-
Uddannelse
Find uddannelse
Studievejledning
Kvalitet
- Forskning
-
Samarbejde
Virksomheder
Kommuner og regioner
Gymnasier
Myndigheder
-
Om AU
Organisation
Kontakt
Om AU
- Organisation
- Ledelse
- Strategi
- AU i tal
- AU's historie
- Internationalt samarbejde
- Bæredygtighed
- Campus 2.0
- Diversitet og ligestilling
- Ledige stillinger
- Presse
- Kontakt
Albumin Biomolecular Drug Designs Stabilized through Improved Thiol Conjugation and a Modular Locked Nucleic Acid Functionalized Assembly
Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review
DOI
- https://doi.org/10.1021/acs.bioconjchem.1c00561
Forlagets udgivne version
- Anders Dinesen
- Alexander Winther ,
- Archie Wall, University College London ,
- Anders Märcher ,
- Johan Palmfeldt
- Vijay Chudasama, University College London ,
- Jesper Wengel, Syddansk Universitet ,
- Kurt V Gothelf
- James R. Baker, University College London ,
- Kenneth A Howard
Albumin-nucleic acid biomolecular drug designs offer modular multifunctionalization and extended circulatory half-life. However, stability issues associated with conventional DNA nucleotides and maleimide bioconjugation chemistries limit the clinical potential. This work aims to improve the stability of this thiol conjugation and nucleic acid assembly by employing a fast-hydrolyzing monobromomaleimide (MBM) linker and nuclease-resistant nucleotide analogues, respectively. The biomolecular constructs were formed by site-selective conjugation of a 12-mer oligonucleotide to cysteine 34 (Cys34) of recombinant human albumin (rHA), followed by annealing of functionalized complementary strands bearing either a fluorophore or the cytotoxic drug monomethyl auristatin E (MMAE). Formation of conjugates and assemblies was confirmed by gel shift analysis and mass spectrometry, followed by investigation of serum stability, neonatal Fc receptor (FcRn)-mediated cellular recycling, and cancer cell killing. The MBM linker afforded rapid conjugation to rHA and remained stable during hydrolysis. The albumin-nucleic acid biomolecular assembly composed of stabilized oligonucleotides exhibited high serum stability and retained FcRn engagement mediating FcRn-mediated cellular recycling. The MMAE-containing assembly exhibited cytotoxicity in the human MIA PaCa-2 pancreatic cancer cell line with an IC50 of 342 nM, triggered by drug release from breakdown of an acid-labile linker. In summary, this work presents rHA-nucleic acid module-based assemblies with improved stability and retained module functionality that further promotes the drug delivery potential of this biomolecular platform.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Bioconjugate Chemistry |
| Vol/bind | 33 |
| Nummer | 2 |
| Sider (fra-til) | 333-342 |
| Antal sider | 10 |
| ISSN | 1043-1802 |
| DOI | |
| Status | Udgivet - feb. 2022 |
Se relationer på Aarhus Universitet Citationsformater
ID: 235660160