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The specific DNA is typically impermeable to the plasma membrane due to its natural characters, but DNA tetra structures (DTNs) can be readily uptake by cells in the absence of transfection agents, providing a new strategy to deliver DNA drugs. In this research, the delivery efficiency of tetrahedral DNA nanostructures was measured on adenocarcinom...
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Citations
... 128 Moreover, the DTNs-AS1411 delivery system induced A549 cell apoptosis through regulating the BCL-2/BAX ratio. 129 in vivo administration showed no acute biotoxicity during the first day post injection which could lead to a novel potential strategy for LC therapy. 129. ...
... AS1411, an aptamer conjugated with nucleolin overexpressed on the surface of cancer cells, was attached to tFNA at one vertex, and was reported to improve the efficiency of cellular endocytosis to deliver therapeutic and imaged tFNA. 58,59,[106][107][108][109] Similarly, Ma et al. adopted an anti-HER2 aptamer carried by tFNAs to target HER2-positive breast cancer cells. These HER2-tFNA complexes mediated the breast carcinoma cell apoptosis and inhibited their growth. ...
With the emergence of DNA nanotechnology in the 1980s, self-assembled DNA nanostructures have attracted considerable attention worldwide due to their inherent biocompatibility, unsurpassed programmability, and versatile functions. Especially promising nanostructures are tetrahedral framework nucleic acids (tFNAs), first proposed by Turberfield with the use of a one-step annealing approach. Benefiting from their various merits, such as simple synthesis, high reproducibility, structural stability, cellular internalization, tissue permeability, and editable functionality, tFNAs have been widely applied in the biomedical field as three-dimensional DNA nanomaterials. Surprisingly, tFNAs exhibit positive effects on cellular biological behaviors and tissue regeneration, which may be used to treat inflammatory and degenerative diseases. According to their intended application and carrying capacity, tFNAs could carry functional nucleic acids or therapeutic molecules through extended sequences, sticky-end hybridization, intercalation, and encapsulation based on the Watson and Crick principle. Additionally, dynamic tFNAs also have potential applications in controlled and targeted therapies. This review summarized the latest progress in pure/modified/dynamic tFNAs and demonstrated their regenerative medicine applications. These applications include promoting the regeneration of the bone, cartilage, nerve, skin, vasculature, or muscle and treating diseases such as bone defects, neurological disorders, joint-related inflammatory diseases, periodontitis, and immune diseases.
... This methodology was also able to reduce cardiotoxicity frequently related with doxorubicin administration. An alternative strategy relies on the use of DNA tetrahedra structures (DTNs), a 3D molecular cage formed with four DNA chains, that comparably to naked DNA offer greater AS1411 flexibility in design and functionality and probably higher stability in cells ( Figure 3B) [40]. In this case, AS1411 was bound to a DTN and administrated in in vitro lung cancer models, where it was observed that DTN itself at different concentrations was not toxic for these cells. ...
... (A) AS1411 as a targeting agent in a multifunctional aptamer-based system in which a double stranded (5′-GC-3′ or 3′-GC-5′ base pairs) is used to deliver the doxorubicin[39]. (B) DNA tetrahedra structures (DTNs), formed with four molecules of AS1411 bound[40]. (C) 4-arm DNA/RNA construct, with one of the arms presenting the AS1411 and the remaining constituted by different siRNA strands (anti-AKT, anti-MDM2 and anti-Survivin)[41]. ...
... (A) AS1411 as a targeting agent in a multifunctional aptamer-based system in which a double stranded (5 -GC-3 or 3 -GC-5 base pairs) is used to deliver the doxorubicin[39]. (B) DNA tetrahedra structures (DTNs), formed with four molecules of AS1411 bound[40]. (C) 4-arm DNA/RNA construct, with one of the arms presenting the AS1411 and the remaining constituted by different siRNA strands (anti-AKT, anti-MDM2 and anti-Survivin)[41]. ...
G-quadruplexes (G4s) are a class of nucleic acids (DNA and RNA) with single-stranded G-rich sequences. Owing to the selectivity of some G4s, they are emerging as targeting agents to overtake side effects of several potential anticancer drugs, and delivery systems of small molecules to malignant cells, through their high affinity or complementarity to specific targets. Moreover, different systems are being used to improve their potential, such as gold nano-particles or liposomes. Thus, the present review provides relevant data about the different studies with G4s as drug delivery systems and the challenges that must be overcome in the future research.
... Furthermore, easy absorption and biodegradation of DNA tetrahedral sequences avoid long-time retention. Guanine-rich aptamer drugs, such as AS1411, have been successfully delivered into A549 tumor cells and performed as targeting agents and inhibitors [18]. Immune regulatory factors, such as CpG and siRNA, can also be delivered to tumor cells via DNA tetra carrier to regulate immune responses [19]. ...
As a nano-sized drug carrier with the advantage of modifiability and proper biocompatibility, DNA tetrahedron (DNA tetra) delivery is hopeful to enhance the inhibitory efficiency of nontargeted anticancer drugs. In this investigation, doxorubicin (Dox) was assembled to a folic acid-modified DNA tetra via click chemistry to prepare a targeted antitumor agent. Cellular uptake efficiency was measured via fluorescent imaging. Cytotoxicity, inhibition efficiency, and corresponding mechanism on colon cancer cell line HT-29 were evaluated by MTT assay, cell proliferation curve, western blot, and flow cytometry. No cytotoxicity was induced by DNA tetra, but the cellular uptake ratio increased obviously resulting from the DNA tetra-facilitated penetration through cellular membrane. Accordingly, folic acid-DNA tetra-Dox markedly increased the antitumor efficiency with increased apoptosis levels. In details, 100 μM was the effective concentration and a 6-h incubation period was needed for apoptosis induction. In conclusion, nano-sized DNA tetrahedron was a safe and effective delivery system for Dox and correspondingly enhanced the anticancer efficiency.
G-quadruplex (G4) aptamers that can competitively binding protein with oncogene promoter G4 hold promise for cancer treatment. In this study, a neutral cytidinyl lipid, DNCA, was shown to transfect and...
Simple Summary
The use of drugs based on nucleic acids is a promising direction in antitumor therapy. Some modified oligonucleotide analogs, such as antisense oligonucleotides, have been developed and used as innovative therapeutic agents in some areas of medicine. Many ways to build DNA nanomaterials with predefined shape and function characteristics have been designed. Thus, molecules of potent antitumor drugs, including doxorubicin, therapeutic oligonucleotides, and complex nanoparticles, have been loaded into or conjugated with DNA-based nanomaterials. It was found that DNA-based nanomaterials can increase the efficiency of drug uptake by cells. In this review, we would like to draw attention to some DNA-based nanomaterials, such as tetrahedrons, origami, DNA nanotubes, and aptamers, that have been used as carriers, drugs or target molecules for anticancer drug delivery.
Abstract
DNA nanotechnology has significantly advanced and might be used in biomedical applications, drug delivery, and cancer treatment during the past few decades. DNA nanomaterials are widely used in biomedical research involving biosensing, bioimaging, and drug delivery since they are remarkably addressable and biocompatible. Gradually, modified nucleic acids have begun to be employed to construct multifunctional DNA nanostructures with a variety of architectural designs. Aptamers are single-stranded nucleic acids (both DNAs and RNAs) capable of self-pairing to acquire secondary structure and of specifically binding with the target. Diagnosis and tumor therapy are prospective fields in which aptamers can be applied. Many DNA nanomaterials with three-dimensional structures have been studied as drug delivery systems for different anticancer medications or gene therapy agents. Different chemical alterations can be employed to construct a wide range of modified DNA nanostructures. Chemically altered DNA-based nanomaterials are useful for drug delivery because of their improved stability and inclusion of functional groups. In this work, the most common oligonucleotide nanomaterials were reviewed as modern drug delivery systems in tumor cells.
Seeman's pioneer idea has led to the foundation of DNA nanostructures, resulting in a remarkable advancement in DNA nanotechnology. Over the last few decades, remarkable advances in drug delivery techniques have resulted in the self-assembly of DNA molecules for encapsulating candidate drug molecules. The beauty of DNA nanostructures is their nuclear targeting capability with high spatial addressability and tremendous potential for active nucleus targeting. However, effectively programming and assembling those DNA molecules remains a challenge, making the path to DNA nanostructures for real-world applications difficult. Because of their small size, most nanostructures are self-capable of infiltrating into the tumor cellular environment. Furthermore, to enable controlled and site-specific delivery of encapsulated drug molecules, DNA nanostructures are functionalized with special moieties that allow them to bind specific targets and release cargo at only targeted sites rather than non-specific sites, resulting in the prevention/limitation of cellular toxicity. In light of this, the current review seeks to shed light on the versatility of the DNA molecule as a targeting and encapsulating moiety for active drug molecules in order to achieve controlled and specific drug release with spatial and temporal precision. Furthermore, this review focused on the challenges associated with the construction of DNA nanostructures as well as the most recent advances in DNA nanostructures functionalization using various materials for controlled and targeted delivery of medications for cancer therapy.
The development of effective drug delivery system is highly important for targeted tumor therapy. Over the past few decades, a number of biomaterials have been extensively explored as potential drug loading vehicles. Among them, DNA has emerged as a highly promising scaffold to construct drug delivery systems, owing to its excellent biocompatibility, precise programmability, multifunctionalities, structural predictability, and versatile modifications for improved biostability. Herein, the drug delivery systems that purely comprise of DNA are reviewed. Drugs can be incorporated into DNA via distinct mechanisms, and various DNA architectures have been developed to load different types of anti-tumor therapeutics. For therapeutic applications, we focus on their intracellular delivery and drug release, and DNA-based platforms with different cellular uptake pathways and stimuli-responsive drug release profiles are discussed. Finally, there search opportunities of the field are speculated to pave the way for future research direction.
Guanine-rich oligonucleotide (GRO) can be developed as an effective anticancer agent owing to its high selectivity, affinity and antiproliferative activity in cancer cells. In this study, to increase the potency of GRO29A, a 29-mer GRO aptamer against nucleolin, an overexpressed protein in cancer cells, GRO29A was incorporated into three or six pods of polypod-like structured DNA (polypodna), tripodna or hexapodna, respectively. The polypod-like structured GROs, tri-G3, consisting of one tripodna and three GRO29A, or hexa-G1, hexa-G3 or hexa-G6, each of which comprises one hexapodna and one, three or six GRO29A, respectively, were designed. Tri-G3, hexa-G1 and hexa-G3 were prepared in high yield, except for hexa-G6. Polypod-like structured GROs had quadruplex structures under physiological salt conditions, and degraded at a slower rate in buffer containing serum. Cellular interaction experiments using fluorescently labelled DNA samples showed that the uptake of hexa-G3 by nucleolin-positive MCF-7 cells was more than 2-fold higher than GRO29A, and the interaction was increasingly dependent on the number of GRO29A in the structures. Hexa-G3 inhibited the proliferation of MCF-7 cells in more than 40%, but not of CHO cells. These results indicate that polypod-like structured GROs are useful DNA aptamers with high selectivity and cytotoxicity against nucleolin-positive cancer cells.
