Pharmacokinetic Properties of DNA Aptamers with Base Modifications

Gupta, Shashi; Drolet, Daniel; Wolk, Steven K.; Waugh, Sheela; Rohloff, John C.; Carter, Jeffery D; Mayfield, Wesley S.; Otis, Matthew R.; Fowler, Catherine R; Suzuki, Tadanao; Hirota, Michio; Ishikawa, Yuichi; Schneider, Daniel J.; Janjić, Nebojša

doi:10.1089/nat.2017.0683

Cited by 24 publications

(16 citation statements)

References 35 publications

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“…RNA Synthesis and Purification. Standard and modified RNA oligonucleotides were synthesized in house via standard phosphoramidite methods using 2′-tert-Butyldimethylsilyl (TBDMS) protecting groups (61) on an ABI 3900 automated synthesizer using commercial reagents [rA(Bz) and rG(iBu) from Thermo Scientific, rC(Ac) and rU(CE) from Bioautomation, and 2′-OMe-rU from Proligo] and 2′-OMe-Bn-dU phosphoramidite, which was synthesized from 2′-OMe-rU (Proligo) as described previously (62). After initial cleavage and base deprotection with t-butyl amine:methanol:water (1:1:2) overnight at 37°C, deprotection of the 2′-O-TBDMS ethers was accomplished using an ammonium fluoride/ dimethylsulfoxide scheme (63).…”

Section: Methodsmentioning

confidence: 99%

Modified nucleotides may have enhanced early RNA catalysis

Wolk

Mayfield

Gelinas

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The modern version of the RNA World Hypothesis begins with activated ribonucleotides condensing (nonenzymatically) to make RNA molecules, some of which possess (perhaps slight) catalytic activity. We propose that noncanonical ribonucleotides, which would have been inevitable under prebiotic conditions, might decrease the RNA length required to have useful catalytic function by allowing short RNAs to possess a more versatile collection of folded motifs. We argue that modified versions of the standard bases, some with features that resemble cofactors, could have facilitated that first moment in which early RNA molecules with catalytic capability began their evolutionary path toward self-replication.

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Section: Methodsmentioning

confidence: 99%

Modified nucleotides may have enhanced early RNA catalysis

Wolk

Mayfield

Gelinas

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Modified base aptamers are able to retain target binding properties, and thus they may enhance the binding affinity [118,119]. For example, a base-modified aptamer, 5-(1-pentynyl)-2′-deoxyuridine, used instead of thymidine, was isolated via a selection experiment against human coagulation protease thrombin ( Figure 16) [118].…”

Section: Modifications On the Bases And Somamersmentioning

confidence: 99%

“…These changes were effective in increasing the chemical diversity of the aptamers. By increasing the rate of discovery of high-affinity ligand to protein targets, they also caused an increase in nuclease resistance, with lower renal clearance for more hydrophilic side chains [119].…”

Section: Modifications On the Bases And Somamersmentioning

confidence: 99%

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies

et al. 2019

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Soon after they were first described in 1990, aptamers were largely recognized as a new class of biological ligands that can rival antibodies in various analytical, diagnostic, and therapeutic applications. Aptamers are short single-stranded RNA or DNA oligonucleotides capable of folding into complex 3D structures, enabling them to bind to a large variety of targets ranging from small ions to an entire organism. Their high binding specificity and affinity make them comparable to antibodies, but they are superior regarding a longer shelf life, simple production and chemical modification, in addition to low toxicity and immunogenicity. In the past three decades, aptamers have been used in a plethora of therapeutics and drug delivery systems that involve innovative delivery mechanisms and carrying various types of drug cargos. However, the successful translation of aptamer research from bench to bedside has been challenged by several limitations that slow down the realization of promising aptamer applications as therapeutics at the clinical level. The main limitations include the susceptibility to degradation by nucleases, fast renal clearance, low thermal stability, and the limited functional group diversity. The solution to overcome such limitations lies in the chemistry of aptamers. The current review will focus on the recent arts of aptamer chemistry that have been evolved to refine the pharmacological properties of aptamers. Moreover, this review will analyze the advantages and disadvantages of such chemical modifications and how they impact the pharmacological properties of aptamers. Finally, this review will summarize the conjugation strategies of aptamers to nanocarriers for developing targeted drug delivery systems. Molecules 2020, 25, 3 2 of 51 molecules [2]. Nowadays, the aptamer field covers various biomedical applications, including [3], therapeutic [4-6], aptasensors [7], biosensors [8,9], diagnostic [10,11], and imaging systems [12].Aptamers need to be stabilized for in vivo use against nuclease degradation, and their small size makes them susceptible to renal filtration. Aptamers' stabilization can be attained by chemically modifying them using different approaches. Moreover, introducing chemical modifications into nucleic acid libraries increases the interaction capabilities of aptamers and thereby their target spectrum [12]. Modified aptamers may show improved chemical diversity relative to aptamers composed entirely of natural DNA or RNA nucleotides and expand their applications in diagnostics, therapeutics, and nanotechnology [1].Chemical modifications of aptamer oligonucleotides are needed mainly to enhance their resistance to nuclease degradation and lowering their renal filtration. Additionally, chemical modifications, in some cases, may increase the aptamer-binding affinity [13]. Many approaches have been introduced to promote the stability of aptamers without altering their binding affinity and specificity against their targets. These approaches include chemical modification of the phosphate...

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“…The small size makes them easier to penetrate tissue, an advantage for therapy as well as in vivo imaging; it also makes them faster to be cleared from the kidney, which means shorter half-life and is disadvantageous for therapy but advantageous for in vivo imaging [34]. Although the disadvantage of short circulating half-life can be overcome by conjugating aptamers with an inert molecule such as polyethylene glycol or cholesterol, this may meanwhile retard tissue uptake; hence, there is a paradox and the designer of aptamers should take all these into consideration and make a good balance between them [26,[35][36][37].…”

Section: Aptamers Mabsmentioning

confidence: 99%

Aptamers, the Nucleic Acid Antibodies, in Cancer Therapy

Xiang

2020

IJMS

102

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The arrival of the monoclonal antibody (mAb) technology in the 1970s brought with it the hope of conquering cancers to the medical community. However, mAbs, on the whole, did not achieve the expected wonder in cancer therapy although they do have demonstrated successfulness in the treatment of a few types of cancers. In 1990, another technology of making biomolecules capable of specific binding appeared. This technique, systematic evolution of ligands by exponential enrichment (SELEX), can make aptamers, single-stranded DNAs or RNAs that bind targets with high specificity and affinity. Aptamers have some advantages over mAbs in therapeutic uses particularly because they have little or no immunogenicity, which means the feasibility of repeated use and fewer side effects. In this review, the general properties of the aptamer, the advantages and limitations of aptamers, the principle and procedure of aptamer production with SELEX, particularly the undergoing studies in aptamers for cancer therapy, and selected anticancer aptamers that have entered clinical trials or are under active investigations are summarized.

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Pharmacokinetic Properties of DNA Aptamers with Base Modifications

Cited by 24 publications

References 35 publications

Modified nucleotides may have enhanced early RNA catalysis

Modified nucleotides may have enhanced early RNA catalysis

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies

Aptamers, the Nucleic Acid Antibodies, in Cancer Therapy

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