Architecture of high-affinity unnatural-base DNA aptamers toward pharmaceutical applications

Matsunaga, Ken-ichiro; Kimoto, Michiko; Hanson, Charlotte; Sanford, Michael; Young, Howard A.; Hirao, Ichiro

doi:10.1038/srep18478

Cited by 53 publications

(47 citation statements)

References 26 publications

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“…Aptamer technology, although discovered for years, is still evolving to fulfill the requirements of more precise diagnosis and personalized therapy [1,2]. Aptamers are RNA or DNA sequences generated to exhibit high affinity and specificity against a broad range of targets, ranging from small molecules to whole cells or tissues [2][3][4]. Like antibodies, they recognize their specific targets due to the unique three-dimensional structure they adopt.…”

Section: Introductionmentioning

confidence: 99%

Aptamer-based liposomes improve specific drug loading and release

Plourde

Derbali

Desrosiers

et al. 2017

Journal of Controlled Release

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Aptamer technology has shown much promise in cancer therapeutics for its targeting abilities. However, its potential to improve drug loading and release from nanocarriers has not been thoroughly explored. In this study, we employed drug-binding aptamers to actively load drugs into liposomes. We designed a series of DNA aptamer sequences specific to doxorubicin, displaying multiple binding sites and various binding affinities. The binding ability of aptamers was preserved when incorporated into cationic liposomes, binding up to 15equivalents of doxorubicin per aptamer, therefore drawing the drug into liposomes. Optimization of the charge and drug/aptamer ratios resulted in ≥80% encapsulation efficiency of doxorubicin, ten times higher than classical passively-encapsulating liposomal formulations and similar to a pH-gradient active loading strategy. In addition, kinetic release profiles and cytotoxicity assay on HeLa cells demonstrated that the release and therapeutic efficacy of liposomal doxorubicin could be controlled by the aptamer's structure. Our results suggest that the aptamer exhibiting a specific intermediate affinity is the best suited to achieve high drug loading while maintaining efficient drug release and therapeutic activity. This strategy was successfully applied to tobramycin, a hydrophilic drug suffering from low encapsulation into liposomes, where its loading was improved six-fold using aptamers. Overall, we demonstrate that aptamers could act, in addition to their targeting properties, as multifunctional excipients for liposomal formulations.

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Section: Introductionmentioning

confidence: 99%

Aptamer-based liposomes improve specific drug loading and release

Plourde

Derbali

Desrosiers

et al. 2017

Journal of Controlled Release

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show abstract

“…To improve its stability, a hairpin and three additional GC-pairs at the 3 0 -terminus were inserted as well as a second, internal hairpin. This engineering led to an increase of the aptamer's melting temperature from 38 to 64 C and an increased stability in human plasma [45].…”

Section: Aptamers With An Extended Genetic Alphabetmentioning

confidence: 99%

Customised nucleic acid libraries for enhanced aptamer selection and performance

Pfeiffer

Rosenthal

Siegl

et al. 2017

Current Opinion in Biotechnology

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“…A randomized oligonucleotide library folds into complex structural pool. Considering the susceptibility of oligonucleotides to serum nucleases, modified oligonucleotide are widely used for generating nuclease resistant aptamers [33][34][35]. A starting aptamer library mostly consists of a central random region ranging from 20-60 nucleotide long, flanked by known sequences to allow primer binding for amplification, enrichment, cloning and characterization.…”

Section: Systematic Evolution Of Ligands By Exponential Enrichment (Smentioning

confidence: 99%

Aptamers in HIV research diagnosis and therapy

et al. 2018

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Aptamers are high affinity single-stranded nucleic acid or protein ligands which exhibit specificity and avidity comparable to, or exceeding that of antibodies and can be generated against most targets. The functionality of aptamers is based on their unique tertiary structure, complexity and their ability to attain unique binding pockets by folding. Aptamers are selected in vitro by a process called Systematic Evolution of Ligands by Exponential enrichment (SELEX). The Kd values for the selected aptamer are often in the picomolar to low nanomolar range. Stable and nontoxic aptamers could be selected for a wide range of ligands including small molecules to large proteins. Aptamers have shown tremendous potential and have found multipurpose application in the field of therapeutic, diagnostic, biosensor and bio-imaging. While their mechanism of action can be similar to that of monoclonal antibodies, aptamers provide additional advantages in terms of production cost, simpler regulatory approval and lower immunogenicity as they are synthesized chemically. Human immunodeficiency virus (HIV) is the primary cause of acquired immune deficiency syndrome (AIDS), which causes significant morbidity and mortality with a significant consequent decrease in the quality of patient's lives. While cART has led to good viral control, people living with HIV now suffer from non-HIV comorbidities due to viral protein expression that cannot be controlled by cART. Hence pathophysiological mechanisms that govern these comorbidities with a focus on therapies that neutralize these HIV effects gained increased attention. Recent advances in HIV/AIDS research have identified several molecular targets and for the development of therapeutic and diagnostic using aptamers against HIV/AIDS. This review presents recent advances in aptamers technology for potential application in HIV diagnostics and therapeutics towards improving the quality of life of people living with HIV.

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Architecture of high-affinity unnatural-base DNA aptamers toward pharmaceutical applications

Cited by 53 publications

References 26 publications

Aptamer-based liposomes improve specific drug loading and release

Aptamer-based liposomes improve specific drug loading and release

Customised nucleic acid libraries for enhanced aptamer selection and performance

Aptamers in HIV research diagnosis and therapy

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