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Fatty Acid-Modified Gapmer Antisense Oligonucleotide and Serum Albumin Constructs for Pharmacokinetic Modulation
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Fatty Acid-Modified Gapmer Antisense Oligonucleotide and Serum Albumin Constructs for Pharmacokinetic Modulation
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Journal Article
Fatty Acid-Modified Gapmer Antisense Oligonucleotide and Serum Albumin Constructs for Pharmacokinetic Modulation
2017
Overview
Delivery technologies are required for realizing the clinical potential of molecular medicines. This work presents an alternative technology to preformulated delivery systems by harnessing the natural transport properties of serum albumin using endogenous binding of gapmer antisense oligonucleotides (ASOs)/albumin constructs. We show by an electrophoretic mobility assay that fatty acid-modified gapmer and human serum albumin (HSA) can self-assemble into constructs that offer favorable pharmacokinetics. The interaction was dependent on fatty acid type (either palmitic or myristic acid), number, and position within the gapmer ASO sequence, as well as phosphorothioate (PS) backbone modifications. Binding correlated with increased blood circulation in mice (t1/2 increased from 23 to 49 min for phosphodiester [PO] gapmer ASOs and from 28 to 66 min for PS gapmer ASOs with 2× palmitic acid modification). Furthermore, a shift toward a broader biodistribution was detected for PS compared with PO gapmer ASOs. Inclusion of 2× palmitoyl to the ASOs shifted the biodistribution to resemble that of natural albumin. This work, therefore, presents a novel strategy based on the proposed endogenous assembly of gapmer ASOs/albumin constructs for increased circulatory half-life and modulation of the biodistribution of gapmer ASOs that offers tunable pharmacokinetics based on the gapmer modification design.
Delivery technologies are required for realizing the clinical potential of molecular medicines. Howard et al. presents an alternative technology platform to preformulated delivery systems by harnessing the natural transport properties of serum albumin using endogenous binding of gapmer antisense oligonucleotides (ASOs)/albumin constructs tuned by chemical modifications.
Publisher
Elsevier Inc,Elsevier Limited,American Society of Gene & Cell Therapy
Subject
/ Animals
/ antisense gapmer oligonucleotides
/ Delayed-Action Preparations - chemistry
/ Delayed-Action Preparations - pharmacokinetics
/ Electrophoretic Mobility Shift Assay
/ Female
/ Humans
/ Mice
/ Oligonucleotides - chemistry
/ Oligonucleotides - metabolism
/ Oligonucleotides, Antisense - chemistry
/ Oligonucleotides, Antisense - pharmacokinetics
/ Original
/ Phosphorothioate Oligonucleotides - chemistry
/ Phosphorothioate Oligonucleotides - pharmacokinetics
/ Serum Albumin, Human - chemistry
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