Dinesen, Anders;
Andersen, Veronica L;
Elkhashab, Marwa;
Pilati, Diego;
Bech, Pernille;
Fuchs, Elisabeth;
Samuelsen, Torbjørn R;
... Howard, Kenneth A; + view all
(2024)
An Albumin-Holliday Junction Biomolecular Modular Design for Programmable Multifunctionality and Prolonged Circulation.
Bioconjugate Chemistry
, 35
(2)
pp. 214-222.
10.1021/acs.bioconjchem.3c00491.
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Abstract
Combinatorial properties such as long-circulation and site- and cell-specific engagement need to be built into the design of advanced drug delivery systems to maximize drug payload efficacy. This work introduces a four-stranded oligonucleotide Holliday Junction (HJ) motif bearing functional moieties covalently conjugated to recombinant human albumin (rHA) to give a "plug-and-play" rHA-HJ multifunctional biomolecular assembly with extended circulation. Electrophoretic gel-shift assays show successful functionalization and purity of the individual high-performance liquid chromatography-purified modules as well as efficient assembly of the rHA-HJ construct. Inclusion of an epidermal growth factor receptor (EGFR)-targeting nanobody module facilitates specific binding to EGFR-expressing cells resulting in approximately 150-fold increased fluorescence intensity determined by flow cytometric analysis compared to assemblies absent of nanobody inclusion. A cellular recycling assay demonstrated retained albumin-neonatal Fc receptor (FcRn) binding affinity and accompanying FcRn-driven cellular recycling. This translated to a 4-fold circulatory half-life extension (2.2 and 0.55 h, for the rHA-HJ and HJ, respectively) in a double transgenic humanized FcRn/albumin mouse. This work introduces a novel biomolecular albumin-nucleic acid construct with extended circulatory half-life and programmable multifunctionality due to its modular design.
| Type: | Article |
|---|---|
| Title: | An Albumin-Holliday Junction Biomolecular Modular Design for Programmable Multifunctionality and Prolonged Circulation |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acs.bioconjchem.3c00491 |
| Publisher version: | http://dx.doi.org/10.1021/acs.bioconjchem.3c00491 |
| Language: | English |
| Additional information: | Copyright © 2024 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY-NC-ND 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | Biopolymers, Functionalization, Half-Life, Molecular Properties, Peptides And Proteins |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10187389 |
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