Deoxyribozymes as Catalytic Nanotherapeutic Agents

Khachigian, Levon M.

doi:10.1158/0008-5472.can-18-2474

Cited by 43 publications

(39 citation statements)

References 104 publications

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“…Among the therapeutic strategies, deoxyribozymes (DNAzymes) are a new class of synthetic DNA molecules, which could specifically bind its target mRNA through the base-pairing mode and then realize the cleavage of mRNA 9,10. As the most important member, the “10–23” subtype of DNAzyme exhibited a favorable catalytic activity to cleave the target mRNA between unpaired purine and paired pyrimidine through the de-esterification reaction 11,12. Particularly, a therapeutic DNAzyme Dz13 targeting and cleaving the c-Jun mRNA has been demonstrated to significantly inhibit the tumor growth through the induction of caspase-2 activation 13–17.…”

Section: Introductionmentioning

confidence: 99%

<p>Inhibition of proliferation and migration of tumor cells through phenylboronic acid-functionalized polyamidoamine-mediated delivery of a therapeutic DNAzyme Dz13</p>

Yang¹,

Zhang²,

Xing³

et al. 2019

IJN

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Background The phenylboronic acid-functionalized polyamidoamine (PP) was employed as a gene carrier for Dz13 delivery, inducing an obvious anticancer response. Materials and methods The Dz13 condensation ability of PP was evaluated through gel retardation assay. The cellular uptake mechanism of PP/Dz13 nanoparticles was studied using confocal laser scanning microscope and flow cytometer. The inhibition ability of cell proliferation, migration and invasion was investigated through MTT assay, flow cytometry, wound healing and Transwell migration assays, using hepatocarcinoma cell line HepG2 as a model. Finally, Western blotting analysis was used to detect the signaling pathway associated with the inhibition of cell apoptosis and migration induced by Dz13 delivery. Results The carrier PP could efficiently condense Dz13 into stable nanoparticles at mass ratios of >1.5. The hydrodynamic diameter and zeta potential of PP/Dz13 nanoparticles were measured to be 204.77 nm and +22.00 mV at a mass ratio of 10.0, respectively. The nanoparticles could realize an efficient cellular uptake in sialic acid-dependent endocytosis manner. Moreover, the nanoparticles exhibited an obvious antiproliferation effect through the induction of cell apoptosis and cell cycle arrest due to the cleavage of c-Jun mRNA. Besides, the suppression of cell migration and invasion could be achieved after the PP/Dz13 transfection, attributing to the decreased expression level of MMP-2 and MMP-9 . Conclusion The PP provided a potential delivery system to achieve the tumor-targeting gene therapy.

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Section: Introductionmentioning

confidence: 99%

<p>Inhibition of proliferation and migration of tumor cells through phenylboronic acid-functionalized polyamidoamine-mediated delivery of a therapeutic DNAzyme Dz13</p>

Yang¹,

Zhang²,

Xing³

et al. 2019

IJN

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“…In addition, compared to RNA, single-stranded DNA is much more cost-effective and inherently more stable in biological fluids. A growing number of 10-23 DNAzyme variants is currently in preclinical model studies and a small selection in clinical trials focusing on the treatment of basal cell carcinoma and Th2-driven asthma [15,20] (also see e.g., Reference [31] for more detailed review of clinically relevant aspects). While the DNAzyme approach offers a very attractive therapeutic strategy, contradicting observations are found in in vivo experiments, including studies that report on limited catalytic activity under physiological conditions [11,22].…”

Section: Biological Aspects and Therapeutic Potential Of The 10-23 Dnmentioning

confidence: 99%

Molecular Features and Metal Ions That Influence 10-23 DNAzyme Activity

et al. 2020

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Deoxyribozymes (DNAzymes) with RNA hydrolysis activity have a tremendous potential as gene suppression agents for therapeutic applications. The most extensively studied representative is the 10-23 DNAzyme consisting of a catalytic loop and two substrate binding arms that can be designed to bind and cleave the RNA sequence of interest. The RNA substrate is cleaved between central purine and pyrimidine nucleotides. The activity of this DNAzyme in vitro is considerably higher than in vivo, which was suggested to be related to its divalent cation dependency. Understanding the mechanism of DNAzyme catalysis is hindered by the absence of structural information. Numerous biological studies, however, provide comprehensive insights into the role of particular deoxynucleotides and functional groups in DNAzymes. Here we provide an overview of the thermodynamic properties, the impact of nucleobase modifications within the catalytic loop, and the role of different metal ions in catalysis. We point out features that will be helpful in developing novel strategies for structure determination and to understand the mechanism of the 10-23 DNAzyme. Consideration of these features will enable to develop improved strategies for structure determination and to understand the mechanism of the 10-23 DNAzyme. These insights provide the basis for improving activity in cells and pave the way for developing DNAzyme applications.

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“…The longer the recognition arms, the more stable the DNAzyme binds to its substrates by Watson-Crick basis pairing (Dass et al 2008;Fokina et al 2012;Santoro and Joyce 1997;Silverman 2005). In this way, the special sequence of recognition arms determines the specificity of the DNAzyme and stabilizes the catalytic core of the DNAzyme to realize the hydrolysis reaction (Khachigian 2019). Of all types of DNAzymes, 10-23 DNAzyme is the most popular one because it can cleave almost any phosphodiester bond between the unpaired purines and the paired pyrimidine (Xu et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Recent advances of DNAzyme-based nanotherapeutic platform in cancer gene therapy

Huo

Wang

et al. 2020

Biophys Rep

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Deoxyribozyme (or denoted as DNAzyme), which is produced by in vitro screening technology, has gained extensive research interest in the field of biomedicine due to its high catalytic activity and structure identification. This review introduces the structural characteristics of RNA-cleaving DNAzyme and its application potential in cancer gene therapy, which plays a significant role in cancer-related gene inactivation by specifically cleaving target mRNA and inhibiting the expression of the corresponding protein. However, the low delivery efficiency and cellular uptake hindered the widespread usage of DNAzyme in gene therapy of cancers. Emerging nanotechnology holds great promise for DNAzyme to overcome these obstacles. This review mainly focuses on DNAzyme-based nanotherapeutic platforms in gene therapy of cancers, including oncogene antagonism therapy, treatment resistance gene therapy, immunogene therapy, and antiangiogenesis gene therapy. We also revealed the potential of DNAzyme-based nanotherapeutic platforms as emerging cancer therapy approaches and their security issues.

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Deoxyribozymes as Catalytic Nanotherapeutic Agents

Cited by 43 publications

References 104 publications

<p>Inhibition of proliferation and migration of tumor cells through phenylboronic acid-functionalized polyamidoamine-mediated delivery of a therapeutic DNAzyme Dz13</p>

<p>Inhibition of proliferation and migration of tumor cells through phenylboronic acid-functionalized polyamidoamine-mediated delivery of a therapeutic DNAzyme Dz13</p>

Molecular Features and Metal Ions That Influence 10-23 DNAzyme Activity

Recent advances of DNAzyme-based nanotherapeutic platform in cancer gene therapy

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