A Modular Albumin-Oligonucleotide Biomolecular Assembly for Delivery of Antisense Therapeutics: Molecular Pharmaceutics

Marwa Elkhashab, Yeter Dilek, Morten Foss, Laura B. Creemers, Kenneth A. Howard*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

1 Citationer (Scopus)

Abstract

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.
OriginalsprogEngelsk
TidsskriftMolecular Pharmaceutics
Vol/bind21
Nummer2
Sider (fra-til)491-500
Antal sider10
ISSN1543-8384
DOI
StatusUdgivet - feb. 2024

Fingeraftryk

Dyk ned i forskningsemnerne om 'A Modular Albumin-Oligonucleotide Biomolecular Assembly for Delivery of Antisense Therapeutics: Molecular Pharmaceutics'. Sammen danner de et unikt fingeraftryk.

Citationsformater