The cell surface membrane (PM) plays an important role in cell structure as a physical barrier that surrounds the cell and maintains the crucial boundaries between cytoplasm and the extracellular environment. The majority of PM mass is made up of proteins with critical specific functions. These proteins determine the methods of interaction between cells and its environment, including sending and receiving chemical signals, transportation metabolites, ions, or larger molecules, attached to neighboring cells and the extracellular matrix, etc.
[17,18][17][18]. The mutation, deletion and overexpression of PM proteins are related to various pathological states of cancers. Currently, PM proteins have become the target for more than half of the approved drugs
[19]. Some PM proteins (such as the human epidermal growth factor receptors 2 (HER2), mucin 1 (MUC1), and epithelial cell adhesion molecules) have been identified as crucial cancer biomarkers. Hence, a large number of specific aptamers have been developed against cell surface membrane biomarkers for basic research in physiology and biochemistry and also for diagnosis, monitoring and treatment of cancers.
2.2. Extracellular Cancer Biomarkers
The extracellular environment has a large impact on tumor and non-tumor tissues, especially in the concentrations of extracellular cancer biomarkers in body fluid
[96][20]. Abnormal changes in cancer biomarker levels in body fluids are measuring standards of disease progression renewal. Therefore, the detection of these abnormal changes is often the key to realize early cancer diagnosis. Currently, the efforts are focused on liquid biopsy that relies on the presence of specific biomarkers in the body fluid of cancer patients. These cancer biomarkers are difficult to detect due to their low concentration levels in a high protein content medium. Enzyme-linked immunosorbent assays (ELISA) are the gold standard method for cancer biomarkers detection in body fluid, which rely on antibodies. Nevertheless, they suffer from some limitations, such as batch to batch variations during their production, and the challenging and cumbersome technique needed for generating specific monoclonal antibodies (especially against non-immunogenic molecules)
[97,98][21][22]. For this reason, aptamers as novel receptors overcome these limitations owing to their unique characteristics of good stability, biocompatibility, safety, efficiency and non-immunogenicity. Herein,
wresearche
rs summarized the various applications of aptamers in cancer diagnosis by introducing extracellular cancer biomarkers that have been detected in different body fluids.
Platelet-derived growth factor (PDGF), as one of serum components, has been proven to promote the proliferation of arterial smooth muscle cells
[99][23]. The PDGF family is composed of four ligands: PDGF-A, B, C and D. PDGF-BB, a homodimer of PDGF-B, is an important cancer biomarker in diagnosis and recognition of cancers. During the past few years, aptamer-based recognition and detection of PDGF-BB for cancer diagnosis has been well-developed. Huang et al. developed an aptamer-modified AuNPs (Apt-GNPs) for the sensitive detection of PDGF-BB based on observing the changes in the color and extinction of the specific aptamer and GNPs by cause of aggregation
[100][24]. This sensor was with a low detection limit of 35 nM and applied to protein analysis and cancer diagnosis. In another study, Tang et al. reported a strategy integrating rolling-circle amplification (RCA) and aptamer-based DNA enzyme-catalyzed colorimetric reaction for sensitive detection of PDGF-BB
[101][25]. The PDGF-BB was recognized using primary aptamer-functionalized microbeads in a sandwich approach, and a secondary aptamer was attached to an RCA primer/circular template complex. The detection limit of this strategy was 8.2 fM. Zhang et al. constructed a AuNPs colorimetric sensor for detecting PDGF-BB by target-triggered strand displacement amplification system
[102][26]. An obvious AuNPs color change can be observed when PDGF-BB concentration was as low as 4.0 nM. Interestingly, Ye et al. proposed a novel and simple aptamer-based one-two-three cascade DNA amplification surface-enhanced Raman scattering (SERS) strategy for the detection of PDGF-BB with the detection limit down to 0.42 pM
[103][27]. Besides the strategies based on colorimetric and Raman scattering readout, fluorescent method is a simple and strong strategy because of its high sensitivity, rapid, simple and comparatively cost-less
[2]. Taking advantages of fluorescent method, various aptamer-based fluorescent strategies have been developed for PDGF-BB detection. However, the labeling of aptamer with fluorophores and quenchers are the main limitations of the existing methods, which are time consuming and expensive. To overcome these limitations, Babu et al. reported an assay for label-free luminescent detecting PDGF by conjugating aptamer to hydrophobic Ru (II) complex as sensor system
[104][28]. This method could detect the PDGF in a mixture of proteins, down to 0.8 pM. Wang et al. introduced a label-free and enzyme-free aptasensor for PDGF-BB quantification by using target-triggered hybridization chain reaction amplification and grapheme oxide (GO)-based selective fluorescence quenching with a detection limit of 1.25 pM
[105][29]. Wang et al. reported another label-free fluorescent aptasensor for PDGF-BB detection by photo-induced electron transfer between DNA-AgNCs and G-quadruplex/hemin complexes. Binding of PDGF-BB to its aptamer caused a conformational change of DNA and the release of G-quadruplex sequence, which resulted in fluorescence change of the system
[106][30]. In addition, Lin et al. developed a FRET based aptasensor using upconversion nanoparticles (UCNPs) as donor and AuNPs as acceptor for the PDGF-BB detection in blood serum of lymphoma patient with a low detection limit of 10 nM
[107][31]. Compared to other biosensing methods, such as optical detection, the electrochemical aptasensors showed highly applicable and attractive for developing point-of-care cancer diagnosis tools owing to its advantages of disposability, accuracy, the ability to work with complex samples, easy control, rapid response, possible of usage for online control, etc.
[108,109][32][33]. Recently, Jiang et al. developed a dual signal amplification for electrochemical aptasensing of PDGF-BB using hydroxyapatite nanoparticles (HAP-NPs)
[110][34]. The phosphate group in both HAP-NPs and the aptamer reacted with molybdate to create a redox-active molybdophosphate precipitated on the surface of a glassy carbon electrode (GCE). When a voltage of 0.21 V (vs. Ag/AgCl) is applied, a current is generated whose intensity depended on the concentration of analyte. This work was applied to the determination of PDGF-BB in serum sample with a detection limit of 50 fg/mL.
3. Aptamer-Based Cancer Therapy
3.1. Aptamer as Therapeutic Agent
Aptamers are a group of potential therapeutic agents. They are known as “synthetic antibodies” because of their synthetic nucleic acid-based nature and excellent specificity and affinity for both protein and non-protein targets. The majority of aptamers utilized for therapeutic purposes are either chosen by in vivo selections using appropriate model systems or through in vitro selection utilizing a purified protein or receptor
[130][35]. In clinical trials, therapeutic aptamers can be utilized as antagonists and agonists. Antagonist aptamers block or inhibit the integration of targets relevant to disease via protein–protein interaction or protein–receptor–ligand interaction
[15]. Agonist aptamers can active the target receptors and also can be utilized as the carrier to carry the cargo to the target cells or tissues. Numerous studies have been reported that therapeutic aptamers applied for cancer therapy.
3.2. Aptamer as Delivery Agents
Aside from their utility as stand-alone therapeutics, aptamers can also serve as chaperones for another therapeutic. A variety of cell type-specific aptamers have been coupled with therapeutic drugs (such as siRNA, microRNA, anti-miR, therapeutic aptamer, chemotherapeutics, or toxins) or delivery vehicles (such as organic or inorganic nanocarriers) for cell type-specific delivery. Owing to the high specificity and affinity of aptamers, therapeutic compounds can be targeted to the desired cells or tissues, enhancing their local concentration and therapeutic efficacy.