRP1 -Increased accumulation of drug

[153]

Dofequidar Fumarate

In vitro

Cancer stem/initiating cells (CSC)-like side population (SP) derived from BSY-1

-Increased anticancer properties of drug

[154]

Dofequidar Fumarate Fluorouracil (CAF)

Phase III

Women with advanced tumor or recurrent breast cancer

-Increased efficacy of drug

[155]

FAC (5-fluorouracil-adriamycincyclophosphamide) CAX (cyclophosphamideadriamycin-xeloda) Taxane

Phase III

Short-term response in a cohort of stage IIA-IIIC breast cancer patients (n = 84)

-Reduced MDR gene expression

[156]


chemotherapy resistance [77]. In addition, MAP4 phosphorylation can dissociate tau protein from microtubules and allow further mitosis. Thus, MAP4 inactivation may theoretically increase microtubule dynamics and paclitaxel resistance. In contrast, expression of nonphosphorylated MAP4 is increased in vinblastine-resistant cells. Additionally, high MAP4 expression has also shown to be responsible for increased paclitaxel and reduced vinca alkaloids sensitivity [71, 73]. Table 3 provides a list of different strategies to overcome multidrug-induced resistance by MTs. Anti-neoplastic agents like epothilones promote microtubule bundling and formation of multipolar spindles, and thus can induce mitotic arrest and cell death. Unlike anthracyclines and taxanes, epothilones-ixabepilone retains cytotoxic activity in β3-tubulin expressed cells [64, 70]. Other agents like trastuzumab has been shown to down-regulate tau protein expression [70, 76]. Moreover, proper drug combination has important advantages like low case-mortality ratios. Combinations of nanotechnology and different anti-cancer agents can result in more efficient cancer treatment [73]. Shao et al. (2013) used lipid-paclitaxel (PTX) with singlewalled carbon nanotube (SWNT) for advanced drug delivery system in resistant cancer types [78]. Conjugation of folic acid (FA) with SWNT-lipid-PTX increased cell penetration capacity, and drug efficacy in in vitro and xenograft mice model of human breast cancer [78]. Furthermore, SWNTlipid-PTX treated MCF-7 cells stimulated G2/M phase cell arrest (74%). Both SWNT-lipid and FA-SWNT drugs displayed non–toxic effects and excellent stability, and can improve free drug PTX efficacy [78]. It seems that SWNT-

lipid-drug can conjugate with tumor-targeting drugs, siRNA or antibodies for combination therapies to overcome multidrug-induced resistance [78]. Introduction of appropriate drug combination with novel antineoplastic agents in (pre) clinical studies has shown to be generally successful in drug resistance issue via MTs and MAPs alteration. Use of nanoparticle albumin-bound paclitaxel in the clinical trial phases II and III showed good efficacy and safety in metastatic breast cancer failed to respond to first-line treatments [79]. P53 FAMILY P53 protein family including p53, p73, p63 and other important members is the mostly mutated tumor suppressor gene in human breast cancer [80, 81]. P53 has 393 amino acids encoded by TP53 gene located on chromosome 17 short arm. These proteins are divided into five regions highly conserved during evolution; N-terminal, C-terminal, a region rich in proline residues contributed in apoptosis, tetramerized domain and a DNA-binding domain or core domain. DNAbinding domain involves most of the inactivating mutations found in the different types of human cancers [82]. Moreover, p63 and P73 have all p53 functional domains, however, p63 comprises a unique sterile α-motif domain participated in the protein–protein interaction [80, 83]. Numerous motivations like ionizing radiations, DNA lesions, nitric oxide, hypoxia, oncogenic stimuli and/or even chemotherapeutic agents can activate p53 [82]. In reaction to various cellular stresses, p53 adjusts a variety of cellular functions such as G1/S and G2/M phase transition,


Table 3.


551

Various approaches to overcoming drug resistance due to microtubules (MTs) alteration on breast cancer. Study Type

Model

Endpoints

Ref.

Ixabepilone

In vitro

Pat-21 cells paclitaxel resistant breast cancer

-Increased drug efficacy

[157]

Isothiocyanates (ITCs)

In vitro

MCF7

- Inhibited growth cell

[158]

Polygamain

In vitro

MDA-MB-435 & -231 cells

-Modulated expression of P-gp & tubulin β III

[77]

Drug

NanotechnologyApplied

PTX

Conjugation of FA to single-walled carbon nanotube (SWNT)-lipid

In vitro

MCF-7 breast cancer cells

-Induced drug accumulation Arrested G2/M phase & induce cell death

[78]

PTX

Conjugation of FA to single-walled carbon nanotube (SWNT)-lipid

In vivo

Mouse xenograft

-Induction of apoptosis in without obvious toxic effects

[78]

KOS-862 (epothilone D)

Phase II

Women with anthracycline & taxane pretreated metastatic breast cancer

-Demonstrated encouraging antitumor activity

[159]

Ixabepilone

Phase II

Women with metastatic breast cancer pretreated with anthracycline

-Increased efficacy & predictable & manageable safety

[160]

Ixabepilone capecitabine

phase III

Patients metastatic breast cancer (n =752) pretreated or resistant to anthracyclines and taxanes

-Demonstrated superior efficacy to capecitabine alone

[161]

Eribulin mesylate (E7389)

Phase II

Metastatic breast cancer patients pretreated with taxane & anthracycline

-Demonstrated good treatment activity

[162]

Ixabepilone capecitabine

phase III

Metastatic breast cancer patients (n =1221) pretreated with anthracycline & taxane

-Decreased disease progression & improved free survival

[163]

Phases II & III

Metastatic breast cancer patients with resistance treatment

-Increased efficacy & safety

[79]

Ixabepilone Trastuzumab Carboplatin

phase II

Metastatic breast cancer patients with HER2+

-Regimen was well tolerated with low toxicity & high efficacy

[164]

Eribulin mesylate (E7389)

phase III

Women (n =762) with eribulin (n =508) & treatment of physician's choice (n =254)

- E7389 improved overall survival compared with treatment of physician's choice

[165]

Paclitaxel

NPs albuminbound paclitaxel (nab-P)


apoptosis, DNA repair, genetic instability, autophagy and cell metabolism [80, 82]. TP53 mutation is the second most prevalent genetic alteration in breast cancers and is defective in almost 30% of the cases [84, 85]. In breast cancer, mutant p53 can directly promote various oncogenic pathways like PI3K/AKT, Ras/MAPK and NF-κB [84]. P53 is a stable parameter for breast cancer diagnosis, and is also used to predict outcomes of chemotherapy [86]. Therefore, the molecular pathological analysis of the structure and expression of p53 family members can be helpful in diagnosis, prognosis, and treatment of breast cancer [87]. Moreover, some novel strategies to restore p53 function and other therapeutic approaches targeting the p53 pathway have been evolved to improve clinical outcomes in breast cancer [87]. Evidence from cell line, animal and clinical studies showed high sensitivity of p53 in various chemotherapeutic

modalities [80]. On the other hand, p73 mutation is rather unusual in human neoplasia, but reportedly, its overexpression has been observed in some breast tumor, lymph node metastasis, vascular invasion and high-grade malignancy [86, 87]. In addition, chemotherapeutic agents can enhance the expression of p63 N-terminal domain and activate apoptosis via proapoptotic genes such as CD95, bax, BCL2L11 and Apaf1. Therefore, inhibition of p63 can affect apoptosis and drug resistance [80, 88]. Malfunctioned p53 can prevent cell death during chemotherapy or radiotherapy [89, 90]. Clinical studies suggested that anticancer drug classes can also be an important factor affecting various responses to p53 status. For example, when DNA damaging agents such as anthracycline is used, p53 usually causes tumor cell apoptosis, while alkylating agents may arrest cell cycle and improve recovery of damaged cells [80].

552


Ranji et al.

Table 4 lists different strategies, especially NPs used to overcome p53 drug resistance. Delivery of the wild type p53 gene into targeted breast cancer cells is one important strategy to overcome drug resistance [91]. (Pre) clinical reports have demonstrated that inducing adenovirus of p53 transfer can set cell apoptosis [92]. Nevertheless, the viral vectors have limitations for gene delivery because of the risk factors of the pathogenicity and the immunogenicity [91]. Conversely, NPs vectors have no major limitations and risk factors. For example, organically modified silica (ORMOSIL) NPs showed a hopeful direction for non-viral p53 gene delivery into breast cancer cells [91]. Gold nanorod (AuNR) has appeared as a hopeful carrier for genes and drugs for cancer thermal therapy and cell imaging. Localized photothermal properties of AuNRs can also enhance the drug tumor sensitivity [93]. In addition, the mesoporous silica shell around AuNRs can heighten large surface area for drug loading and maintain the optical effects of drugs which can be important to light-driven processes of the separated AuNRs [93]. A recent study has shown that the AuNR-based mesoporous silica can be the basic nanoplatform for simultaneous thermal- and chemo-therapies in selectively targeted cancer cells, and can permit the usage of concurrent fluorescence imaging [94, 93]. In summery, applying nanoparticles can improve effective drugs’ selectivity, and minimize their side effects in p53 mutant breast cancer cells. AuNR-based mesoporous silica NPs can increase the sensitivity of MCF-7/ADR cells to DOX [93]. Transferrin–conjugated PLGA raises the Table 4.

cellular uptake and the therapeutic efficacy of paclitaxel in MCF-7 and MCF-7/ADR cells [95]. In addition, nanoparticles apply as a non-viral vector for wild type p53 gene delivery in some in vitro studies to overcome drug resistance. For wild type p53 gene delivery, PLGA and organically modified silica (ORMOSIL) can reduce the growth of breast cancer cells [91, 96]. Yet, nanoparticles have not been vastly used in clinical trials with p53-induced drug resistance. In this regard, it seems that nanotechnology approaches have a great potential to adopt in clinical trials to treat p53-induced drug resistance cases. HER2 Human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein, encoded by HER2/neu gene can amplify and/or over-express in ~15-20% of breast cancers [97, 98]. HER-2 belongs to the family of the epidermal growth factor (EGF) receptor tyrosine kinases (RTK) that are the cell-surface enzymes with a single transmembrane, intracellular kinase and extracellular ligandbinding domains. Binding to the extracellular domain of RTK, Her-2 promotes the formation of receptor dimers and activates the intrinsic tyrosine kinase. This consequently causes the recruitment of the target proteins and begins a complex signaling cascade [99, 100] that can adjust cell growth, survival, adhesion, migration and differentiation [101]. Overexpression of HER2 increases the metastasis rate and makes the tumor tissue resistant to the current chemotherapy regimens, and also provokes poor prognosis

Various approaches to overcoming drug resistance due to p53 on breast cancer. Drugs

Nanotechnology-Applied

Study Type

Models

Endpoints

Refs.

Paclitaxel

Transferrin (Tf) -conjugated poly(lactic-co-glycolide) (PLGA)

In vitro

MCF-7 and MCF-7/Adr cells

-Increased cellular uptake & therapeutic efficacy

[95]

Wild type p53

Organically modified silica (ORMOSIL)

In vitro

MCF-7 cells

-Reduced growth cell

[91]

Wild type p53

Poly(D,L-lactide-co-glycolide) (PLGA)

In vitro

Breast cancer cell line

-Improved beneficial in cancer treatment.

[96]

DOX

Gold nanorod (AuNR)-based mesoporous silica Nanocarriers (Au@SiO 2)

In vitro

MCF-7/ADR cells

-Increased cell sensitivity to drug by localized photothermal effects of AuNRs

[93]

Adenoviral vector (Ad5) with human wild-type p53 (AdCMV-p53) Docetaxel Doxorubicin

Phase II

Locally advanced breast cancer

-Ad5CMV-p53 combined with drugs show a safe and efficacious gene- replacement strategy

[92]

Anthracycline– cyclophosphamide combination

Phase II

Patients with stage II–III breast cancer

- Cyclophosphamide in ER(-) p53-mutated breast cancer patients improved drug response

[166]

Irinotecan UCN-01 (7-hydroxystaurosporine)

Phase I

Women with triple negative breast cancer (TNBC) pretreated with anthracyclines & taxanes

-Enhanced apoptosis in TP53 mutant tumors by inhibition of Checkpoint kinase 1

[167]




[98, 102]. Nevertheless, according to previous studies, Her-2 may not be a suitable prognostic factor for decision-making process in adjuvant systemic therapy [97, 103]. Moreover, overexpression of Her-2 can over-activate Src, STAT, PI3K, and MAPK; all are key factors for breast cancer metastasis. Because of the proximity of Her-2 and Topo ΙΙ genes on chromosome 17, one third of Her-2 positive tumors are Table 5.

TOP2A-amplified [99, 104]. In this regard, sixty percent of Her-2 positive metastatic breast cancers do not respond to contemporary anti-Her2 therapies [98, 105]. A current therapeutic method for treatment of Her-2 positive metastatic breast cancer is a combination of Her2-targeted monoclonal antibody (trastuzumab) and common chemotherapy including docetaxel or vinorelbine [98]. In addition, anti-Her2 antibody

Nanotechnology-applied to overcoming drug resistance due to HER-2-positive breast cancer.

Drug


Study Type

Model

Endpoints

Refs.

Cationic lipid-nucleic acid nanoparticle conjugate with antibody-lipopolymer (anti-HER2 scFv (F5)-PEG-DSPE)

In vitro

SK-BR-3 breast cancer cells (HER-2 positive)

-Improvement specific transfection activity

[106]

Short interfering RNA (siRNA)

Chitosan/QD quantum dots NPs

In vitro

SKBR3 cell lines

-Showed gene-silencing effects of conjugated siRNA

[112]

Paclitaxel Herceptin

Cationic micellar NPs

In vitro

MCF7, T47D & BT474 cell lines

-Demonstrated significantly higher cellular uptake in HER2overexpressing BT474 cells

[109]

Herceptin

Dumbbell-like Au-Fe(3)O(4) NPs

In vitro

Sk-Br3 cell lines

-Enhanced sensitive diagnostic & therapeutic applications

[113]

Near-infrared (NIR) resonant gold-gold sulfide NPs (GGS-NPs)

In vitro

SK-BR-3 cell lines

-Appropriate combined therapeutic and diagnostic

[116]

Docetaxel

Polyethylene glycol (PEG) poly lactideco-glycolid acid (PLGA)

In vitro

BT-474 & SKBR3 cell lines

-Increased immunonanocarriers cytotoxicity

[114]

Tamoxifen (TAM)

Poly(d,l-lactic-co-glycolic acid) coating with poly (vinyl alcohol) & copolymer polyvinyl-pyrrolidone

In vitro

MCF-7 cell line

-Improved therapeutic efficiency by increasing selective drug delivery and uptake of drug

[115]

Single-walled carbon nanotubes (CNTs) tumor-specific monoclonal antibodies (MAbs)

In vitro

HER-2 positive cell lines

-Improved majority effective thermal ablation of tumor cells

[107]

Docetaxel

Cetuximab-conjugated micelles of vitamin E & D-alpha-tocopherylpoly (ethylene glycol) 1000 succinate (TPGS)

In vitro

SK-BR-3, MCF7, TNBC, MDA-MB468, MDA-MB-231 & HCC38 cell lines

-Enhanced therapeutic effects of drug on MDA-MB-468 & MDAMB-231 cells

[108]

Herceptin

Gold nanorods (GNRs) poly(ethylene glycol)

In vivo

Tumor-bearing nude mice

- Increased successful accumulation of drug into tumor

[117]

Pseudomonas Exotoxin A (PE)

Poly(lactic-co-glycolic acid) conjugated with anti-HER2 monoclonal antibody

In vivo

Mice breast tumor xenograft

-Demonstrated low immunogenicity

[118]

Anti-HER2 antibody conjugated with quantum dots (anti-HER2ab-QDs)

In vivo

Rat breast tumor

- Controlled adverse effect of quantum dots & can be used in vivo imaging

[101]

Doxorubicin Trastuzumab

Nonpegylated liposome

Phase I

Patients (n = 40) with HER2/neu 2+ or 3+ breast tumor

-Demonstrated low risk of cardiac toxicity

[110]

Trastuzumab Doxorubicin Docetaxel


Phases I & II

Metastatic breast cancer HER2/neu 2+ (n = 45)

-Showed safety & promising activity as first-line treatment of metastatic breast cancer patients

[111]

Doxorubicin Trastuzumab Paclitaxel


Phase III

Metastatic breast cancer HER2/neu 2+

-Improved survival rate & explored clinical benefits

[168]


553

554


Ranji et al.

(herceptin or trastuzumab) conjugated nanocarriers and anticancer drug combination have showed to have an effective treatment module in Her-2 positive breast cancer [106-108]. Table 5 lists nanotechnology strategies to overcome Her-2 drug resistance. Single-walled carbon nanotubes (CNTs) combined with specific monoclonal antibodies (MAbCNTs), cetuximab-conjugated micelles of vitamin E, TPGS and cationic lipid-nucleic acid nanoparticle conjugated with antibody-lipopolymer [anti-HER2 scFv (F5)-PEG-DSPE], all have demonstrated to improve treatment efficacy in Her-2 overexpressed breast cancer cells [106-108]. Cationic micellar NPs with paclitaxel and herceptin have a significantly high cellular uptake in Her-2 overexpressed BT474 cells [109]. Theodoulou et al. (2009) used nonpegylated liposomal doxorubicin (NLD) combined with trastuzumab on forty patients with Her-2/neu 2+ or 3+ tumors [110]. They demonstrated that NLD combined with trastuzumab is more effective, and relatively well-tolerated than conventional doxorubicin plus trastuzumab in advanced breast cancers [110]. Simultaneous use of chemotherapy and nanotechnology are known to be more useful than monotherapy in metastatic breast cancer in terms of response rate, time-to-progression and overall survival. Additionally, phase II clinical trial with non-pegylated liposomal doxorubicin, docetaxel and trastuzumab has shown to be a safe and promising treatment in Her-2 positive metastatic breast cancer, and can be considered as the first-line treatment [111]. As mentioned above, nanoparticles can be conjugated with tumor-targeting siRNA or antibodies, especially with anti-Her2 antibody as one important strategy to overcome drug resistance in Her-2 positive breast cancer. Chitosan/quantum dot NP-siRNA combination activates gene-silencing effects of siRNA in SKBR3 breast cancer cells [112]. Moreover, in vitro studies showed that dumbbelllike Au-Fe3O4 NPs, polyethylene glycol (PEG), poly lactideco-glycolid acid (PLGA), PLGA-PEG, PLGA coated with poly-vinyl alcohol (PVA) and copolymer polyvinylpyrrolidone (PVP) all could increase herceptin selective delivery, and cell uptake of docetaxel and tamoxifen [113115]. In other studies, near-infrared (NIR) resonant of goldgold sulfide NPs (GGS-NPs) was shown to be an appropriate choice of combined therapeutic and diagnostic agent [116]. Data collected from in vivo studies also demonstrated that application of gold nanorods (GNRs) with PEG improved tumor drug accumulation [117, 118]. MISCELLANEOUS CANDIDATES DRUG RESISTANCE

IN

CANCER

Topoisomerase The eukaryotic topoisomerase I and II (Topo I and II), classified as nuclear enzymes, are mainly originated from different genes located on chromosome 17. These nuclear enzymes contribute to breast cancer pathophysiology with BRCA1, HER2, RAD51C, RARA and TP53 genes [119, 120]. DNA Top1 relaxes both positive and negative supercoiling in some important cell functions such as DNA replication and transcription. Another important function of Topo I is the regulation of gene expression by controlling promoter activity [121, 122]. Topo II has two isoforms in human cells; 170-kd Topo IIα (TOP2A) and 180-kd Topo

IIβ. Topo IIα function is essential in separation of newly replicated chromosomes pairs, chromosome condensation, forming chromosome scaffolds, and changing DNA superhelicity [99, 123]. Functionally, Topo IIα depends on cell cycle, whereas its β -isoform is cell cycle-phase independent [99, 124]. In addition, Topo IIα usually associates with hormone receptor breast cancers [125]. Topo II is a major molecular target for a great group of clinically related antitumor drugs known as Topo IIinhibitors including anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin), epipodophyllo-toxins (etoposide, teniposide), actinomycin and mitoxantrone [99, 126]. Topo I can also be an important target for anti-cancer drugs such as camptothecin, topotecan and irinotecan [127]. Previous studies showed that Topo IIα expression in cancer cells may influence the tumor sensitivity to Topo II-inhibitors. Moreover, high concentration of Topo IIα can also increase the tumor sensitivity to Topo II-inhibiting drugs [99, 128]. Some preliminary studies showed that amplification of Topo IIa in primary tumors can be a strong predictor of clinical response and survival rate [125, 129]. Table 6 displays a list of different strategies to overcome drug resistance due to topoisomerases changes. Nanocarriers can deliver intracellular topotecan (TPT) and/or camptothecin as Topo I-inhibitors. Drummond et al. (2010) showed that anti-EGFR and anti-HER2-immunoliposomal formulations can increase topotecan uptake in the multiple resistance breast cancer [130]. These researchers also showed the more anti-tumor activity of topotecan against Her-2 overexpressed human breast cancer [130]. In another study, Mesoporous Silica Nanoparticles (MSNs) covalently encapsulating photosensitizer (PS) was synthesized and functionalized with galactose, and used with an anticancer drug like camptothecin (CPT). MSN-PS-galactose with CPT has shown to have the high cytotoxicity and the synergic anticancer activity when combined with photosensitizer in breast cancer [131]. In summary, in vitro and in vivo studies demonstrated that application of NPs with Topo I and II inhibitors such as camptothecin, irinotecan and topotecan could modulate topoisomerase-induced drug resistance (Table 6). Utilization of topoisomerase inhibitors with NPs could decrease drug toxicity, and improve their solubility and stability, and increase their anticancer activity. Sterically stabilized micelles (SSM) composed of polyethylene glycol (PEGylated) phospholipids and mesoporous silica nanoparticles (MSN) with galactopyranoside derivative (gal) and photosensitizer (PS) (MSN-PS-gal) could boost the therapeutic effects of camptothecin [131, 132]. Besides, the polymer lipid supported mesoporous silica nanoparticle (PLS-MSNs) enhanced irinotecan uptake, and improved its antitumor efficacy in MCF-7/BCRP cells [133]. Data collected from in vivo studies demonstrated that polyanionbased intraliposomal with topotecan and PLS-MSNs with irinotecan produced a good efficacy with promising clinical treatment for drug-resistant tumors due to topoisomerase drug resistance [130, 133]. BRCA1 AND BRCA2 Mutations in BRCA1 and BRCA2 genes account for 2060% of breast cancers in the families with the multiple


Table 6.


555

Nanotechnology-applied to overcoming drug resistance due to topoisomerase and BRCA1 on breast cancer. Topoisomerase Inhibitor Drug


Study Type

Model

Endpoints

Refs.

Camptothecin (CPT)

Sterically stabilized micelles (SSM) with polyethylene glycol (PEGylated) phospholipids

In vitro

MCF-7 cell lines

-Improved drug solubility, stability, freeze-drying properties, & anti-cancer activity

[132]

CPT

Mesoporous Silica NPs (MSN) galactopyranoside derivative photosensitizer

In vitro

MDA-MB-231cell lines

-Demonstrated higher cytotoxicity & synergic anti-cancer activity by of photosensitizer, drug & MSN combination

[131]

Irinotecan (CPT-11)

Polymerlipid mesoporous silica NPs (PLS-MSNs)

In vitro

MCF-7/BCRP

-Enhanced cell uptake by tumor cells

[133]

Topotecan

Polyanion-based intraliposomal

In vivo

HER-2+ mice xenograft

-Improved anti-tumor activity

[130]

Irinotecan (CPT-11)

Polymerlipid supported mesoporous silica nanoparticle (PLS-MSNs)

In vivo

MCF-7/BCRP mice xenograft

-Reduced the systemic toxicity & improved survival rate

[133]

Phase II

Patients (n = 493)

-Increased therapy responses

[169]

Docetaxel Cyclophosphamide Trastuzumab

BRCA1 and BRCA2 Rapamycin

-

In vitro

MDA-MB-231 cell lines

-Induced apoptosis

[170]

C-1305

-

In vitro

BT-20

-Demonstrated anti-proliferation & pro-apoptotic activities

[171]

17-allylamino-17demethoxygeldanamycin [17-AAG (Tanespimycin)] (heat-shock protein 90 Inhibitor)

-

In vitro

MCF-7

-Induces BRCA1 ubiquitination & proteasomal degradation

[141]

AZD2281 (PARP inhibitor)

-

In vivo

Mice breast cancer

- Inhibited tumor growth

[172]

Olaparib

-

Phase II

Women with confirmed BRCA1 or BRCA2 mutations

-Displayed therapeutic effects

[173]

Gemcitabine Carboplatin Iniparib

-

Phase II

Patients with metastatic triple-negative breast cancer (n = 123)

-Increased clinical benefits & survival rate

[174]


heritage individuals [134, 135]. Furthermore, BRCA1 mutations have been found in ~60% of the triple negative breast cancers (TNBC) [136]. BRCA1 (208 kDa) and BRCA2 (384 kDa) are large phosphoproteins, involved in DNA damage repair through homologous recombination [137]. They also participate in cellular development via transcriptional regulation and cell cycle checkpoint [138, 139]. BRCA1 has also been implicated in transcriptional regulation of several genes activated in response to DNA damage [134, 140]. Genetic studies conducted in BRCA1and BRCA2-defective cells have further revealed that these tumor suppressor genes require for maintenance of genome integrity, and normal levels of resistance to DNA damage

[137, 138, 141]. Inhibition of poly (ADP-ribose) polymerase (PARP), a key element of base excision repair pathway, is a target in tumors with deficient homologous recombination and deficiency of BRCA1 or BRCA2 [142]. PARP inhibitor could accumulate unrepaired DNA damage and prevent subsequent cell death in BRCA1 mutant breast cancer [136, 143, 144]. In this regard, a surprising mechanism of drug resistance was independently discovered by two groups. The first developed BRCA2-mutant cells that were resistant to a PARP inhibitor, while the second were resistant to platinum salts [145]. Accordingly, drug resistance in PARP inhibitor and platinum salts probably causes by secondary mutations in the BRCA2 gene itself [145].

556


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Drug

MTs/MAPs alteration Drug resistance

MTs/MAPs MTs/MAPs alteration MTs polymerization

Mitotic arrest

Cell apoptosis Fig. (3). Drug resistance mechanisms of microtubules to chemotherapy. Microtubules (MTs) can be an important target for cancer chemotherapy due to important function in cell. Some chemotherapy agents such as taxanes and epothilone, act by inducing polymerization, and consequently lead to mitotic arrest and apoptosis. Alteration microtubule and microtubule-associated proteins (MAPs) including mutations the drug -binding sites and overexpression of β3-tubulin are some important drug resistance mechanisms of MTs to chemotherapy. Polymer coating Targeting ligand

Wild type p53

Carrier

Coding p53 protein

Fig. (4). Nanoparticle vectors for wild p53 gene delivery. Delivery of wild type p53 gene into a target breast cancer cell line is one important strategy to overcome drug resistance which is resulting in p53 mutant. In this regard, Nanoparticle vectors can conjugate with tumor-targeting or another type of drug molecule, or antibodies and can be used for delivery of wild type p53 gene into a target breast cancer cell line without limitations of viral vectors.

Targeted cancer therapy with aim of nanotechnology can effectively target DNA repair, and is a promising module in cancer treatment. Herein, there is a lack of considerable (pre) clinical studies with nanotechnology approaches to overcome resistance of BRCA1-deficient cells. Therefore, most studies have addressed the new generation of PARPi that were applied in in vitro, in vivo and clinical trials. It seems that targeted cancer therapy with nanotechnology in

DNA repair pathways, BRCA1 and BRCA2 mutations would become a new challenge in the near future. Despite the absence of enough evidence on nanotechnology utilization in BRCA1 and BRCA2 mutations, data collected from beneficial effects of nanotechnology in other multidrug resistance agents suggest that use of nanotechnology with PARPi, especially in combination therapy, will improve treatment of BRCA1-deficient cells in future.



CONCLUSION

MDR

=

Multidrug resistance

Drug resistance, a significant factor in breast cancer, limits the efficiency of the current chemotherapeutic drugs. Drug resistance can be caused by alterations in the activity or the expression level of surface receptors, transporters and drug targets including P-gp, MRP1, MTs, HER2, Topo, P53 and BRCA1. Therefore, strategies must be focused for overcoming these obstacles. Applying nanobiotechnology gained immense popularity during last decade due to their potential capability to improve therapeutic effects. Protecting drugs from enzymatic degradation and providing their controlled release and prolonged blood circulation are some advantages of the NPs encapsulated drugs. Other related beneficial effects of nanotechnology use are modifying pharmacokinetics, decreasing toxicity and limiting nonspecific drug uptake. In addition, NPs as a non-viral vector for wild type p53 gene delivery can avoid viral vector disadvantages and overcome drug resistance in p53 mutant breast cancer. NPs can also be conjugated with tumortargeting or other drug molecules, siRNA, and antibodies for the purpose of combination therapies in order to overcome multidrug resistance. Herein, NPs conjugated with antiHER2 antibody and anti-cancer drug is one important strategy to overcome drug resistance in breast cancer. To the best of our knowledge, the number of clinical studies conducted to use nanotechnology in order to overcome drug resistance from Topo, MTs, p53, BRCA1-deficient cells are not sufficient. Therefore, preclinical studies with NPs and different phases of clinical trials can be a valuable option in cancer drug resistance arena in the early future.

MSN

=

Mesoporous Silica Nanoparticles

MT

=

Microtubules

NIR

=

Near-infrared

NLD

=

Nonpegylated liposomal doxorubicin

NPs

=

Nanoparticles

CONFLICT OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content of the paper. ACKNOWLEDGEMENTS This study was supported by Tehran University of Medical Sciences (Grant Number: 26012). LIST OF ABBREVIATIONS

ORMOSIL =

Organically modified silica

OS

=

Overall survival

PARP

=

Poly (ADP-ribose) polymerase

PBCA

=

Poly (butyl cyanoacrylate) nanoparticles

PEG

=

Polyethylene glycol

P-gp

=

Permeability glycoprotein

PLA

=

Poly (l-lactide)

PLD

=

Pegylated liposomal doxorubicin

PLD

=

Pegylated liposomal doxorubicin

557

PLS-MSNs =

Polymer lipid supported mesoporous silica nanoparticle

PS

=

Photosensitizer

PTX

=

Paclitaxel

PVA

=

Poly-vinyl alcohol

PVP

=

Polyvinyl-pyrrolidone

RGD

=

Arginine-glycine-aspartic acid

RTK

=

Receptor tyrosine kinases

siRNA

=

Small interference RNA

SLNs

=

Solid lipid nanoparticles

SSM

=

Sterically stabilized micelles

SWNT

=

Single-walled carbon nanotube

TNBC

=

Triple negative breast cancer

TOP2A

=

Topoisomerase ΙΙ

TPGS-CT

=

Tocopheryl polyethylene glycol succinatecarbon tube

ABC

=

ATP-binding cassette

ATP

=

Adenosinetriphosphate

AuNR

=

Gold nanorod

BRAC1

=

Breast cancer type 1

TPT

=

Topotecan

CNTs

=

Carbon nanotubes

TTF

=

Time to treatment failure

CPT

=

Camptothecin

TTP

=

Time to progression

FA

=

Folic acid

GGS

=

Gold-gold sulfide nanoparticles

HBDL

=

Hyperbranched dendritic-linear

HER2

=

Human epidermal growth factor receptor 2

HMSNs

=

Hollow mesoporous silica nanoparticles

MAbs

=

Monoclonal antibodies

MAPs

=

Microtubule-associated proteins

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Accepted: July 02, 2015