Association of antisense oligonucleotides with lipoproteins prolongs the plasma half-life and modifies the tissue distribution

Smidt, P.C. de; Doan, Trung Le; Falco, Sandro De; Berkel, Theo J.C. Van

doi:10.1093/nar/19.17.4695

Cited by 147 publications

(79 citation statements)

References 16 publications

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“…However, this study actually uses a drug-targeting technology, because the [ 11 C]PS-ODN 25-mer included cholesterol conjugated at the 5Ј terminus. The addition of a cholesterol moiety to ODNs increases cellular uptake in tissue culture (19,20). The conjugation of cholesterol to drugs is a ''lipidization'' drug-targeting strategy.…”

Section: Discussionmentioning

confidence: 99%

Antisense imaging of gene expression in the brain in vivo

Shi

Boado

Pardridge

2000

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

101

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Antisense radiopharmaceuticals could be used to image gene expression in the brain in vivo, should these polar molecules be made transportable through the blood-brain barrier. The present studies describe an antisense imaging agent comprised of an iodinated peptide nucleic acid (PNA) conjugated to a monoclonal antibody to the rat transferrin receptor by using avidin-biotin technology. The PNA was a 16-mer antisense to the sequence around the methionine initiation codon of the luciferase mRNA.

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Section: Discussionmentioning

confidence: 99%

Antisense imaging of gene expression in the brain in vivo

Shi

Boado

Pardridge

2000

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

101

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“…Общее количество ДНК, размер фрагментов и время её циркуляции в крови определяются активностью нуклеаз крови [39,45], структурой ДНК (наличием/отсутствием метилированных цитозинов) [46], формой цирДНК (свободная или в составе комплексов) [47], а также наличием биополимеров [48][49], которые могут связываться с нуклеиновыми кислотами, защищая их от нуклеазной атаки или, напротив, дестабилизируя нуклеопротеиновые компоненты. Эти аспекты циркуляции ДНК в кровотоке будут более детально рассмотрены ниже.…”

Section: состав циркулирующих в крови комплексов внеклеточных днкunclassified

Generation of blood circulating DNA: the sources, peculiarities of circulation and structure

Bryzgunova

Laktionov

2015

BIOMED KHIM

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Внеклеточные нуклеиновые кислоты (внНК) в циркуляции как здоровых, так и больных людей были впервые описаны в 1948 г., однако оставались без внимания до середины 60-х годов прошлого века. внНК особенно интенсивно исследуются в последние 5 лет. Основное внимание уделяется исследованию внНК как источнику диагностического материала; однако механизмы генерации внеклеточных нуклеиновых кислот, а также механизмы, обеспечивающие их долговременную циркуляцию в кровотоке, однозначно не установлены. По данным одних авторов, основным источником циркулирующих дезоксирибонуклеиновых кислот в крови (цирДНК) являются процессы некроза и апоптоза, другие ссылаются на возможную секрецию нуклеиновых кислот как здоровыми, так и опухолевыми клетками. Известно, что цирДНК могут циркулировать в крови в течение длительного времени, ускользая от действия ДНК-гидролизующих ферментов крови и, по-видимому, находясь в составе надмолекулярных комплексов. В этом обзоре представлены данные разных авторов и приведены доказательства в пользу всех предложенных теорий появления цирДНК, описаны особенности строения цирДНК, а также факторы, влияющие на время циркуляции ДНК в крови.Ключевые слова: циркулирующая ДНК, апоптоз, некроз, активная секреция, ДНКазы, метилирование.

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“…First, we conjugated cholesterol to the 5= end of R-F t2. The conjugation has been shown to increase the circulation half-life of oligonucleotides, through association with plasma lipoproteins, and promote hepatic cell uptake (26)(27)(28). Inverted dT was attached to the 3= end of R-F t2 to prevent RNase attack.…”

Section: Cholesterol-or Galactose-peg Conjugated R-f T2 Efficiently Ementioning

confidence: 99%

Inhibition of Hepatitis C Virus (HCV) Replication by Specific RNA Aptamers against HCV NS5B RNA Replicase

Lee

Kim

et al. 2013

J Virol

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This study identified specific and avid RNA aptamers consisting of 2=-hydroxyl-or 2=-fluoropyrimidines against hepatitis C virus (HCV) NS5B replicase, an enzyme that is essential for HCV replication. These aptamers acted as potent decoys to competitively impede replicase-catalyzed RNA synthesis activity. Cytoplasmic expression of the 2=-hydroxyl aptamer efficiently inhibited HCV replicon replication in human liver cells through specific interaction with, and sequestration of, the target protein without either off-target effects or escape mutant generation. A selected 2=-fluoro aptamer could be truncated to a chemically manufacturable length of 29 nucleotides (nt), with increase in the affinity to HCV NS5B. Noticeably, transfection of the truncated aptamer efficiently suppressed HCV replication in cells without escape mutant appearance. The aptamer was further modified through conjugation of a cholesterol or galactose-polyethylene glycol ligand for in vivo availability and liver-specific delivery. The conjugated aptamer efficiently entered cells and inhibited genotype 1b subgenomic and genotype 2a full-length HCV JFH-1 RNA replication without toxicity and innate immunity induction. Importantly, a therapeutically feasible amount of the conjugated aptamer was delivered in vivo to liver tissue in mice. Therefore, cytoplasmic expression of 2=-hydroxyl aptamer or direct administration of chemically synthesized and ligand-conjugated 2=-fluoro aptamer against HCV NS5B could be a potent anti-HCV approach. Hepatitis C virus (HCV) is the main causative agent of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (1, 2). Although HCV infection causes worldwide health problems, efficient and specific antiviral therapy has not yet been developed.HCV belongs to the genus Hepacivirus in the family Flaviviridae. The enveloped virus contains a single, positive-stranded RNA genome about 9.6 kb in length encoding a single polyprotein of about 3,010 amino acids (3). This polyprotein precursor is co-or posttranslationally processed by cellular and viral proteases to yield functional structural and nonstructural proteins (4). The structural proteins include the core protein, C, and the envelope glycoproteins E1 and E2. The nonstructural (NS) proteins comprise the protease NS2, the multifunctional protein NS3 consisting of serine protease and helicase, the serine protease cofactor NS4A, the proteins NS4B and NS5A, and the RNA-dependent RNA polymerase NS5B, which are components of a complex responsible for HCV replication (5). NS5B is the central catalytic enzyme in HCV RNA replication. A number of drugs targeting HCV NS5B replicase are under development. However, the rapid appearance of drug-resistant escape mutant viruses has been reported (6).RNA aptamers are small structured single-stranded RNAs which have emerged as attractive and feasible alternatives to small-molecule and antibody-based therapy. Aptamers can be evolved by systematic evolution of ligands by exponential enrichment (SELEX), an iterative selection method...

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Association of antisense oligonucleotides with lipoproteins prolongs the plasma half-life and modifies the tissue distribution

Cited by 147 publications

References 16 publications

Antisense imaging of gene expression in the brain in vivo

Antisense imaging of gene expression in the brain in vivo

Generation of blood circulating DNA: the sources, peculiarities of circulation and structure

Inhibition of Hepatitis C Virus (HCV) Replication by Specific RNA Aptamers against HCV NS5B RNA Replicase

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