Noninvasive and Quantitative Monitoring of the Distributions and Kinetics of MicroRNA-Targeting Molecules in Vivo by Positron Emission Tomography

Abstract

MicroRNAs (miRNAs) are endogenous, small, noncoding ribonucleic acids (RNAs) that bind to the 3′ untranslated regions of messenger RNAs (mRNAs) and induce translational repression or mRNA degradation. Although numerous studies have reported that miRNAs are of potential use for disease diagnostics and gene therapy, little is known about their fates in vivo. This study elucidated the whole-body distributions and kinetics of intravenously administered miRNA-targeting molecules in vivo by positron emission tomography (PET) imaging. A 22-mer sequence targeting miR-15b was conjugated with three different chelators and labeled with gallium-68 ( 68 Ga). These tracers were compared with a scrambled 22-mer sequence; 22-mer with two single base substitutions; anti-miR-34 22-mer; hexathymidylate (T 6 ), a 6-mer sequence; and an unconjugated chelator. miR-15b was chosen as a target because it is important for bone remodeling. All three 68 Ga-labeled anti-miR-15b molecules had similar biodistributions and kinetics, and they all accumulated in the bones, kidneys, and liver. The bone accumulation of these tracers was the highest in the epiphyses of long tubular bones, maxilla, and mandible. By contrast, the scrambled 22-mer sequence, the 6-mer, and the unconjugated chelator did not accumulate in bones. PET imaging successfully elucidated the distributions and kinetics of 68 Ga-labeled chelated miRNA-targeting molecules in vivo. This approach is potentially useful to evaluate new miRNA-based drugs.

Tailed‐Hoogsteen Triplex DNA Silver Nanoclusters Emit Red Fluorescence upon Target miRNA Sensing

“…[43,48] While methods like magnetic resonance imaging (MRI), positron emission tomography (PET), surface-enhanced Raman spectroscopy (SERS) allow for long-term monitoring of miRNA activity in live cells, they are often inaccessible to most researchers due to their complexity and cost. [49][50][51][52] Despite the advancements, highthroughput methods like microarrays and NGS can be costly for day-to-day use, urging the scientific community to develop more cost-effective techniques. Bioluminescence-based optical imaging offers some alternatives, but they mainly provide information about miRNA activity rather than visualizing their presence and localization.…”

Bringing MicroRNAs to Light: Methods for MicroRNA Quantification and Visualization in Live Cells

“…Recently, MRI has been applied to trace circulating miRNAs in serum and allowed for disease prognosis (Regev et al, 2017 ). Positron emission tomography (PET) imaging was used to localize specific miRNAs using radiolabeled tracer oligonucleotides complementary to the target miRNAs (Mäkilä et al, 2019 ).…”

Molecular Imaging Using Cardiac PET/CT: Opportunities to Harmonize Diagnosis and Therapy

“…One example is the capacity to target micro-RNAs, conjugating oligonucleotide sequences with radiometal chelator for visualization of micro-RNA upregulation in disease. Proof-of-concept studies displayed extended retention in bones and bone marrow of healthy rats [ 25 ], but high background signal and poor clearance remain at issue. The potential of micro-RNA-based therapies provides an opportunity for complementary molecular imaging [ 26 ].…”