Aptamers as outstanding agents for targeting of nanoparticulate systems

Review Article

Mahdiyeh Karimpour¹, Shabnam Hashemi^2,*

¹ Student Research Committee, Azad University, Tabriz Branch, Tabriz, Iran.

²Faculty of Novel Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.

Abstract

Aptamers can selectively bind to specific targets. In recent years, the progress in methods to select cell-specific aptamers has presented novel applications for these molecules in targeted drug delivery areas. In the present review, the chief emphasis will be on aptamer-nanoparticulate organizations for drug delivery aims. According to literature, polymeric nanoparticles, metallic nanoparticles, inorganic nanoparticles and, carbon nanotubes can form perfect complexes with aptamers. Porous nanoparticles also can apply as stimuli-responsive capping carriers to form intelligent drug delivery schemes. Aptamers can cover the pores of nanoparticles as biomolecular cap and then they can be considered as gatekeepers. Besides, different contrast agents can also be inserted to produce versatile nano-systems. Delivery systems based on aptamer-nanoparticle conjugations will be used as a unique therapeutic agent for the controlled release of drugs in the near future.

Keywords: Aptamer, Nanoparticles, Biomolecular cap, Drug delivery.

1. Introduction

To efficient delivery, the therapeutic agents must be accumulated in the relevant tissue [1]. Innovative drug delivery structures can improve therapeutic efficacy and decrease side-effects by concentrating the therapeutic materials at specific locations in the body [2-5]. Many kinds of drug delivery systems have been extended for targeted uses. Smart drug delivery systems are the chief group of them that possess the ability to regulate drug release rates in reply to a physiological need [6, 7]. The intelligent drug delivery systems that use molecular targeting agents are advanced for many requests such as isolation, detection, and, the release of the therapeutic agents [8]. Aptamer as a new class of molecular targeting agents has introduced in 1990 by Ellington and Szostak [9]. They reported on the production and characterization of aptamers during their studies on self-splicing group I introns and ribozymes [10]. In fact, aptamers are the artificial nucleic acid sequences that can bind specific targets.  In other words, they are single-stranded short oligonucleotide sequences with high affinity to specific targets [11].

The aptamer screening process is known as the systematic evolution of ligands by exponential enrichment (SELEX) [9-11]. To find aptamers, large libraries of ssDNA or RNA can screen which selectively bind to target by in vitro system. So far, various modified methods for the selection of aptamers have been developed the random pool of 1014–1016 molecules [11, 12].

Targeted delivery of therapeutic agents has always been a wanted purpose to achieve maximum efficiency in the body.  Drug delivery systems in the form of nanoparticles are in the core of attention due to the improvement of the therapeutic efficiency of the drugs [13, 14]. Aptamers are influential targeting agents for nanoparticles owing to their relatively straightforward immobilization on nano-surfaces without changing the affinity properties [10, 15]. The functionalization of nanoparticles with molecules such as aptamers has shown promising applications in the biomedical areas.  Like antibody-antigen reaction, aptamers interact directly with their targets by a binding reaction. Owing to their molecular nature, aptamers have some advantages compared to antibodies such as; low toxicity and immunogenicity, providing a long shelf-life, high stability, easy and low-cost production methods, can tolerate heat up to 95°C or various solvents or harsh environments and able to return to their original confirmation [16-18]. Macugen® is the first aptamer-based drug for the treatment of age-related wet macular degeneration. The system is based on the PEGylated form of an antivascular endothelial growth factor aptamer [19]. Some other aptamer-based drugs are in numerous steps of training as well. In the present review, we will briefly focus on aptamer- nanoparticle conjugation schemes for drug delivery aims.

2. Aptamer-nanoparticle conjugations

Nanotechnology is the science of the engineering of functional materials or systems at the molecular scale [20]. These nanomaterials have unique physical, optical and electronic properties [21]. Aptamers themselves can home to their specific targets even in vivo media (figure 2). According to reports, aptamer-nanoparticle conjugates have been used for vast applications include; in vitro detection of cancer cell, in vivo imaging, targeted drug delivery and especially as dual nanoparticles for magnetic extraction and fluorescent labeling [10, 12, 17]. Recently, due to their eminent potentials, aptamers are used as aptamer-nanoparticle conjugates for smart drug delivery. When these conjugates applied as carriers bound with therapeutic agents (drugs or functional proteins), they enable targeted and controlled drug delivery [22]. Drugs can be encapsulated in nanoparticles either covalently or non-covalently. Electrostatic adsorption and hydrophobic interaction are frequently used for non-covalent introduction of therapeutic agents [10, 22].

Many desirable properties of aptamers such as small size, lack of immunogenicity and ease of isolation lead to their rapid development in biomedical applications as drug delivery vehicles. Nanoparticles- aptamer conjugations can categorize into polymeric nanoparticles, metallic nanoparticles, and inorganic nanoparticles. Carbon nanotubes also formed ideal and potent complexes with aptamers. A brief sight of each system is presented in the following [23, 24].

3. Aptamer – metal nanoparticles

The combination of the unique possessions of metal nanoparticles and the various outstanding potentials of aptamer leads to potent nano-conjugates. This binding can improve the traditional or common applications of metals in diagnosis, treatment and prevention of diseases.

3.1. Gold nanoparticles

gold nanoparticles due to their nontoxicity, high ability to functionalization, polyvalent effects, ease of detection and photothermal activity are considered to be so valuable in the development of aptamer-gold nanoparticle conjugates [25, 26]. The natural affinity of sulfur for gold leads to quite facile attachment compared to the more complex attachment used for nucleic acids and some other metallic nanoparticles [27, 28].  The drug was then physically attached to the aptamer- gold nanoparticle conjugates and delivered to the target cells [29]. Shiao and et al tested aptamer- gold nanoparticles to deliver two anticancer drugs for enhancing drug efficiency. The surface of gold nanoparticles was capped with AS1411 aptamers. According to authors this co-delivery system successfully improved the therapeutic effectiveness in tumor cells [29]. Gold nanoparticles offer also other sole possessions that convert them to ideal recognition materials. Their aggregation or disaggregation caused to the color change and then attachment of them to the aptamers has been used in the expansion of analyses and tests. The color alteration can be detected with the naked eye and can be applied in the pregnancy test [30, 31].

3.2. Silver nanoparticles

It has been demonstrated that silver is locally used as an antibacterial agent even in the ultra-low concentrations and conjugation of it with aptamer can make it possible to use in treating infections anywhere in the body [32]. It has also been demonstrated that aptamer- silver nanoparticle has proper biocompatibility and stability. Therefore, these conjugations not only can act as a high contrast imaging agent for both dark-field light scattering microscope and Transmission electron microscopy (TEM) imaging but also can inspire supersensitive single nanoparticle spectra for potential intercellular microenvironment analysis [33]. Aptamer- silver nanoparticles also can be designed as an optical probe for simultaneous intracellular protein imaging and single nanoparticle spectral analysis, wherein silver nanoparticles performance as a luminophore and the aptamer as a biomolecule specific detection part, respectively [33].

3.3. Silica nanoparticles

Silica nanoparticles have involved much investigation care as a consequence of their biocompatibility and ease of preparation, as well as surface alteration [34, 35]. Besides, silica mesoporous nanoparticles can be used as intelligent capping to make intelligent delivery schemes. To achieve cell or tissue specificity the surface of silica mesoporous nanoparticles can be modified with organic molecules, peptides, aptamers and antibodies. Aptamers can be caped the pores of nanoparticles as biomolecular cap agent and then these nanoparticles can be considered as gatekeepers. Different triggers such as alteration in pH, light, enzymatic action, reducing environment, ultrasound or, electromagnetic field are used to eliminate cap from nanoparticle and then the drug release is achieved.

3.4. Magnetic nanoparticles

Magnetic nanoparticles can be applied to physically directing aptamer-magnetic nanoparticle to their wanted and available target cells or tissues applying an external magnetic field [27]. Due to potent recompences such as perfect surface modification, competency to move at cellular level by an external magnetic field and ability to heat the particles after internalization (hyperthermia effect) magnetic nanoparticles have a specific position in nanomedicine [17, 37, 38]. The functionalization of these nanoparticles with aptamer recovers their application, particularly in cancer therapy areas. In general, a functional magnetic nanoparticle may consist of a number of components include the magnetic core, the protective coating, organic linker and the surface functionality group(s). Magnetic nanoparticles should also possess active cargo for biomedical applications according to application case. The active cargo can be bounded to the surface of these nanoparticles and then can be released in the target site [39,40].

4. Aptamer- inorganic nanoparticles

Inorganic nanoparticles can be used as materials to the controlled release of drugs from the delivery system [41]. [42, 43]. The functionalization of inorganic nanoparticles with aptamers may lead to excellent drug delivery systems. Aptamers can act as a dual-functional molecule that performances as not only a targeted molecular agent but also as a cap for porous inorganic nanoparticles [44, 45]. Either intracellular or external triggers can apply to remove the cap from nanoparticle and then the drug release is performed.

4.1. Calcium carbonate (CaCO3) nanoparticles

CaCO3 nanoparticles have been used more in drug delivery owing to their longer biodegradation times [46, 47]. The pH-sensitive possessions of CaCO3 nanoparticles have been stated in various studies [48, 49]. Generally, a carrier with pH-related futures can be a good applicant for drug delivery to cancer tissues as tumors are generally more acidic than in normal tissues [49-51].

An aptamer- CaCO3 nanoparticles loaded with doxorubicin was developed by Zhou et al. Their results showed that these smart nanostructures can precisely be bound and internalized to target cancer cells. Then, they can selectively have reached the lysosomes via receptor-mediated endocytosis and at relatively low lysosome pH (4.5–5.5), doxorubicin was easily released [49]. Figure 3 shows aptamer-CaCO3-drug nanoparticles which selectively reach the lysosomes through receptor-mediated endocytosis and the release of drug is done in an acidic condition of the lysosome.

4.2. Hydroxyapatite nanoparticles

Hydroxylapatite, also called hydroxyapatite (HA), is a natural mineral material with the formula Ca5(PO4)3(OH). Recently nanoparticles of HA have engrossed more helpfulness in drug delivery fields owing to their brilliant belongings such as bioactivity, biocompatibility, pH- sensitivity and osteoinductivity [52]. HA can combine with the drug molecules via different types of bonds so that the drug maintains intact until it reaches the target location. These nanoparticles can also slowly degrade and therefore it delivers the drug in a controlled way [53].

A controlled-release hydroxyapatite nano-carrier was developed using cell-type-specific aptamers as a cap. Aptamers play a dual-functional role that acts as a cover for capping of pores of HA and also as a targeted molecular that can effectively concentrate in cancer cells. When the doxorubicin-loaded type of these nanoparticles was incubated with MCF-7 cells, they internalized into MCF-7 cells. Due to the acidic condition of cancer cells, the opening of pore opening and release of drug results. Furthermore, owing to the high biocompatibility and biodegradability of these nanostructures, they can use as a contrast agent of targeting fluorescence and magnetic resonance imaging [44].

5. Aptamer-polymeric nanoparticles

Polymeric nanoparticles are fine polymeric particles with a size variety of nanometer. These particles can be in different forms and structures such as spherical, branched, or core-shell constructions [54]. Normally polymer-drug conjugations are not considered as nanoparticles except their size can be organized within 100 nm [54].

5.1. Aliphatic polyesters

Biodegradable and biocompatible polymers with controlling release are preferred for therapeutic applications [55]. Aliphatic polyesters such as polylactic acid (PLA) and polyglycolic acid (PGA), and their well-known copolymer poly lactic-co-glycolic acid (PLGA) are current polymers which have been used in controlled release in pharmaceutics [23, 56]. PLA and PLGA are broadly applied for preparing polymeric nanoparticles–aptamer conjugates [57, 58]. The drug can be encapsulated in their hydrophobic cores and can be successfully released in a controlled manner and then allow to moderate constant doses over extended periods of time [55, 59].

5.2. Chitosan nanoparticles

This material and its derivatives are so valuable resources for pharmaceutical aims [60]. They are very tough polymers of N-acetyl-D-glucosamine with highly cationic nature [61]. The highly cationic nature makes them very valuable for drug and aptamer delivery. If chitosan nanoparticles properly targeted using antibodies, magnetic nanoparticles, and aptamers, they have been evaluated for overpass from the blood-brain barrier [27]. Recently Chen et al investigated chitosan nanoparticle – aptamer complexes [62]. They found that these complexes have high efficiency and low cytotoxicity for delivering aptamers to the cell. According to authors this carrier system is able to preserve and prolong aptamer S58 antagonized TGF- β- induced myofibroblast trans differentiation in human tenon’s capsule fibroblasts (HTFs) [62]. Some other polymers such as poly (orthoesters), poly (caprolactone), poly (butyl cyanoacrylate), polyanhydrides, and Poly-N-isopropyl acrylamide are used in formulating polymeric nanoparticles for biomedical applications [27].

6. Carbon nanotubes (CNT)

CNTs are a hollow cylindrical form of carbon in the nanometer range which has been synthesized by Lijima in 1991 [63]. Since then, CNTs have been used in many fields of science. The antimicrobial action of carbon-based nanomaterials (especially single-walled nanotubes) may remarkably be examined due to their high surface/volume ratio, large inner volume, and other distinctive chemical and physical belongings. Then aptamer – single-walled nanotube conjugate might better be direct the action of these nanoparticles. The hollow edifices of CNTs can be loaded with drug molecules for prolonged release of drugs [64, 65].

Improved targeted delivery of daunorubicin to acute lymphoblastic leukemia was reported by Taghdisi et al. They prepared a complex of Sgc8c aptamer, daunorubicin, and single-walled nanotube and their results presented that this tertiary complex can internalize successfully into human T cell leukemia cell (MOLT-4 cells) but not to U266 myeloma cells  [66]. Other hydrophobic drugs such as paclitaxel and docetaxel have also been attached to CNT’s surface but due to their comparatively bulky structure, their loading efficiency and stability were much lower [67].

7. Conclusion

Molecular recognition of specific cells has a key role in the diagnosis and therapy of acute diseases such as different types of cancer. Aptamers are a potent group of ligands with applications in numerous biomedical arenas. Because of their various capacities, aptamer-nanoparticle conjugations have gained great attention in the drug delivery field. The unique possessions of aptamers are applied in composed with nanoparticles as useful conjugates for biomedical sensing, detection, and as well as intelligent drug delivery. The conjugates of aptamers with nanoparticles provide controlled delivery of drugs. Targeted drug delivery carriers will haply have a role in future therapeutic quality. Owing to the limited number of aptamers, determination and expansion of more novel aptamers particularly for cancer cells look to be essential. Although aptamers cannot be substituted antibodies, they will show their particular role of applications.

Acknowledgments

The author state that there is no financial support for this study.

Conflict of interest

The author has no conflict of interest in this paper.

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HOW TO CITE

Karimpour, M., Hashemi, S., & Maleki Dizaj, S. (2019). Aptamers as outstanding agents for targeting of nanoparticulate systems. Journal of Advanced Chemical and Pharmaceutical Materials (JACPM), 2(2), 142-149. Retrieved from http://advchempharm.ir/journal/index.php/JACPM/article/view/92

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