An Albumin-Oligonucleotide Assembly for Potential Combinatorial Drug Delivery and Half-Life Extension Applications
The long blood circulatory property of human serum albumin, due to engagement with the cellular recycling neonatal Fc receptor (FcRn), is an attractive drug half-life extension enabling technology. This work describes a novel site-specific albumin double-stranded (ds) DNA assembly approach, in which...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253117302652 |
| _version_ | 1818214835733659648 |
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| author | Matthias Kuhlmann Jonas B.R. Hamming Anders Voldum Georgia Tsakiridou Maja T. Larsen Julie S. Schmøkel Emil Sohn Konrad Bienk David Schaffert Esben S. Sørensen Jesper Wengel Daniel M. Dupont Kenneth A. Howard |
| author_facet | Matthias Kuhlmann Jonas B.R. Hamming Anders Voldum Georgia Tsakiridou Maja T. Larsen Julie S. Schmøkel Emil Sohn Konrad Bienk David Schaffert Esben S. Sørensen Jesper Wengel Daniel M. Dupont Kenneth A. Howard |
| author_sort | Matthias Kuhlmann |
| collection | DOAJ |
| description | The long blood circulatory property of human serum albumin, due to engagement with the cellular recycling neonatal Fc receptor (FcRn), is an attractive drug half-life extension enabling technology. This work describes a novel site-specific albumin double-stranded (ds) DNA assembly approach, in which the 3′ or 5′ end maleimide-derivatized oligodeoxynucleotides are conjugated to albumin cysteine at position 34 (cys34) and annealed with complementary strands to allow single site-specific protein modification with functionalized ds oligodeoxynucleotides. Electrophoretic gel shift assays demonstrated successful annealing of complementary strands bearing Atto488, 6-carboxyfluorescein (6-FAM), or a factor IXa aptamer to the albumin-oligodeoxynucleotide conjugate. A fluorometric factor IXa activity assay showed retained aptamer inhibitory activity upon assembly with the albumin and completely blocked factor IXa at a concentration of 100 nM for 2 hr. The assembled construct exhibited stability in serum-containing buffer and FcRn engagement that could be increased using an albumin variant engineered for higher FcRn affinity. This work presents a novel albumin-oligodeoxynucleotide assembly technology platform that offers potential combinatorial drug delivery and half-life extension applications. |
| first_indexed | 2024-12-12T06:26:30Z |
| format | Article |
| id | doaj.art-51d4e0deff5046be96587b3e4baa4f58 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-12T06:26:30Z |
| publishDate | 2017-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-51d4e0deff5046be96587b3e4baa4f582022-12-22T00:34:45ZengElsevierMolecular Therapy: Nucleic Acids2162-25312017-12-019C28429310.1016/j.omtn.2017.10.004An Albumin-Oligonucleotide Assembly for Potential Combinatorial Drug Delivery and Half-Life Extension ApplicationsMatthias Kuhlmann0Jonas B.R. Hamming1Anders Voldum2Georgia Tsakiridou3Maja T. Larsen4Julie S. Schmøkel5Emil Sohn6Konrad Bienk7David Schaffert8Esben S. Sørensen9Jesper Wengel10Daniel M. Dupont11Kenneth A. Howard12Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkInterdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkInterdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkInterdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkInterdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkInterdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkInterdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkInterdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkInterdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkInterdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkNucleic Acid Center, Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, DenmarkInterdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkInterdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, DenmarkThe long blood circulatory property of human serum albumin, due to engagement with the cellular recycling neonatal Fc receptor (FcRn), is an attractive drug half-life extension enabling technology. This work describes a novel site-specific albumin double-stranded (ds) DNA assembly approach, in which the 3′ or 5′ end maleimide-derivatized oligodeoxynucleotides are conjugated to albumin cysteine at position 34 (cys34) and annealed with complementary strands to allow single site-specific protein modification with functionalized ds oligodeoxynucleotides. Electrophoretic gel shift assays demonstrated successful annealing of complementary strands bearing Atto488, 6-carboxyfluorescein (6-FAM), or a factor IXa aptamer to the albumin-oligodeoxynucleotide conjugate. A fluorometric factor IXa activity assay showed retained aptamer inhibitory activity upon assembly with the albumin and completely blocked factor IXa at a concentration of 100 nM for 2 hr. The assembled construct exhibited stability in serum-containing buffer and FcRn engagement that could be increased using an albumin variant engineered for higher FcRn affinity. This work presents a novel albumin-oligodeoxynucleotide assembly technology platform that offers potential combinatorial drug delivery and half-life extension applications.http://www.sciencedirect.com/science/article/pii/S2162253117302652albuminaptameroligodeoxynucleotidesdrug deliveryhalf-life extensionneonatal Fc receptorcysteine 34factor IXaanticoagulantcovalent conjugation |
| spellingShingle | Matthias Kuhlmann Jonas B.R. Hamming Anders Voldum Georgia Tsakiridou Maja T. Larsen Julie S. Schmøkel Emil Sohn Konrad Bienk David Schaffert Esben S. Sørensen Jesper Wengel Daniel M. Dupont Kenneth A. Howard An Albumin-Oligonucleotide Assembly for Potential Combinatorial Drug Delivery and Half-Life Extension Applications Molecular Therapy: Nucleic Acids albumin aptamer oligodeoxynucleotides drug delivery half-life extension neonatal Fc receptor cysteine 34 factor IXa anticoagulant covalent conjugation |
| title | An Albumin-Oligonucleotide Assembly for Potential Combinatorial Drug Delivery and Half-Life Extension Applications |
| title_full | An Albumin-Oligonucleotide Assembly for Potential Combinatorial Drug Delivery and Half-Life Extension Applications |
| title_fullStr | An Albumin-Oligonucleotide Assembly for Potential Combinatorial Drug Delivery and Half-Life Extension Applications |
| title_full_unstemmed | An Albumin-Oligonucleotide Assembly for Potential Combinatorial Drug Delivery and Half-Life Extension Applications |
| title_short | An Albumin-Oligonucleotide Assembly for Potential Combinatorial Drug Delivery and Half-Life Extension Applications |
| title_sort | albumin oligonucleotide assembly for potential combinatorial drug delivery and half life extension applications |
| topic | albumin aptamer oligodeoxynucleotides drug delivery half-life extension neonatal Fc receptor cysteine 34 factor IXa anticoagulant covalent conjugation |
| url | http://www.sciencedirect.com/science/article/pii/S2162253117302652 |
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