Strategies for developing long-lasting therapeutic nucleic acid aptamer targeting circulating protein: The present and the future

Abstract

Aptamers are short, single-stranded DNA or RNA oligonucleotide sequences that can bind specific targets. The molecular weight of aptamers (<20 kDa) is lower than the renal filtration threshold (30∼50 kDa), resulting in very short half-lives in vivo, which limit their druggability. The development of long-lasting modification approaches for aptamers can help address the druggability bottleneck of aptamers. This review summarized two distinct kinds of long-lasting modification approaches for aptamers, including macromolecular modification and low-molecular-weight modification. Though it is a current approach to extend the half-life of aptamers, the macromolecular modification approach could limit the space for the dosage increases, thus causing potential compliance concerns due to large molecular weight. As for the other modification approach, the low-molecular-weight modification approach, which uses low molecular weight coupling agents (LMWCAs) to modify aptamers, could greatly increase the proportion of aptamer moiety. However, some LMWCAs could bind to other proteins, causing a decrease in the drug amounts in blood circulation. Given these issues, the outlook for the next generation of long-lasting modification approaches was proposed at the end, including improving the administration method to increase dosage for aptamer drugs modified by macromolecule and developing Artificial intelligence (AI)-based strategies for optimization of LMWCAs.

CAR‐Aptamers Enable Traceless Enrichment and Monitoring of CAR‐Positive Cells and Overcome Tumor Immune Escape

“…This often leads to attenuation of binding affinity, off‐target interactions, and susceptibility to exonucleases in biofluids, thus impeding the aptamer's use in biomedical applications. [ 13 , 30 ] There have been abundant reports on prolonging the half‐life of aptamers in vivo by increasing their stability in various ways, [ 30 ] such as aptamer/albumin complexes, [ 31 ] conformation‐stabilized aptamers with photochemically covalent lock, [ 32 ] or screening for L‐DNA aptamers resistant to degradation, [ 33 ] etc., which had broadened the development and application of aptamers in the field of detection and therapy.…”

A bimolecular modification strategy for developing long-lasting bone anabolic aptamer

“…NMR spectroscopy was used to determine the structures of small molecules. All NMR spectra were recorded on a Bruker spectrometer at 400 MHz ( 1 H NMR), 101 or 126 MHz ( 13 C NMR). Chemical shifts (δ value) were reported in ppm with the solvent signals as reference (d-DMSO as solvent) and coupling constants ( J ) are given in Hertz (Hz).…”

“…Among these choices, PEG has emerged as the predominant option for enhancing the pharmacokinetics attributes and extending the circulation half-life of aptamer candidates in vivo . 11 , 12 , 13 , 14 , 15 Riccardi et al. engineered NU172-T H 9 with an extended in vivo half-life of 28.6 h through PEGylation, resulting in enhanced thrombin inhibitory activity.…”

“… 22 Mechanistically, LMWCAs can be employed to modify aptamers, producing conjugates that, upon binding to HSA, form molecular complexes with an average mass exceeding the TVr for extending the half-life. 13 Advantageously, the molecular weight of LMWCAs is substantially lower than that of the aptamer, allowing the aptamer to account for a large proportion of the LMWCA-aptamer conjugate (over 95%). Two reported molecules have strong binding affinity to HSA.…”

Aptamer-engineered (nano)materials for theranostic applications

“…(Nano)materials and biomolecules can be developed for enhanced drug loading, increased half-life in the body, and selective distribution by modifying their composition, size, and morphology 38 . PEGylation can reduce the bottleneck in developing aptamers into therapeutics, through extending their circulation half-life and reducing nanoparticle aggregation 39 , 40 . One study showed that Apt-paclitaxel (PTX)-NP exhibited a much longer elimination half-life and slower clearance rate than PTX-Apt 41 .…”