Conjugation to Polyethylene Glycol Polymer Promotes Aptamer Biodistribution to Healthy and Inflamed Tissues

Abstract

Here, we examine biodistribution of radiolabeled aptamers and assess the relative ability of different stabilized aptamer compositions (mixed 2'-F/2'-O-Me; fully 2'-O-Me modified) to access inflamed tissues in a murine inflammation model. Biodistribution of 3H-labeled aptamers, including pegylated and unpegylated compositions, was assessed 3 hours postadministration using quantitative whole body autoradiography (QWBA). Aptamer penetration of cells in kidney and liver was also examined at a qualitative level by microautoradiography. To evaluate aptamer distribution to diseased tissues, inflammation was induced locally in animal hind limbs by treatment with carrageenan just prior to aptamer dosing. Aptamer compositions examined exhibited significant variation in distribution levels among organs and tissues. Highest concentrations of radioactivity in whole body tissues for all animals were observed in the kidney and urinary bladder contents. Relatively little radioactivity was associated with brain, spinal cord, and adipose tissue. Overall, the total level of radioactivity in whole body tissues was significantly higher for a 20-kDa PEG conjugate than for other aptamers. Comparatively high levels of the 20-kDa conjugate were seen in well-perfused organs and tissues, including liver, lungs, spleen, bone marrow, and myocardium. A fully 2'-O-Me composition aptamer had the lowest level of radioactivity in whole body tissues but distributed to higher concentrations in the gastrointestinal tract contents relative to other aptamers. Interestingly, the 20-kDa PEG-conjugated aptamer showed significantly higher levels of distribution to inflamed paw tissues than did either unconjugated or fully 2'-O-Me-modified aptamers.

Biodistribution of Novel 68Ga-Radiolabelled HER2 Aptamers in Mice

“…This result is in accordance with previous studies which showed that aptamers are not able to cross the BBB passively [35][36][37]. There were no significant differences between the two HER2 aptamers and the negative control aptamer, except a significant increase in kidney uptake for the negative control aptamer, which may be related to the difference in nucleotide sequence and therefore difference in hydrophilicity.…”

Aptamer photoregulation in vivo

“…The spatiotemporal control of drug delivery afforded by our approach may enhance the efficacy and therapeutic index of many drugs. Our strategy involves less synthetic workup than approaches that change oligonucleotide biodistribution via chemical modification (e.g., PEGylation) (14,(50)(51)(52).…”

Selection of a novel DNA thioaptamer against HER2 structure

“…However, unmodified oligonucleotides are susceptible to hydrolysis by nucleases, limiting their potential for in vivo biomedical applications. To improve aptamers' function as tumor-targeting ligands, various chemical modifications for enhancing their stability have been introduced [28][29][30][31][32]. Among these modification methods, phosphate backbone modification with phosphorothioate is a promising strategy, since it does not hamper the target-binding affinity of the oligonucleotides.…”