Synthesis of multi-galactose-conjugated 2′-O-methyl oligoribonucleotides and their in vivo imaging with positron emission tomography

Mäkilä, Jussi; Jadhav, Satish; Kiviniemi, Antti M.; Käkelä, Meeri; Liljenbäck, Heidi; Poijärvi-Virta, Päivi; Laitala-Leinonen, Tiina; Lönnberg, Harri; Roivainen, Anne; Virta, Pasi

doi:10.1016/j.bmc.2014.10.034

Cited by 16 publications

(10 citation statements)

References 52 publications

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“…Tuning the number of GalNAc moieties per oligonucleotide influences this distribution (i.e. greater than three GalNAc molecules per ASO drives preferential delivery to liver 110 ). Interestingly, the presence of phosphorothioate bonds enhances the potency of GalNAc-delivered siRNAs 109 .…”

Section: Conjugate Mediated Deliverymentioning

confidence: 99%

The chemical evolution of oligonucleotide therapies of clinical utility

2017

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After nearly 40 years of development, oligonucleotide therapeutics are nearing meaningful clinical productivity. One of the key advantages of oligonucleotide drugs is that their delivery and potency properties are derived primarily from the chemical structure of the oligonucleotide, while their target is defined by the base sequence. Thus, as oligonucleotides with a particular chemical design demonstrate appropriate distribution and safety profiles for clinical gene silencing in a particular tissue, this will open the door to the rapid development of additional drugs targeting other disease-associated genes in the same tissue. To achieve clinical productivity, the chemical architecture of the oligonucleotide needs to be optimized as a whole, using a combination of sugar, backbone, nucleobase and 3′/5′-terminal modifications. A portfolio of chemistries can be used to confer drug like properties onto the oligonucleotide as a whole, with minor chemical changes often translating into major improvements in clinical efficacy. Outstanding challenges in oligonucleotide chemical development include optimization of chemical architectures to ensure long-term safety and to enable robust clinical activity beyond the liver.

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Section: Conjugate Mediated Deliverymentioning

confidence: 99%

The chemical evolution of oligonucleotide therapies of clinical utility

2017

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“…15,16 Although 68 Ga-labeled anti-miR-15b has been previously investigated, this study evaluated the fate of anti-miR-15b tracers in more detail, with a particular focus on blood pharmacokinetics and the specificity of bone uptake. 19,22…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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“…99,132 Recently a new solid phase synthesis has been introduced. 127,133,134 Besides those methods, there are less used ones such as clickable compounds, 99 coupling with thiols, 135 or the use of maleimidoethylmonoamide NOTA. 136 The disadvantage of this conjugation is the loss of one carboxylic acid arm, which becomes a less coordinating amide bond.…”

Section: Deferiprone (Hpo-ligands)mentioning

confidence: 99%