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Back to Journal »International Journal of Nanomedicine» Volume 15

Aptamer hybrid nanocomplexes as targeted components for antibiotic/gene delivery systems and diagnostics: a review

Authors Rabiee N, Ahmadi S, Arab Z, Bagherzadeh M, Safarkhani M, Nasseri B, Rabiee M, Tahriri M, Webster TJ, Tayebi L 

The 2020 volume will be published on June 17, 2020: 15 pages 4237-4256

DOI https://doi.org/10.2147/IJN.S248736

Single anonymous peer review

Editor approved for publication: Prof. Dr. Anderson Oliveira Lobo

Navid Rabiee,1 Sepideh Ahmadi,2,3 Zeynab Arab,1 Mojtaba Bagherzadeh,1 Moein Safarkhani,1 Behzad Nasseri,4,5 Mohammad Rabiee,6 Mohammadreza Tahriri,7 Thomas J Webster,8 Lobat Tayebi7 1 Department of Chemistry, Sharif University, Tehran, Iran; 2 Student Research Committee, Department of Medical Biotechnology, Faculty of Advanced Medical Technology, Shahid Beheshti Medical University, Tehran, Iran; 3 Cell and Molecular Biology Research Center, Shahid Beheshti Medical University, Tehran, Iran; 4 Department of Chemical Engineering and Department of Bioengineering, Hacettepe University , Beytepe, Ankara 06800, Turkey; 5 Department of Chemical Engineering and Applied Chemistry, Ankara University, Ankara, Turkey; 6 Biomaterials Group, Department of Biomedical Engineering, Amir Kabir University of Technology, Tehran, Iran; 7 Marquette University School of Dentistry, Milwaukee, Wisconsin 53233, USA; 8 Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA Corresponding Authors: Thomas J Webster; Mohammadreza Tahriri Email [Email Protection]; [Email Protection] Abstract: Over time With the progress of society, the emergence and incidence of diseases are getting higher and higher, and treatments need to be improved. In this regard, nowadays, aptamers that are more effective than antibodies in diagnosing and treating diseases have become the focus of attention. Here, in this review, we first studied the functions of aptamers in various fields (such as pathogen detection and repair, nanoparticle modification, antibiotic delivery, and gene delivery). Then, we use the aptamer-bound nanocomplex as the main and effective factor for gene delivery. Finally, we focus on targeted co-delivery of genes and drugs through nanocomposites as a new and exciting method for cancer treatment in the coming decades to meet our growing social needs. Keywords: aptamer, polyethyleneimine, hybrid nanocomposite, antibiotic, targeting, gene delivery system

DNA and RNA are the most important molecules, they are equivalent to a huge hard disk to store information. They can also be used as diagnostic tools and treatment "doers". 1-4 The results of many types of studies indicate that the specific structural features of these molecules have opened up new research areas that lead to the design of aptamers. Aptamers are oligonucleotides, including ssRNA, ssDNA (single-stranded RNA, DNA), or peptides. Due to their specific structural characteristics, they bind to selected targets with significant dependence and exclusivity. 5,6 Aptamers are considered a suitable substitute for antibodies due to their ability to overcome many of the shortcomings of using antibodies. 7-9 For example, it is well known that oligonucleotides are stronger than proteins at higher temperatures, so they can maintain their structure during frequent denaturation and renaturation cycles. Therefore, compared with protein-based antibodies, the biggest advantage of oligonucleotide-based aptamers is their constant properties at high temperatures, even after denaturation at 95 °C. 10-13

Aptamers are the least toxic molecules with low immunogenicity, because nucleic acids are usually not recognized by the human immune system as external foreign factors. 14,15 Aptamers are derived from SELEX (systematic evolution of exponentially enriched ligands) or in vitro evolution. Therefore, toxins and other molecules that do not cause a strong immune response can be used as targets for the development of aptamers. Therefore, based on the above advantages, aptamers are more suitable for different disease applications. They are considered a biological material and a diagnostic and therapeutic tool, and they have been used to expand new drugs, drug delivery, gene delivery, and antibiotic delivery systems. 16-18 They are actually considered to be gene delivery systems that target the time and place of antibiotics and control the release of drugs or their effects on gene delivery. 19

Aptamers have been effectively established against metal ions, proteins, bacteria, viruses and whole cells. High affinity and specificity are some of their characteristics comparable to antibodies. Unlike antibodies, they can be selected under non-physiological conditions, such as very high or low temperature or pH 20. These characteristics make the aptamer a suitable applicant for clinical application. Many aptamers have been designated for various diseases, such as cancer types. 21,22 Table 1 describes a list of the most common differences between antibodies and aptamers. Table 1 Different characteristics between antibodies and aptamers

Table 1 Different characteristics between antibodies and aptamers

Some published review articles have studied the role of aptamers in the diagnosis and treatment of cancer and diseases. 23-25 ​​However, this work is limited and does not emphasize that aptamers must revolutionize the major prospects of medicine. This review was conducted to emphasize their importance in future antibiotic therapy, cancer diagnosis and treatment. Specifically, this review summarizes recent research on the use of aptamers in disease diagnosis and treatment, antibiotic delivery, and gene delivery, and reviews the use of aptamer-coupled nanocomplexes in anti-cancer applications. 26,27

Pathogenic diseases are one of the most common diseases that threaten the lives of many people all over the world. It is produced by various microorganisms. Due to the large consumption of antibiotics by the immune system, the inefficient transfer of antibiotics to the infected site and side effects, as well as the slow development of new and improved anti-pathogen drugs, are important global issues that need to be resolved now. The development of targeted therapies and proprietary diagnostic methods for diseases caused by pathogens, infections and cancers is increasing. In recent years, aptamer-based targeted therapy has been developed to overcome these problems. Research has been conducted on the use of aptamers in the fields of diagnosis and targeting and early treatment. 28,29

To give an example, Francis tularensis is an aerobic bacteria. It is a pathogen that causes tularemia in humans and animals. The pathogen is considered to be one of the most important biological threats, highly infectious, highly pathogenic and high mortality rate (30%-60% reported in the field of former antibiotics). In fact, it can be pointed out the importance of using aptamers in the detection of biological combat factors. 30-32

An outstanding study produced an aptamer (ssDNA) that binds to Tulabacterium subspecies. In this study, a set of aptamers containing 25 aptamers was isolated to specifically bind to Tularemia subspecies. Studies on these aptamers under certain conditions have shown that the aptamer complex is specifically coupled to the Tularemia antigen, which enables it to be used as a tool for the diagnosis of biological factors such as Tularemia. 33-35

Another popular bacterial infection is caused by Vibrio parahaemolyticus and Staphylococcus aureus (S. aureus). Vibrio parahaemolyticus is a common cause of intestinal diseases after eating uncooked or raw seafood and environmental waters. The symptoms of Vibrio parahaemolyticus are watery diarrhea, abdominal pain, vomiting, nausea, fever, headache, and bloody diarrhea. Therefore, it is essential to provide a rapid and specific detection method. 36,37

The first whole bacterial SELEX application was performed on Vibrio parahaemolyticus to detect specific DNA aptamers. This strategy is used for a set of FAM-labeled ssDNA molecules to identify aptamers specifically linked to Vibrio parahaemolyticus. This identification is done by using flow cytometry analysis. According to the obtained results, the aptamer A3P has a high binding affinity (76%) to Vibrio parahaemolyticus. Even in food, this function can be used to detect this kind of bacteria. In addition, linking this sequence to magnetic nanoparticles (NP) and combining it with sensitive detection probes can help control food safety. 34,38

Staphylococcus aureus is a round bacteria that can cause disease and threaten human health. 39 It is very effective to evaluate Staphylococcus aureus by the molecular recognition program using the aptamer detector. 40 In addition, enrichment and separation by magnetic particles and fluorescence detection by fluorescence detection. Gold nanoclusters (AuNC) have become a powerful tool for evaluating them due to their controllability and high sensitivity. 41,42 In a study, Cheng et al. proposed a new method for detecting Staphylococcus aureus, in which recognition molecules, such as aptamers, are combined with antibiotics. In this study, Staphylococcus aureus was functionalized by using aptamer-coated magnetic beads (Apt-MB) and vancomycin (Van) functionalized fluorescent nanoclusters ([email protection], 2.0±0.6 nm) Other non-targeted bacteria have also been detected in real samples, including milk and human serum.

[email protected] After synthesis, its formation was confirmed by transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). Since the nanoprobe should have chemical and photochemical stability, [email protection] The stability of the nanoprobe is checked by ultraviolet radiation and surrounding buffer. The observation results show the successful synthesis and stability of [email protected] in various buffers and pH levels. Next, the attachment of [email protection] to bacteria was proved by fluorescence microscope and TEM. The detection range of Staphylococcus aureus from complex samples and real samples is 32–108 CFU/mL, and the detection limit (LOD) is 16 CFU/mL. Finally, it was confirmed that magnetic beads coated with aptamers and fluorescent AuNCs coated with antibiotics can be used to quantify and detect bacteria in complex samples during the binary evaluation process. Apt-MBs and [email protected] dual recognition can efficiently detect Staphylococcus aureus in milk and human serum as real samples (96.94% to 101.24%, respectively), so it can be used to evaluate Staphylococcus aureus and related food contamination Infectious disease identification 43 (Figure 1). Figure 1 Schematic diagram of the process of identifying Staphylococcus aureus using [email protected] and Apt-MB (I) dual identification test. Characterization (II) (AF) stands for optical, fluorescence and transmission electron microscopy to characterize this synthetic particle. This image is reproduced with permission from Cheng D, Yu M, Fu F, etc. Using aptamer-coated magnetic beads and antibiotic-terminated gold nanoclusters to perform a dual identification strategy for specific and sensitive detection of bacteria. analytical chemistry. 2016;88(1):820–825. Copyright © 2016 American Chemical Society. 43

Figure 1 Schematic diagram of the process of identifying Staphylococcus aureus using [email protected] and Apt-MB (I) dual identification test. Characterization (II) (AF) stands for optical, fluorescence and transmission electron microscopy to characterize this synthetic particle. This image is reproduced with permission from Cheng D, Yu M, Fu F, etc. Using aptamer-coated magnetic beads and antibiotic-terminated gold nanoclusters to perform a dual identification strategy for specific and sensitive detection of bacteria. analytical chemistry. 2016;88(1):820–825. Copyright © 2016 American Chemical Society. 43

Compared with previous studies, this strategy has several advantages, including its ease of use, the synthesis of AuNC@Van is much cheaper than antibodies, and the ability to detect bacteria at concentrations as low as ppm. However, due to the limitations of this study, there is no pre-separation of bacteria and other interfering components before the fluorescence measurement, which is unlikely to produce real results.

Also in another study, Charoenphol et al. applied the cell-specific aptamer-DNA nanostructure system for therapeutic purposes. 44 DNA nanostructures are widely used in various applications due to their special characteristics such as programmability, uniform structure, biocompatibility and biodegradability. For example, DNA nanostructures can carry a variety of therapeutic substances (such as aptamers, small interfering RNA (siRNA), etc.) without any chemical correction. In this study, they incorporated the AS1411 aptamer into the DNA pyramid and observed selective inhibition of the growth of Hela cells (a type of cancer cell). In addition, it was found that DNA pyramids displaying aptamers are more stable than single-stranded aptamers to nuclear decay changes. However, in this study, a single cargo type was pointed out, but DNA could be used in combination therapy. 44 For example, the combination of chemotherapy and small RNA-based therapies (siRNA) is an example of these combination therapies. It is assumed that chemotherapy and siRNA can be delivered to the same tumor cell at the same time to exert their synergistic effects. However, the development of these systems through systemic drug delivery still faces challenges. 45

With the development of nanomedicine and aptamer selection methods, aptamer-functionalized nanoparticles have opened up new directions for diagnostic and therapeutic applications. There have been many reports on the use of NP-aptamer conjugates to deliver NPs to cancer cells. Early diagnosis of cancer is a challenge for effective treatment, and aptamers attached to NPs are considered to be very promising molecular detectors in this field and deserve more attention and clinical trials. 46,47

Magnetic nanoparticles related to the fluorescent part can detect and induce shedding tumor cells. Recently, a study based on the application of double NPs coupled with aptamers with two characteristics (including magnetic and fluorescence) to detect and elicit tumor cells shed from the blood has been carried out. Since the number of these cells surrounded by various other cells is small, there is a need for a method to create selective extraction and sensitive detection. To this end, researchers use aptamer-coupled NPs (ACNPs) and fluorescent NPs (FNPs) to extract and detect tumor cells. When the various parameters are combined, the ACNP system with the most selectivity and sensitivity is specified. This method can be adjusted for a variety of cancers to determine possible ACNPs for identifying and extracting cancer cells. 41 In another study, Bamrungsap et al. used aptamers coupled with magnetic NP (ACMNP) to diagnose cancer cells. 48 The ability to detect at least 10 cancer cells in a 250 µL cancer cell sample is a feature of this biosensor. ACMNPs use the characteristics of aptamers to specifically bind to target cancer cells. The broad surface of these NPs provides conditions for the binding of multiple aptamers. In addition, a set of ACMNPs can be used to accurately detect molecules at the molecular and cellular levels, as well as in fetal bovine serum, human plasma and whole blood.

Breast cancer is a serious cancer and the second cause of death among women today. Investigations have shown that more circulating tumor cells (CTCs) are detected in the peripheral blood cells of breast cancer patients. Therefore, the diagnosis of blood CTCs is a promising method for detecting and measuring breast cancer cells. There are two types of cancer cells that cause breast cancer: human epidermal growth factor receptor 2 (HER2) and mucin 1 (MUC1). HER2 and MUC1 are overexpressed in 15-20% and 90% of breast cancer patients, respectively. Therefore, by using the multi-target method of HER2 and MUC1 probes, the CTC of breast cancer can be detected with high precision and precision. NPs have been used in various studies to identify breast cancer due to their easy surface modification and other advantages. 49-51

In a unique study, a dual aptamer system for the diagnosis of breast cancer was considered, including HER2 and MUC1 modified SiNP (Dual-SiNP). The dual aptamer method provides the first extensive detection and diagnosis system for HER2 and MUC1 breast cancer cells. This synthetic probe is evaluated by techniques such as fluorescence spectroscopy, dynamic light scattering, and ultraviolet-visible spectroscopy. Due to several difficulties in the in vivo system, the application of this system is limited to the in vitro system, including: inconsistency of nucleic acid in blood, attenuation of probe fluorescence signal in blood, nanoparticles with short half-life in blood flow, etc.52,53

Heavy metals are an important environmental pollutant. For example, mercury ion (Hg2+) is a toxic and non-biodegradable heavy metal, and its accumulation in organisms can have irreparable effects and even cause death. There are many analytical methods for measuring Hg2+, such as UV-Vis spectroscopy, atomic absorption/emission spectroscopy (AAS/AES) and X-ray absorption spectroscopy. These methods require expensive and complicated instruments, so they are very inclined to develop new and more efficient Hg2+ ion detection methods. An effective method of identifying Hg2+ ions requires the use of oligonucleotides. In order to form a thymine-Hg2+-thymine complex (T-Hg2+-T), Hg2+ ions interact with thymine bases, and an aptamer-thymine-Hg2+-thymine nanocomposite for biological applications can also be prepared Things. 54-56

From another perspective, the detection of Hg2+ ions has been regarded as a strategic method through mercury DNA (MSD) functionalized gold nanoparticles (AuNPs) designed for Hg2+ ion detection. The mechanism of this process is based on the T-Hg2+-T complex and inhibits the fluorescence characteristics of AuNPs. The AuNPs-MSD probe is formed by combining fluorescein (FAM) labeled MSD and AuNPs through the Au-S bond. Study Hg2+ detection by changing the fluorescence signal. In addition, this method shows high selectivity to Hg2+ among other metal cations (such as Fe3+, Ca2+ and Mg2+, Cr3+, Mn2+, Cu2+, Ni2+, Pb2+ and Co2+). In addition, this method can be used for Hg2+ detection in aqueous solutions. In addition, this method can be used to detect heavy metal ions in body fluids by combining them with aptamers and forming aptamer nanocomposites. 57-59 Table 2 describes the types of aptamer-based nanostructures used for diagnosis and their advantages and limitations. Table 2 Types of aptamer-based nanostructures and their advantages and disadvantages for diagnosis

Table 2 Types of aptamer-based nanostructures and their advantages and disadvantages in diagnosis

Antibiotic delivery aptamers have been described in many reports. The 65-67 aptamer is used to immobilize antibiotic molecules instead of targeting them. For example, nanocarriers of neomycin (aminoglycoside antibiotic) were developed by aptamers for delivery purposes, where the aptamers immobilize antibiotic molecules through affinity binding. Mesoporous silica NPs (MSNs) may be suitable nanocarriers in stimulus-responsive drug delivery systems. 68-70

In one study, the aptamer gate mechanism was designed using the aptamer (AS1411). By transforming the aptamer sequence into a hairpin structure, the specific molecular phyla of Staphylococcus aureus (bacteria) was obtained. The interaction between the surface antigen of Staphylococcus aureus and the succession of the aptamer destroys the structure of the aptamer. The increase in fluorescence depends on the presence of the objective lens. In this study, SA20hp was selected as a molecular gate aptamer due to its high fluorescence peak response. The destruction mechanism of pathogens is as follows: Van (antibiotic) is absorbed into the pores of MSNs and covered by SA20hp molecules. When the nanoparticles bind to the surface of Staphylococcus aureus cells through the aptamer sequence, Van antibiotics are released to destroy the bacteria. These aptamer-gated silica NPs provide control of antibiotic dosage and unique internal release, and then make it possible to use stronger therapeutic compounds. 71,72 In addition, some well-known articles discussed different analysis methods and biosensors for different types of metal nanoparticles with biomolecules and porous nanomaterials (Figure 2). 73 Figure 2 Due to the binding reaction between ATP aptamer and adenosine molecule, AuNPs-aptamer is capped on the surface of MSA. In the presence of the target molecule (ATP), the delivery of the captured guest (fluorescein) is selectively triggered by an effective displacement reaction. Reprinted with permission from Zhu CL, Lu Qi, Song XY, Yang Huahua, and Wang Xinrui. The biological response of mesoporous silica nanoparticles covered with aptamer-based molecular gates is controlled release. J Am Chem Soc. 2011;133(5):1278-1281. Copyright (2020) American Chemical Society. 73

Figure 2 Due to the binding reaction between ATP aptamer and adenosine molecule, AuNPs-aptamer is capped on the surface of MSA. In the presence of the target molecule (ATP), the delivery of the captured guest (fluorescein) is selectively triggered by an effective displacement reaction. Reprinted with permission from Zhu CL, Lu Qi, Song XY, Yang Huahua, and Wang Xinrui. The biological response of mesoporous silica nanoparticles covered with aptamer-based molecular gates is controlled release. J Am Chem Soc. 2011;133(5):1278-1281. Copyright (2020) American Chemical Society. 73

Nowadays, scientists are looking for new ways to treat and control diseases, such as gene therapy. Gene therapy is a process in which nucleic acids are transferred to patient cells by virus or non-virus carriers to repair defective genes or provide further biological functions. In this method, genes and nucleic acids are used, including plasmid DNA (pDNA), anti-microRNA (miRNA) oligonucleotides, or siRNA. For nucleic acids, physical properties such as negative charge limit their binding to the cell surface and inactive diffusion through the cell membrane. Therefore, the delivery procedure is the only major and difficult challenge in gene and nucleic acid therapy. Although gene delivery through viral vectors is well known, many shortcomings (such as irregular cytotoxicity, etc.) limit their clinical applications. In contrast, non-viral vectors have many advantages, such as low toxicity, no risk of infection, flexibility, and production and modification capabilities. Non-viral vectors (including liposomes, cationic polymers, cationic lipids, peptides and dendrimers) are well-known for their applications in gene delivery. In addition, since the success of gene therapy relies on the effective delivery of genes to specific cells (targeted gene delivery), many targeting ligands (such as antibodies, nanobodies, peptides, and aptamers) have been used to transfer genes and drugs. Metastasis to specific cancer cells. 74–78

Some cancer cells, such as melanoma (skin cancer), are resistant to radiotherapy, have little diagnostic significance, and deform quickly (the BRAF gene mutation in many melanomas makes treatment difficult), so they are in clinical practice today Cannot be treated easily. Compared with ordinary treatments (such as radiotherapy), gene therapy is a sufficient treatment method for melanoma because it has high specificity and low toxicity. Therefore, the use of SiRNA (small RNAi) targeting the BRAF gene for gene therapy may be an effective treatment for melanoma. 79,80

A new strategy proposed by Liyu et al., in which a nuclide targeting liposome is constructed to deliver SiBraf (anti-BRAF SiRNA), is expected to be used for therapeutic purposes (Figure 3). AS1411 is an aptamer with specific binding ability to nucleolar protein. AS1411 is labeled as PEGylated (PEGylated) liposome (ASLP) and used as a targeting probe. AS1411ePEG-Liposomes (ASLP) and siRNA bind to each other through electrostatic means to form an ASLP/siRNA complex. Observation shows that AS1411 aptamer binds to liposomes, targets specific cancer cells (A375) and shows considerable silencing activity in this cell line. Therefore, the application of ASLP and AS411 aptamers to deliver siRNA has shown high efficacy in the treatment of melanoma and should be further studied in clinical trials. 80,81 Figure 3. Schematic diagram of cationic nanoparticles for targeted delivery of siRNA-aptamer chimeras. Fix the pre-formed siRNA aptamer chimera on the positively charged QD-PMAT-PEI nanoparticles. The aptamer block folded on the carrier leads to a decrease in binding activity. Two-step immobilization of the chimera on the surface of cationic nanoparticles. SiRNA molecules with sulfhydryl reactive end groups are first adsorbed on the surface of QD-PMAT-PEI to reduce the positive charge; then aptamers with a single thiol group are introduced to form siRNA-aptamer chimeras on the surface of nanoparticles. Adapted with permission from Bagalkot V, Gao X. SiRNA-aptamer chimera on nanoparticles: retain the targeting function to achieve effective gene silencing. ACS nano. 2011;5(10):8131-8139.82,138 Copyright (2011) American Chemical Society.

Figure 3 Schematic diagram of cationic nanoparticles for targeted delivery of siRNA-aptamer chimeras. Fix the pre-formed siRNA aptamer chimera on the positively charged QD-PMAT-PEI nanoparticles. The aptamer block folded on the carrier leads to a decrease in binding activity. Two-step immobilization of the chimera on the surface of cationic nanoparticles. SiRNA molecules with sulfhydryl reactive end groups are first adsorbed on the surface of QD-PMAT-PEI to reduce the positive charge; then aptamers with a single thiol group are introduced to form siRNA-aptamer chimeras on the surface of nanoparticles. Adapted with permission from Bagalkot V, Gao X. SiRNA-aptamer chimera on nanoparticles: retain the targeting function to achieve effective gene silencing. ACS nano. 2011;5(10):8131-8139.82,138 Copyright (2011) American Chemical Society.

Polyethyleneimine (PEI) is a polycationic molecule that can compress DNA (through the electrostatic interaction between the anionic phosphate of nucleic acid and the primary amine of PEI) into NP, and has a high conversion rate under in vitro and in vivo conditions. Infection efficiency is a very effective non-viral vector. PEI transports gene-containing NPs into the cytoplasm before being degraded by certain enzymes (such as lysosomal enzymes) through the proton sponge (proton buffer) mechanism. For PEI, molecular weight is very important because it affects transfection efficiency. The low molecular weight of PEI represents low cytotoxicity and transfection efficiency. To this end, scientists designed a ligand-coupled PEI vector with low toxicity and high transfection efficiency. Aptamers are the best choice as functional targeting ligands for specific targeting. 83-86

The non-specific binding of the pDNA/PEI complex to the proteoglycan on the cell membrane can result in the inability to transfer genes to specific cells. An outstanding research team has developed methods in which the pDNA/PEI complex is covered with polyadenylic acid (PolyA) as a polynucleotide. Molecular evaluations based on aptamers indicate that these aptamer-coated complexes can enter cells through cellular uptake. In addition, studies have shown that MUC1 is sufficient for tumor targeting. Therefore, Kurosaki et al. synthesized the pDNA/PEI/MUC1 complex for the treatment of cancer cells through targeted gene delivery. In this study, several pDNA/PEI/aptamer weight ratio complexes were constructed. The experiment was done in vivo and in vitro using human and mouse lung cancer cell line A549 cells. The transfection efficiency of aptamer complexes with different weight ratios in vivo and in vitro was studied. The results showed that for A549 cells with MUC1 cell surface protein, the weight ratios of pDNA, PEI and MUC1 were 1:1:0.25, 1:1:0.5, and 1:1:1 pDNA-based aptamer complexes. Material and 1:1:2 increase gene expression. In addition, a large number of MUC1 aptamers reduced the expression of aptamer complex genes. It seems that the strong anionic surface charge acts on the cell membrane, and the recoil may be higher than the binding strength of MUC1 aptamer and MUC1.

In addition, the results indicate that the application of non-specific aptamers reduces transgene expression. In addition, studies have shown that the aptamer complex for tumor-specific gene delivery can be used in other specific gene delivery systems by simply changing the aptamer. Targeting and coating systems may be the pioneer knowledge of cell-specific gene delivery. 87-89

Lymphocytes are the main cell type in the lymphatic pattern. The special functions of these cells (such as reintroduction, mobility and distribution throughout the body) provide conditions for gene therapy of genetic and pathogenic diseases. Hamedani et al. designed a novel complex in which the sgc-8c aptamer is non-covalently bound to the PEI polycation to improve the transfection efficiency of pDNA-targeted gene delivery to MOLT-4 cells. Generally, when there is a balance between the condensation and rapid diffusion of pDNA in the cytoplasm, the efficient transfection of pDNA will be achieved by the vector. Ethidium bromide (EtBr) molecules were used to measure the condensation of DNA and PEI-aptamer conjugates. These molecules show fluorescence until they are contained in double-stranded nucleic acids. By adding PEI to the pDNA/EtBr solution and concentrating pDNA by PEI, because some of the contained EtBrs molecules are released from pDNA and the interaction between them is negligible (because pDNA transforms from a helical structure to a spherical form), the fluorescence intensity reduce. 90–93

In addition, the addition of aptamers has no effect on fluorescence and curve shape. In this study, particle size and zeta potential are additional measurable characteristics. It is necessary to distinguish carriers based on these two factors, because the size of nanoparticles and their surface charges affect the efficiency of gene delivery. By using small particles ≤ 500 nm in size, cells can be absorbed faster and easier and the transfection efficiency can be improved. Generally, in this study, the addition of 10% w/w aptamer (negatively charged) to the 10kDa PEI-pDNA complex resulted in an increase in particle size and a decrease in zeta potential (reduction of net positive surface charge). The positive surface charge of PEI interacts with the negative charge of the cell membrane, causing PEI to become cytotoxic and unstable in the cell membrane. In addition, the cytotoxicity of pDNA-based aptamer complexes was determined for protein tyrosine kinase 7 (PTK7) positive and negative, MOLT-4 (human, peripheral blood, leukemia, T cells) and U266 cell lines. All vectors showed low toxicity. However, by increasing the ratio of PEI/pDNA, the toxicity increased, and the presence of aptamers had no significant effect on cytotoxicity. Researchers have used many strategies to treat lymphocytes, such as treating them with large amounts of genetic material, but because these cells are resistant to most gene transfection systems, the association of the vector increases cytotoxicity. One study used a targeting vector based on aptamer PEI to improve transfection efficiency. Evaluation of the transfection efficiency and targeted delivery of PEI aptamers to PTK7 receptors in MOLT-4 and U266 cell lines showed that in MOLT-4 cells with PTK7 receptors, PEI/pDNA complexes and sgc- The 8c aptamer coupling improves transfection efficiency. In addition, the information shows that the binding of the non-specific aptamer to the PEI/pDNA complex prevents the expression of the luciferase gene. Finally, the results obtained in this study show that labeling the cell-specific sgc-8c aptamer of the PEI vector through electrostatic interaction can improve the transfection efficiency. In addition, the sgc-8c aptamer maintains its conformation after electrostatically binding to PEI, and retains the specificity and dependence of PTK7 to selectively bind to MOLT-4 cells. 94-97

Also in a recent study, a new EpCAM aptamer-PEI- siRNA nanocomposite (PEI-EpApt-SiEP) target (Figure 4). In recent years, by using SELEX technology, RNA and DNA aptamers instead of antibodies have been developed for EpCAM. In addition, siRNA (running in RNA interference (RNAi)) is considered a suitable nucleic acid for targeted gene therapy, especially in humans. In this study, in order to prepare the best PEI nanocore, sodium citrate was used to stabilize its charge. For the synthesis of nanocomposites, siRNA is first added to the PEI nanocore, and then aptamers are added to create a nanocomposite with EpCAM detection capabilities. Since the precise concentration of aptamer (200 nM) and siRNA can saturate the PEI-citrate nanospheres, SiEp and EpApt at the optimized concentration were mixed with PEI-citrate to construct a new PEI-EpApt-SiEp nanocomposite. Since higher concentrations of PEI lead to higher cytotoxicity (ie 3 µg/mL), 0.3 µg/mL PEI was used to functionalize aptamers and siRNA. The Zeta potential and particle size of PEI nanocore and nanocomposite were studied. To evaluate the application of this nanocomplex in in vivo systems, serum was shown to affect the size and charge of the nanocomposite, as determined in RPMI. Figure 4 Schematic diagram of the newly synthesized aptamer-PEI-siRNA nanocomplex (PEI-EpApt-SiEP) and its function of silencing target genes and reducing cell proliferation. The figure is copied from Subramanian N, Kanwar JR, Athalya P, etc. EpCAM aptamers use polymer nanocomplexes to mediate cancer cell-specific delivery of EpCAM siRNA. J Biomedical Science. 2015;22(1):4. Copyright © Subramanian et al.; Licensee BioMed Central. 2015. Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0). 98

Figure 4 Schematic diagram of the newly synthesized aptamer-PEI-siRNA nanocomplex (PEI-EpApt-SiEP) and its function of silencing target genes and reducing cell proliferation. The figure is copied from Subramanian N, Kanwar JR, Athalya P, etc. EpCAM aptamers use polymer nanocomplexes to mediate cancer cell-specific delivery of EpCAM siRNA. J Biomedical Science. 2015;22(1):4. Copyright © Subramanian et al.; Licensee BioMed Central. 2015. Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0). 98

The results show that the difference in size and charge of the nanocomposite is negligible in the presence and absence of serum. Cell uptake and cell binding of the complex (PEI-EpApt-SiEp) were studied in breast cancer and WERI-Rb1 cell lines. Observations showed that, compared with WERI-Rb1 cells, EpCAM protein expression and aptamer binding were higher in MCF-7. Regarding the cellular uptake of these two types of cells, the combination of cells and PEI-EpApt-SiEp resulted in an increase in the intensity of the fluorescence spectrum compared with EpApt alone. Compared with EpApt, the binding of PEI-EpApt-SiEp nanocomplex is stronger, and ScrApt-nanocomplex or ScrApt is not connected to the two cell lines, which indicates the cell specificity of EpCAM aptamer. The silencing effect of EpCAM using the PEI-EpApt-SiEp nanocomplex was evaluated by examining the amount of protein and mRNA using Western blot and qPCR techniques, respectively. When MCF-7 and WERI-Rb1 were treated with PEI-EpApt-SiEp, the down-regulation of EpCAM gene was higher than that of SiEp treatment (64%, 72% and 56%, 62%, respectively). In addition, cells treated with PEI-ScrApt-SiEp and PEI alone did not indicate any EpCAM silencing. Compared with untreated cells, EpCAM protein expression and mRNA levels did not change significantly. For MCF-7 and WERI-Rb1 treated with PEI-EpApt, EpCAM levels were reduced by 38% and 52%, respectively. 98

According to the previously obtained results, although the EpCAM silencing in this method is less than that of siRNA delivered by the targeting antibody, the nanocomposite exhibits more functional activity, and EpApt in the structure induces cytotoxicity, and the overexpression level of EpCAM . This new type of nanocomplex includes aptamers and siRNA, which can effectively target EpCAM-positive cells and has suitable gene silencing activity suitable for in vivo systems. 70,99

Bcl-xL (B-cell lymphoma-extra large) is a transmembrane molecule in the mitochondria. It is a protein with anti-apoptotic properties, which leads to programmed cell death by preventing the release of mitochondrial contents. In many cases, overexpression of Bcl-xL protein can cause lung cancer. Due to some characteristics of lung cells (such as low enzyme activity and wide surface area), gene and drug delivery is an effective treatment for lung cancer. However, a large number of studies have been conducted on the transfer of nucleic acids from PEI derivatives to the lungs, but more attempts should be made to introduce new strategies based on cationic polymer carriers to achieve a more effective gene delivery system. 100-102

Recently, a new vector based on poly(L-lysine) (PLL)-alkyl-PEI copolymer was designed, and the effect of aptamer conjugation on short hairpin RNA (shRNA) plasmid gene delivery efficiency was studied , The gene used in the modified vector is delivered to lung cancer cells. In addition to PEI, PLL is a cationic polymer non-viral vector that can be used for most gene delivery purposes. Both of these polymers have shortcomings that limit their use as gene transfer vectors. In this research, a new type of copolymer carrier including PEI (with DNA condensation ability) and PLL (biodegradable) was designed to overcome the shortcomings of these polymers. To prepare the copolymer, at the beginning, the alkyl carboxylate (6-bromohexanoic acid) was coupled with PLL in three molar ratios. Next, PEI is conjugated with PLL (via caproate connector) to produce PLL-hexanoate-50%-PEI (PLPE36%) copolymer and PLL-hexanoate-10%-PEI (PLPE8%). Carriers have multiple roles in gene delivery (such as carrying nucleic acid cargo and their aggregation and preventing extracellular degradation), so their optimal size and charge density are essential for all medical applications.

These two characteristics are measured by laser Doppler velocimeter and DLS. The results showed that after successful coupling (precise coupling of PEI and alkylcarboxylation-PLL), the positive surface charge and nanoparticle size increased. The buffer capacity of the carrier is very important in polycation-mediated gene delivery. Studies have shown that, unlike PLL, which has a weaker buffering capacity, the copolymer has suitable buffering capacity, which is almost the same as PEI polycation. In addition, fluorescence suppression analysis of EtBr molecules showed that the modified polymer was able to condense DNA with a definite C/P ratio higher than 0.5. The information obtained indicates that the electrostatic interaction from the linkage of the AS1411 aptamer and the modified copolymer can increase the transfection efficiency, while the effect on the charge density and size is negligible. Finally, the aptamer coupled at the determined C/P was selected for shRNA delivery to silence the expression of human Bcl-xL gene in A549 cells. After the shRNA plasmid was transfected with the aptamer-vector system for the Bcl-xL gene, the protein expression and mRNA level of Bcl-xL were significantly reduced. Therefore, this study proposes an effective new vector (apt-PLPE8%) for targeted non-viral gene delivery in lung cancer and lung systems. 77–79,103

It is well known that shRNA and siRNA can be used for therapeutic purposes, and there are two major challenges in targeted gene delivery, including the low toxicity of synthetic vectors and high transfection efficiency. PEI is a polycation, an effective non-viral vector with buffering capacity. In fact, branched PEI is composed of primary, secondary, and tertiary amines, so it can be protonated and provide a buffer. In addition, the molecular weight of PEI also plays an important role in the transfection efficiency of the molecule. As the molecular weight of PEI increases, it will lead to an increase in surface positive charge and a decrease in transfection efficiency. Alkyl carboxylation of PEI can improve transfection efficiency. 104–107

Since single-walled carbon nanotubes (SWNT) easily pass through the plasma membrane, they can be used in delivery systems. Due to the poor solubility of single-walled carbon nanotubes, they cannot be used as effective carriers. By introducing a positive charge on the surface of SWNTs, in addition to simplifying their solubility in water, they can also be attached to negatively charged molecules, including DNA and siRNA. Generally, polycation as the conjugation of PEI is an effective strategy to enhance CNT DNA aggregation. 108,109

For example, a new system based on single-wall nanotubes and piperazine-PEI functionalization and an aptamer for transferring siRNA to breast cancer cells demonstrate that gene delivery can be used to diagnose the presence of cancer cells. EpCAM is a membrane protein that can be overexpressed in tumors and is considered a promising marker for cancer stem cells; it can be a cancer stem cell marker (CSC). In this study, PEI-piperazine was attached to functionalized SWNT. Afterwards, SWNT-PEI-piperazine NPs labeled EpCAM aptamers. In order to combine SWNT with PEI, the surface carbon on SWNT is oxidized to COOH. Therefore, the functional group can be combined with the PEI amine group by forming an amide bond. In order to obtain effective gene vectors, the therapeutic medium must be selectively delivered to specific cells. For this purpose, targeting aptamers are used. Previous studies have shown that the combination between aptamers and NPs improves delivery efficiency. Therefore, the SWNT-PEI-piperazine/DNA complex binds to the EpDT3 aptamer. Observation shows that the transfection efficiency is greatly improved. Therefore, in this study, the effect of the new SWNT-PEI-piperazine NP to transfer BCL91 siRNA to EpCAM cells was evaluated. This type of vector-aptamer derivatives can effectively increase DNA transfection. This strategy can also be used to treat breast cancer through gene therapy. 110-112

In a similar study, a new type of targeted nanocomposite, including PEI-CNT conjugated with 5TR1 aptamer, was used to specifically deliver Bcl-xL shRNA for breast cancer cell therapy. 113 The first step is to synthesize functionalized single-walled SWCN. Since SWCN has negligible solubility in aqueous solutions, they are oxidized by concentrated nitric acid solution at the edge carboxylate groups. In addition, SWNT and poly(ethylene glycol) (PEG)/PEI are covalently bound to prevent aggregation in the biological environment and improve their DNA aggregation ability. PEI (10kDa) is modified with various bromoalkyl carboxylic acids. In fact, the PEI vector produced by the carboxylation of PEI primary amine alkyl has higher lipophilicity, which leads to reduced PEI toxicity and increased gene delivery efficiency. In order to combine PEI and modified PEI with SWCNT-PEG, the -COOH group of PEG is covalently bound to the primary amine of PEI. The formation of modified SWCNT and PEI was verified by infrared spectroscopy. The presence of strong absorption bands at 1645.66 cm-1 and 1657 cm-1 confirms the presence of amide bonds between SWCNT-COOH/PEG and amide-conjugated PEI/SWCNT-COOH-PEG. In order to evaluate the aggregation of pDNA, the fluorescence intensity of NPs was studied in the vicinity of pDNA and EtBr. The decrease in fluorescence intensity proves that pDNA aggregates through SWCNT-PEG-PEI NPs. The evaluation of the results showed that compared with SWNT-PEG-nx%-PEI (with lower primary amine percentage) and SWCNT-PEG modified PEI, SWNT-PEG-PEI can condense pDNA to reduce the C/P ratio, and the size is smaller than At 150 nm, the zeta potential is between 6.3-30.8 mV. This method can study the binding ability of different forms of genetic material with different conjugates of MWCNT, and the morphology of the synthesized MWCNT is an important parameter in the binding ability process (Figure 5). 114 SEM image of Figure 5 Carbon nanotubes: DNA complexes formed at a charge ratio of 6:1: (AC) MWNT-NH3 +: DNA; (DF) SWNT-NH3 +: DNA. Reprinted with permission from Singh R, Pantarotto D, McCarthy D, etc. Combination and condensation of plasmid DNA on functionalized carbon nanotubes: construction of nanotube-based gene delivery vectors. J Am Chem Soc. 2005;127(12):4388-4396.114,139 Copyright (2020) American Chemical Society.

Figure 5 SEM image of carbon nanotubes: DNA complex formed at a charge ratio of 6:1: (AC) MWNT-NH3 +: DNA; (DF) SWNT-NH3 +: DNA. Reprinted with permission from Singh R, Pantarotto D, McCarthy D, etc. Combination and condensation of plasmid DNA on functionalized carbon nanotubes: construction of nanotube-based gene delivery vectors. J Am Chem Soc. 2005;127(12):4388-4396.114,139 Copyright (2020) American Chemical Society.

Since the targeted gene delivery of functionalized NPs through aptamers improves the efficacy of anti-tumor therapy, 5TR1 aptamers are used to complete the targeted gene delivery of NPs. Image analysis showed that about half of the aptamers were covalently bound to the NPs, and the remaining aptamers were electrostatically conjugated to the surface of the NPs. Evaluation of the cytotoxicity of MCF-7 (MUC1+) and MDA-MB231 (MUC1-) with and without aptamer complexes by MTT colorimetric test showed that these cells are not toxic. Evaluation of the transfection efficiency of the complex using Renilla luciferase shows that SWCNT-PEG-10-10%-PEI has the maximum transfection efficiency at a C/P ratio of 6. Finally, use SWCNT-PEG-10-10% vector to transfect plasmid Bcl-xL shRNA into MCF-7 and MDA-MB231 cells (breast cancer cells) and evaluate the expression of Bcl-xL protein. Analysis of the data obtained showed that, unlike MDA-MB231, the expression of Bcl-xL was reduced to 41% by transfecting MCF-7 cells with the plasmid Bcl-Xl shRNA using SWCNT-based aptamer. Therefore, this new nanocomposite containing Bcl-Xl shRNA and SWCNT-based aptamers can be used to induce cell death in MCF-7 cell lines, and of course, MUC1, which has low toxicity, high selectivity and high efficiency. 115 -117

Cancer is the most common disease in the world. Many efforts have been used to treat it more effectively and quickly, with fewer side effects. Although chemotherapy is the most impressive and commonly used method to control cancer, many features that cause cytotoxicity and destructive side effects of healthy cells (such as low specificity, development of drug-resistant cancer cells, etc.) limit its application. In addition, in most cases, drug resistance developed during chemotherapy will eventually lead to chemotherapy failure. In addition to overcoming these difficulties, gene therapy can also inhibit the activity of oncogenes, increase the expression of tumor suppressors, and cause an immune response against tumors. 118,119

In recent years, many scholars have been studying a better way to combine chemotherapeutic drugs with nucleic acids (such as siRNA and shRNA) and use their synergistic therapeutic effects to reduce the harmful side effects and drug resistance of anti-cancer drugs. Designing a safe and effective delivery system is a major challenge for the combined delivery of drugs and genes. 120,121

A new system based on SWCNT-PEG-10-10%-PEI nanocomposite has been designed as an effective tumor-targeted drug gene delivery system. It is suitable for AS1411 modified by SWCNT-PEG-10-10%-PEI. The therapeutic effects of ligand NPs, Bcl-xL shRNA and doxorubicin (Dox, a chemotherapy drug used to treat cancer) have been evaluated. 122 Agarose gel electrophoresis proved the conformation of Apt-NPs. In addition, the obtained results show that 80% of the AS1411 aptamers are covalently bound to the nanoparticles, and the remaining aptamers are electrostatically adsorbed on the surface. The size and surface charge of NPs and NPs-aptamers were measured. The size of the modified fragment of AS1411 aptamer, to be precise, SWCNT-PEG-10-10%-PEI, with pDNA is about 80±3 nm, and the surface charge is 18.15±2.14mv. After attachment, the particle size increased to 109±1.13 nm, and the positive charge decreased to 10.35±2.8 mv. Immunocytochemical analysis and color spot studies proved that nucleolin receptors exist on AGS cells (human gastric adenocarcinoma cell line), but not L929 cells (NCTC clone 929 strain L). In order to prove the main role of AS1411 aptamer in targeting Apt-NP complex to cancer cells, due to the connection of AS1411 aptamer and AGS cell nucleolar protein, AGS cells were saturated with an increased amount of AS1411 aptamer; this The absorption of this aptamer is very low. Therefore, the results indicate that the aptamer has an effective effect on the modified fragments on tumor cells and proved to be the main function of the aptamer in targeted drug/gene delivery.

Evaluation of Bcl-xL inhibition was performed by Western blot analysis. The results showed that in L929 cells and AGS treated with aptamer modified fragments, Bcl-xL shRNA down-regulated the expression of Bcl-xL protein. However, due to the lack of nucleolar protein receptors on L929 cells, adding an aptamer to L929 cells based on SWCNT-based shRNA has no effect on Bcl-xL expression. Therefore, all observations and results confirm that the functionalized CNT-Apt complex can induce cancer cell apoptosis by using Bcl-xL shRNA to down-regulate the Bcl-xL gene. Study the loading of Dox on the surface of SWCNT-PEG-10-10%-PE-aptamer-I/pBcl-xL shRNA by evaluating the fluorescence intensity. The combination of Dox and the complex reduces the fluorescence intensity of free Dox at 595nm. Finally, the synergistic effect of Dox and Bcl-xL shRNA on AGS cells was studied through MTT test. Compared to Dox alone, the combination of Dox (100Nm)/SWCNT-based shRNA resulted in decreased cell viability and increased cell death. Therefore, this high-targeting Dox/Bcl-xL shRNA co-delivery system has a significant anti-tumor effect due to the nanoneedle structure of SWCNT and the combination of aptamers with specific cell nucleolar protein receptors. 122-124

miRNA is a small RNA molecule that plays a major role in RNA silencing and gene expression regulation, and can be used as an important therapeutic agent for tumor gene therapy. As a miRNA, MiR-34a can inhibit the occurrence and development of cancer by reducing the expression level of protein-coding genes such as Bcl-2 and survivin. In addition, in many types of studies, it has been demonstrated that the co-delivery of chemotherapeutic agents and miRNAs through nanosystems exerts effective therapeutic effects both in vivo and in vitro. Scholars are trying to create a stimulus-responsive delivery system that leads to the accumulation of nanocarriers and the rapid release of cargo at tumor sites and within tumor cells. 125-127

Based on the co-delivery capability of ATP-responsive aptamer duplex (aptamer and its supplement ss-DNA) designed with Dox and miR-34a using PEI 25kDa vector, a new ATP-triggered nanosystem has been developed to prevent cell proliferation and migration . The hybridization process is completed to convert the ATP aptamer and its nucleic acid sequence into a duplex. After that, load Dox onto Duplex to create Dox-Duplex. The loading process is evaluated by fluorescence spectroscopy. In addition, the release of Dox in response to ATP is done in the vicinity of ATP. The results show that Dox is released from Dox-Duplex at high concentrations of ATP. Generally, it has been proven that Dox can be encapsulated and released by duplexes suitable for ATP-responsive delivery systems. The PEI 25kDa vector is used to concentrate Dox-Duplex and miR-34a and co-deliver these two cargoes. The best mass ratios of PEI/miR-34a and PEI/Dox-Duplex obtained were 1.5 and 2, respectively, so the ternary nanocomposite with a mass ratio of 3:1.5:2 was used in the following research. The size and zeta potential of this optimal nanocomposite are 262.73±2.32 nm and +33.10±1.25 mv, respectively, which enables the nanocomposite to be used for cellular uptake and anti-tumor efficacy. The fluorescence intensity evaluation confirmed that the intracellular miR-34a/Dox is released through PEI/Dox-duplex/miR-34a because of the high ATP concentration in the cytosol. In addition, it was demonstrated which Dox is placed more in the nucleus and miR-34a is released in both the cytoplasm and the nucleus.

The use of MTT test to evaluate cell proliferation inhibition showed that in various samples, such as PEI, miR-34a, Dox-Duplex, two PEI/Dox-Duplex/miR-34a nanocomplexes showed a significant inhibitory effect on cell proliferation. In addition, a live/dead test was completed to study the anti-proliferative effect. Observation proves that the number of dead cells in the structure of PEI/Dox-Dox-Duplex/miR-34a is more than that of PEI/Dox-Duplex and PEI/miR-34a. In fact, the synergy of Dox/miR-34a (due to the control of cancer cell proliferation through miR-34a's RNA interference and Dox's DNA insertion) and its rapid release lead to significant cell proliferation inhibition. The evaluation of apoptosis was studied by V-FITC/PI and PI staining. In this case, compared with a single cargo structure, the PEI/Dox-Duplex/miR-34a nanocomposites with mass ratios of 3:1.5:2 and 4:1.5:2 showed higher apoptosis. In addition, cell cycle prevention was also evaluated. The results showed that compared with PEI/Dox-duplex, PEI/Dox-duplex/miR-34a reduced the G2 phase. Therefore, it can be concluded that the anti-proliferative effect of the PEI/Dox-Duplex/miR-34a nanocomposite is the result of the death of cancer cells and the process of cycle arrest. The effect of PEI/Dox-Duplex/miR-34a on the expression level of specific proteins was studied, and the results showed that Dox/miR-34a co-delivery could prevent Bcl-2 expression. In addition, observations indicate that ATP response to the co-delivery system causes significant cell migration inhibition. Therefore, the PEI/Dox-Duplex/miR-34a nanocomposite has a synergistic effect and ATP-triggered multi-load release, which can have effective anti-proliferation and anti-migration effects. 128-130

In recent years, scholars have tried to synthesize new nanosystems with targeted drug delivery and controlled drug release capabilities. Polymers sensitive to acidic environment and proton sponge effect of lysosomes can accelerate drug release and siRNA in tumor cells. 131 For example, a new grafted polymer micelle was synthesized as a carrier with double-stranded pH/redox sensitivity and AS1411 aptamer as a targeting ligand carrying genes and anti-cancer drugs. The chitosan-ss-PEI-urethane acid (CSO-ss-PEI-UA, (CPU)) graft polymer was synthesized through the acylation reaction between the primary amine of CSO or PEI and the carboxyl group of UA. 1H NMR evaluation showed that PEI was conjugated with CSO-ss and UA was introduced into CP. In the CPU copolymer, CSO is covalently connected to PEI through disulfide bonds to reduce the positive surface charge of PEI and UA as a hydrophobic agent, and is added to the Dox load. In addition, in order to reduce the cytotoxicity of CPU micelles and improve its safety and efficiency as a carrier, AS1411 aptamer (which specifically binds to nucleolar protein and is highly expressed in the membrane of cancer cells (such as A549 cells)) is used as CPU The micelles are added to the CPU micelles. Targeting ligand. 1H NMR evaluation shows that the CPU copolymer and AS1411 aptamer are covalently bound together. The TEM image of AS1411-chitosan-ss-polyethyleneimine-urethane acid (ACPU) micelles showed a particle size of 124.6±1.068 nm and an average zeta potential of 24.2±0.529 mV. In addition, the comparison of the CD spectra of AS1411 aptamer and ACPU confirmed that the secondary structure of AS1411 aptamer was preserved after being connected to the CPU micelle. In addition, the low critical micelle concentration (CMC) of the ACPU copolymer indicates that it self-assembles into stable micelles in vitro.

The pH/redox sensitivity of ACPU micelles was determined by examining the changes in micelle size during incubation in weakly acidic phosphate buffered saline (PBS) and PBS plus GSH. Using PBS (pH 7.4)+GSH and PBS (pH 5.1), the micelles swelled from 124 nm to 365.3 and 622.6 nm, respectively. GSH enhances the release of drugs and genes by breaking disulfide bonds. Dox release in Dox micelles and siRNA release in micelles are performed in pH 5.3 PBS or GS​​H 10Mm. These two factors include the protonation of UA in an acidic environment and the rupture of disulfide bonds under reducing conditions leading to the rapid release of Dox and siRNA.

Cell uptake experiments show that Dox and siRNA are delivered to cells through micelles and then released into the nucleus and cytoplasm. Therefore, these results demonstrate that the drug and Dox are simultaneously delivered to the cell via the Dox-siRNA ACPU micellar system. In order to specify the transfection efficiency of siRNA-ACPU micelles, toll-like receptor 4 (TLR4) mRNA levels and protein expression were evaluated by quantitative polymerase chain reaction (qPCR) and Western blot techniques. After treatment with siRNA-ACPU micelles, the mRNA level and protein expression of TLR4 decreased. The anti-tumor efficacy of Dox-siRNA ACPU micelles was evaluated by the luc-A549 cell orthotopic tumor model. The results confirmed that tumor suppression from Dox-siRNA ACPU micelles was very significant. In addition, Dox-siRNA ACPU micelles down-regulate TLR4 protein levels to prevent tumor invasion and improve tumor treatment effects. It is promising to use this novel co-delivery nanosystem in other related diseases. 57–59,132–134

Table 3 describes the structure types based on aptamers and their roles in gene delivery systems. Table 3 Structure types based on aptamers in gene delivery systems

Table 3 Structure types based on aptamers in gene delivery systems

The scientific community is looking for new technologies to control, diagnose and treat diseases through gene therapy. Gene therapy is a treatment process that transfers nucleic acid to patient cells through viral or non-viral vectors to repair defective genes or provide further biological functions. Pathogenic diseases are some of the most common diseases that threaten many people all over the world through microorganisms. One of the most important goals of cancer research is to specifically target cancer cells, thereby improving the effectiveness of treatment and reducing the side effects of drugs and genes. Since the appearance of aptamers, we have made significant progress in the past two decades. So far, various types of anti-cancer drugs (such as chemotherapy drugs and siRNAs) have been successfully delivered to cancer cells in vitro. However, only a few studies have achieved successful delivery of gene-based drugs to tumor tissues after systemic injection of aptamer-based compounds. In fact, before realizing aptamer-based drugs, we still need to do more work, including clinical trials and the final management of daily cancer patients. The AS1411 aptamer has been used in multiple stages of clinical trials, and it represents a candidate approved by the U.S. Food and Drug Administration (FDA).

With the progress of this field, the inefficient transfer of antibiotics to infected cells and the control of side effects and release rate are considered to be important problems that aptamers can solve. In recent years, targeted therapies for gene therapy and pathogenic diseases have been developed based on aptamer hybrid nanocomposites to overcome these problems.

Nanotechnology will also play an important role in the delivery of genes and therapeutic agents in the future. The production of nanostructured complexes will improve the efficiency of aptamer transfer and delivery. The large surface area of ​​NPs can play an important role in the simultaneous binding of multiple aptamers and targets. However, there are many challenges in providing genes based on NPs. In many cases, delivery and increased permeability may be effective, such as liposome-based drugs that have been approved by the FDA. However, the half-life of NPs is important because if it is too long, certain nanoparticle chemicals may cause toxicity in different organs, requiring more optimization and research.

Generally, aptamers can form constructive interactions between different types of structures and lead to positive selection for any given goal. The chemical structure, geometry, and relative reactivity with target molecules make them a cost-effective and valuable choice for many disease diagnosis, treatment, and array-based applications. In addition, the different attachment mechanisms of aptamers and antibiotic molecules provide valuable affinity ligands, making this field of research very worthwhile.

This article does not contain any research conducted by any author on human or animal subjects.

The construction of this review follows all ethical standards.

All authors declare that they have no conflicts of interest.

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