Functionalization of polymeric nanoparticles with targeting VNAR ligands using vinyl sulfone conjugation

Adam Leach, Marie Finnegan, Mariana S. Machado, Laura Ferguson, John Steven, Peter Smyth, Andrew Porter, Caroline Barelle, Efrosyni Themistou*, Christopher J. Scott*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Actively targeted drug loaded nanoparticles represent an exciting new form of therapeutics for cancer and other diseases. These formulations are complex and in order to realize their ultimate potential, optimization of their preparation is required. In this current study, we have examined the conjugation of a model targeting ligand, conjugated in a site-specific manner using a vinyl sulfone coupling approach. A disulfide-functionalized poly(L-lactide)-b-poly(oligo(ethylene glycol) methacrylate)-stat-(bis(2-methacryloyl)oxyethyl disulfide) (PLA-b-P(OEGMA-stat-DSDMA)) diblock copolymer was synthesized by simultaneous ring opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. Subsequently, the disulfide bonds of the polymer were reduced to thiols and divinyl sulfone was attached to the polymer using thiol–ene chemistry to produce the vinyl sulfone (VS)-functionalized PLA-b-P(OEGMA-stat-VSTEMA) amphiphilic block copolymer. Single emulsion – solvent evaporation was employed using a blend of this polymer with poly(D,L-lactide-co-glycolide) (PLGA) to produce VS-functionalized polymeric nanoparticles. The ability of these novel nanoparticles to attach ligands was then exemplified using a single domain variable new antigen receptor (VNAR) with a free carboxyl terminal cysteine residue. The resulting VNAR-functionalized nanoparticles were found to maintain specific affinity to their cognate antigen (DLL4) for at least 72 h at 4 °C. The simplicity of the degradable amphiphilic block copolymer synthesis and the efficiency of VNAR conjugation to the VS-functionalized nanoparticles show the potential of this platform for therapeutic development.

Original languageEnglish
Pages (from-to)4181-4190
Number of pages10
JournalJournal of Materials Chemistry B
Volume11
Issue number19
Early online date17 Apr 2023
DOIs
Publication statusPublished - 21 May 2023

Keywords

  • General Materials Science
  • Biomedical Engineering
  • General Chemistry
  • General Medicine

ASJC Scopus subject areas

  • General Chemistry
  • General Materials Science
  • Biomedical Engineering

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