Advances in Aptamers-Based Applications in Breast Cancer: History
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Tooba Gholikhani
,
Shalen Kumar
,
Hadi Valizadeh
,
Somayeh Mahdinloo
,
Khosro Adibkia
,
Parvin Zakeri-Milani
,
Mohammad Barzegar-Jalali
,
Balam Jimenez

Aptamers are synthetic single-stranded oligonucleotides (such as RNA and DNA) evolved in vitro using Systematic Evolution of Ligands through Exponential enrichment (SELEX) techniques. Aptamers are evolved to have high affinity and specificity to targets; hence, they have a great potential for use in therapeutics as delivery agents and/or in treatment strategies. Aptamers can be chemically synthesized and modified in a cost-effective manner and are easy to hybridize to a variety of nano-particles and other agents which has paved a way for targeted therapy and diagnostics applications such as in breast tumors.

  • aptamer
  • drug delivery
  • cancer diagnostics

1. Introduction

Breast cancer is considered as one of the top five causes of mortality among women worldwide since 1980 [1]. Primary diagnosis and therapy are of pivotal aspects in the prognosis of breast cancer. Recently, constant education on breast cancer symptoms and how to spot breast differences require a medical opinion, and complementarily to the current diagnosis techniques such as mammograms, ultrasounds, MRI scans and biopsies, the survival rate of breast cancer is improved.
The most common ways of diagnosis are based on mammogram (imaging). However, molecular diagnosis techniques such as hormone receptor and protein expression methods (ER, PR, HER2, HERmark™), serum methods (CellSearch®, Biomarker translation test), and gene expression profiling methods (Mammaprint™, OncoVue® Test, GeneSearch™ breast lymph node, nipple fluid aspiration, DiaGenic BCtect®, Oncotype DX®, Theros H/ISM and MGISM) are also used [2]. These techniques has resulted in a 1.8% to 3.4% reduction per year in the breast cancer mortality rate in the last 30 years among U.S woman [3]. However, the current mortality rate is still attributable to a late diagnosis because of the patients’ fear of cancer diagnosis and treatment, competing life priorities, financial problems, embarrassment about having a breast examination, use of traditional methods, lack of information and mammography misinterpretation [4]. Therefore, there is still a need to innovate new strategies to reduce the current mortality rates that are less invasive, fast, do not require woman to expose their breasts and do not require expensive equipment or specialized personnel to interpret the results [5]. Every year 2.26 million new patients are diagnosed with breast cancer and 684,966 deaths are recorded globally due to breast cancer [6]. Woman from rural and remote areas are among the most affected; for example, in rural areas in China, where woman have less access to health care facilities and have a lower income, the mortality of breast cancer has increased in the last 25 years [7]. In 2019, in US approximately 232,000 women were diagnosed with breast cancer and of those, 40,000 died [8].
The proliferation index Ki-67 is an essential indicator of uncontrolled cellular proliferation in malignancy and critical to make a distinction between ‘Luminal A’ and ‘Luminal B (HER2 negative)’ subtypes [9][10][11][12]. Understanding the distinction between different tumor subtypes, has allowed researchers to implement specific treatments for each subtype specially for luminal A and B subtypes [13].

2. Affinity SELEX

Affinity column SELEX is suitable for target molecules such as metal ions, small organic and inorganic molecules, peptides, proteins and various cell types [14][15]. The target molecule is conjugated to a solid phase such as sepharose beads, magnetic particles, nitrocellulose membranes or graphene oxide polymers using functional groups such as amines, carboxyl and thiol groups [16]. The type of chemistry used for the target conjugation to the substrate depends on the substrate and the functional group. Following co-incubation of oligo pool with the affixed target, the oligo demonstrating affinity to the functionalized target is separated and enriched using PCR [17].
Blok et al. [18] used a thrombin affinity column prepared with concanavalin A, to find aptamers specific for thrombin.
Xie et al. [19] adopted carboxylated magnetic beads for HBsAg immobilization by some deoxynucleotide aptamers which can bind with high specificity to the surface antigen of hepatitis B virus (HBV) [20]. In immobilized metal affinity chromatography (IMAC), metal ions such as Zn(II), Cu(II), Ni (II), and Co(II) are immobilized on a support to fractionate and purify proteins in solutions; the IMAC method is used to enrich most of the phosphopeptides from whole cell lysates, and it is reported that titanium dioxide (TiO2) beads have an equivalent ability to enrich phosphopeptides [21][22].

3. Aptamer Utilization for Breast Cancer

Many reports have listed aptamers for diagnosis and therapeutic applications of various cancer targets. In particular, various groups have reported the identification of aptamers against biomarkers for breast cancer. Among the certified biomarkers against breast cancer, HER2 is considered as one of the most suitable and pivotal biomarkers and applied either for molecular division or for the targeted therapy of breast tumors in medical treatment. Namazi et al. [23] utilized Cell-SELEX to select an anti-HER2 single-strand DNA aptamer (known as H2) that demonstrated affinity to HER2 with a Kd of 270 nM. Qaureshi et al. [24] developed a label-free capacitive apta-sensor using H2 and continued micro-electrodes of the capacitor for HER2 identification in solutions. The highly sensitive apta-sensor was used to identify HER2 in specimen within a reasonable level of 0.2–2 ng/mL. In addition to HER2, other biomarkers of breast tumors were targeted to develop aptamers for detection of breast tumor cells [25][26][27][28][29]. Ahirware et al. [30] applied the HT-SELEX method to develop an ERα-specific DNA aptamer. The aptamer was internalized by breast tumor cells positively expressing Erα. Following internalization, the aptamer localized in the nucleus. The aptamer was utilized to represent mRNA level of ERα in breast tumor cells, and the findings were related to IHC identification of ERα in breast tumor tissues that were either positive or negative for ERα. Lie et al. [31] developed a label-free biosensor for a regulator protein, i.e., nucleolin, which has a modulating role in the stability of Bcl-2 mRNA in tumor cells. The AS1411 aptamer was applied on alarm cantilevers in the microcantilever array. AS1411 interactions with nucleolin in clinical samples stimulated surface stress alterations, causing various flaws between the reference and sensor cantilevers [32][33]. The complex showed increased sensitivity with a LOD of 1.0 nM.
Identification of breast tumors particularly by targeting circulating tumor cells (CTCs) in the serum of patients is pivotal for initial prognosis, diagnosis and monitoring of treatment effects of cancer [34]. Aptamers developed from either SELEX or Cell-SELEX is a potential option for identifying breast tumors [35][36][37][38][39]. Caei et al. [40] improved aptamer-based fluorescence detection by targeting mucin 1 (MUC1) using ssDNA aptamers combined with luminescent terbium (TbIII) for sensitive identification of breast tumor cells. In the presence of breast tumors, the aptamer attaches to MUC1 on the cell surface and the stimulation of Tb3+ induced fluorescence dictates the positive signal [41]. The apta-sensor displayed great sensitivity towards breast tumors with a confinement level of detection as low as 65 cells/mL. Moreover, Joe et al. [42] developed an apta-sensor that detected HER2 and MUC1 in of MCF-7 cells reaching 10 cells/mL level of detection sensitivity. Li et al. [43][44] combined aptamers with silver nanoparticles using MUC1 aptamers for the imaging of MCF-7 cells. The system could effectively differentiate breast tumor MCF-7 cells from more metastatic A549 human lung cancer and MDAMB-231 breast tumors.

4. Therapeutic Use of Aptamers

The applicability of aptamers is not only limited to analytical systems but also paves a way for therapeutic uses [45][46]. Aptamers with small molecular weights of ~20,000 Da are easy to penetrate tumors tissues so they have been considered as drugs [47][48]. Currently, there are a number of aptamers that have been examined for the treatment of clinical diseases, while some of them have already received FDA approval for the therapeutic utilization, such as Macugen (Pegaptanib Sodium Injection) for treatment of macular degeneration [33][49][50]. AGRO100 is an aptamer that binds to nucleolin, a protein found intranuclear in all cells, but is uniquely expressed on the surface of tumor cells. Pre-clinical testing demonstrated the inhibitory effect of AGRO100 on nucleolin function and proved its anti-cancer effects against lung, prostate, breast, cervical, and colon cancer, as well as malignant melanoma and leukemia.
In vivo therapeutic application of aptamers is limited due to nuclease decomposition and metabolism of aptamers in physiological conditions [51][52]. To reduce the decomposition and enhance effects of aptamer utility in in vivo therapeutics application, the original aptamers generally require chemical alteration. Modifications such as internucleotide linkage with 3–3′ and 5–5′capping in the terminus with an inverted nucleotide [53][54], 2′-substitutions and phosphodiester linkage replacement with 2-F, 2-NH2, 2-OMe, and sugar rings [55][56], incorporating unnatural nucleotides into the oligonucleotide chain [57], cyclization of nucleic acids by linking 5- and 3-termini [58][59], and dialkyl lipid/PEG/cholesterol modifications at the 5′-End [60][61][62] on the oligo backbone inhibit the nucleases from digesting the oligo aptamers.

Therapeutic Application of Aptamers in Breast Cancer

A therapeutic agent is something that acts directly on the target. Aptamers are able to modulate the performance of the targeted protein or mRNA, and could influence their physiological roles such as the initiation of apoptosis [63][64][65]. Balae et al. [66][67] adopted glutathione-attaching RNA aptamers to induce the apoptosis of tumor cells in breast cancer. The aptamers gathered reactive oxygen species (ROS), responsible for the regulation of caspases function in breast tumors. The AS1411 aptamer, capable of binding the Bcl-2 mRNA-attaching protein nucleolin, was assessed for the capability to stimulate Bcl-2 gene cytotoxicity and instability in MDA-MB-231 and MCF-7 breast tumors [68][69]. The AS1411 aptamer could suppress the homeostasis of MDA-MB-231 and MCF-7 cells, reducing the life-span of Bcl-2 genes in tumor cells, and hinder nucleolin from attaching to the full element of the AU region in the Bcl-2 gene, eventually triggering apoptotic pathway. Varshney et al. [70] adopted RNA aptamers (hTERTapt8.1, hTERTapt7.7, hTERTapt 9.5, and CR4/CR5) that were specified for the sequence of RNA interactive domain 2 (RID2) of Human telomerase reverse transcriptase (hTERT) [71]. It can specifically and tightly attach to the peptide of hTERT and modulate the performance of the enzyme of telomerase in MCF-7 tumor cells, indicating the RNA aptamers’ potential in the treatment of patients with breast cancer [71].

5. Drug Delivery Pathways of Aptamer

Chemotherapy is the key therapeutic strategy utilized for the treatment of the tumor cells of cancers [72]. Some chemotherapeutic medicines can act on normal healthy cells in addition to tumoral cells thus leading to multiple adversary effects. Targeted delivery of chemotherapeutic substances could reduce adverse effects improving the specificity and efficacy of the therapeutic agent [73]. Aptamers’ ability to specifically bind to its target allows for aptamers’ utility as a targeted drug delivery system in breast cancer treatment. Liu et al. [74] developed an aptamer to target HER2 and made a complex with doxorubicin (a drug commonly used in breast cancer treatment). The doxorubicin–aptamer complex was used as a targeted drug delivery system to HER2-positive breast tumor cells. The aptamer–doxorubicin complex successfully delivered the complex to HER2-positive breast tumors, while minimal cytotoxicity was reported for normal cells. Dai et al. [75] improved a MUC1-targeting system of drug delivery using a MUC1–aptamer complex. The DNA tetrahedron (Td) contained the drug inside its DNA structure. The complex of aptamer–Td can adoptively attach and present doxorubicin (Dox) to MUC1 positive breast tumors, resulting in increased cytotoxicity towards MUC1-positive MCF-7 breast tumors versus normal cells, which are negative for the MUC1 marker in vitro (p < 0.01). Tao and Wei, et al. reported that they can produce upgraded polydopamine (pD)-reformed nano-substance-aptamer bio-conjugates (Apt-pDDTX/NPs) for the therapy of breast tumor cells with in vivo applications [76]. Both in vivo animal and in vitro cell experiments showed that the Apt-pD-DTX/NPs can improve targeted medicinal delivery, decrease the deleterious aspects of the drugs and enhance the wellbeing of the surviving patients in the treatment of breast tumors [77].
In last decades, aptamer nanomaterial conjugates have been used as medicine delivery agents in breast cancer. Beqa et al. [78] generated a novel mixture of nano-material which consisted of gold nano-substances for photothermal treatment of breast tumors [79]. By using gold nanoparticle-decorated SWCNTs with SKBR-3 breast cancer cell specific S6 aptamers, SK-BR-3 breast tumors were eliminated by applying 10 min of laser radiation at 785 nm with a power of 1.5 w/cm2. S6 aptamers interact with cancer cells specifically, then conjugated AuPOP-decorated SWCNT aggregates on the surface of cancer cells so that the application of a laser will kill that particular cell [80]. Similarly, other scientists considered utilizing the benefits of gold nanomaterials due to the ability to absorb extended wavelength of plasmon (700–1000 nanometer) [81]. Cell-SELEX was utilized to develop a new KW16-13 DNA aptamer, which had affinity for metastatic tumors in the breast tissue [35]. Conjugation of AuNPs–aptamer (KW16-13–AuNPs) demonstrated a 71-fold affinity for metastatic tumors of breast tissue compared to KMF2–1a-AuNPs [82][83]. Maik et al. [84] conjugated aptamer AS1411 to gold nanospheres (AuNSs) for targeted therapy of breast cancer. AS1411–AuNSs demonstrated high durability both in serum and solutions, and was simply internalized by target cells in higher doses and lead to an elevated anti-cytotoxic/proliferative effects when compared to either the pure AS1411 aptamer or AuNSs [85]. Moreover, compared to unconjugated AS1411 or GNS linked to control oligonucleotides, the injection of AS1411–AuNSs in vivo remarkably suppressed the growth of xenografted tumors in mice without any toxic side effects, indicating AS1411–AuNSs is a suitable therapeutic candidate for clinical application in breast cancer treatment.
In addition to nanomaterials and chemical drugs, aptamers can deliver small interfering RNA for treatment of gene disorders [86][87][88]. Theil et al. [87] attached an RNA aptamer specific for HER2 to siRNA targeting the anti-apoptotic Bcl-2 gene for utility in HER2 positive tumors. The aptamer–siRNA conjugate was internalized by HER2-positive tumor cells and silenced expressed levels of Bcl-2, improving the sensitivity of HER2-positive breast tumors to chemotherapy. Wang et al. [89] developed an aptamer–siRNA conjugate; survivin exerts a negative feedback of the cell death pathway in cancerous stem cells of DOX-resistant breast cancer cells. Epithelial cell adhesion molecule (EpCAM), which is present at low levels in normal epithelial cells is highly overexpressed (up to 800-fold) in many solid cancers. Therefore, utilizing an active targeting system containing the RNA aptamer specific for EpCAM presented an elevated dose of siRNA to cancerous stem cells that silenced survivin and elevated tumor cell chemosensitivity, thus finally inhibiting the cancerous cell growth, and extending the mice survival carrying xenograft mammalian tumors.

This entry is adapted from the peer-reviewed paper 10.3390/ijms232214475

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