Academic Journal
A Modular Albumin-Oligonucleotide Biomolecular Assembly for Delivery of Antisense Therapeutics:Molecular Pharmaceutics
| العنوان: | A Modular Albumin-Oligonucleotide Biomolecular Assembly for Delivery of Antisense Therapeutics:Molecular Pharmaceutics |
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| المؤلفون: | Elkhashab, Marwa, Dilek, Yeter, Foss, Morten, Creemers, Laura B., Howard, Kenneth A. |
| المصدر: | Elkhashab , M , Dilek , Y , Foss , M , Creemers , L B & Howard , K A 2024 , ' A Modular Albumin-Oligonucleotide Biomolecular Assembly for Delivery of Antisense Therapeutics : Molecular Pharmaceutics ' , Molecular Pharmaceutics , vol. 21 , no. 2 , pp. 491-500 . https://doi.org/10.1021/acs.molpharmaceut.3c00561 |
| سنة النشر: | 2024 |
| المجموعة: | Aarhus University: Research |
| مصطلحات موضوعية: | Antisense oligonucleotide, Albumin, Biomolecular assembly, FcRn, ADAMTS5, osteoarthritis, Oligonucleotides, Antisense/chemistry, Humans, Oligonucleotides/chemistry, Deoxyribonucleases, Albumins, Endothelial Cells/metabolism, Serum Albumin, Human/metabolism |
| الوصف: | Antisense nucleic acid drugs are susceptible to nuclease degradation, rapid renal clearance, and short circulatory half-life. In this work, we introduce a modular-based recombinant human albumin-oligonucleotide (rHA-cODN) biomolecular assembly that allows incorporation of a chemically stabilized therapeutic gapmer antisense oligonucleotide (ASO) and FcRn-driven endothelial cellular recycling. A phosphodiester ODN linker (cODN) was conjugated to recombinant human albumin (rHA) using maleimide chemistry, after which a complementary gapmer ASO, targeting ADAMTS5 involved in osteoarthritis pathogenesis, was annealed. The rHA-cODN/ASO biomolecular assembly production, fluorescence labeling, and purity were confirmed using polyacrylamide gel electrophoresis. ASO release was triggered by DNase-mediated degradation of the linker strand, reaching 40% in serum after 72 h, with complete release observed following 30 min of incubation with DNase. Cellular internalization and trafficking of the biomolecular assembly using confocal microscopy in C28/I2 cells showed higher uptake and endosomal localization by increasing incubation time from 4 to 24 h. FcRn-mediated cellular recycling of the assembly was demonstrated in FcRn-expressing human microvascular endothelial cells. ADAMTS5 in vitro silencing efficiency reached 40%, which was comparable to free gapmer after 72 h incubation with human osteoarthritis patients’ chondrocytes. This work introduces a versatile biomolecular modular-based “Plug-and-Play” platform potentially applicable for albumin-mediated half-life extension for a range of different types of ODN therapeutics. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | https://pure.au.dk/portal/en/publications/1435ebea-c451-4428-884a-a52abb767e96 |
| DOI: | 10.1021/acs.molpharmaceut.3c00561 |
| الاتاحة: | https://pure.au.dk/portal/en/publications/1435ebea-c451-4428-884a-a52abb767e96 https://doi.org/10.1021/acs.molpharmaceut.3c00561 |
| Rights: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.1A6B81B1 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acs.molpharmaceut.3c00561 |
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