Confinement of Therapeutic Enzymes in Selectively Permeable Polymer Vesicles by Polymerization-Induced Self-Assembly (PISA) Reduces Antibody Binding and Proteolytic Susceptibility

Research output: Contribution to journalArticle

Authors

  • Lewis D Blackman
  • Spyridon Varlas
  • Zachary H Houston
  • Nicholas L Fletcher
  • Kristofer J Thurecht
  • Muhammad Hasan
  • Matthew I Gibson

Colleges, School and Institutes

External organisations

  • Department of Chemistry, The University of Warwick , Gibbet Hill Road, Coventry CV4 7AL, United Kingdom.
  • School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
  • ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Warwick Medical School, University of Warwick, Gibbet Hill Road, CV4 7AL Coventry, United Kingdom.

Abstract

Covalent PEGylation of biologics has been widely employed to reduce immunogenicity, while improving stability and half-life in vivo. This approach requires covalent protein modification, creating a new entity. An alternative approach is stabilization by encapsulation into polymersomes; however this typically requires multiple steps, and the segregation requires the vesicles to be permeable to retain function. Herein, we demonstrate the one-pot synthesis of therapeutic enzyme-loaded vesicles with size-selective permeability using polymerization-induced self-assembly (PISA) enabling the encapsulated enzyme to function from within a confined domain. This strategy increased the proteolytic stability and reduced antibody recognition compared to the free protein or a PEGylated conjugate, thereby reducing potential dose frequency and the risk of immune response. Finally, the efficacy of encapsulated l-asparaginase (clinically used for leukemia treatment) against a cancer line was demonstrated, and its biodistribution and circulation behavior in vivo was compared to the free enzyme, highlighting this methodology as an attractive alternative to the covalent PEGylation of enzymes.

Details

Original languageEnglish
Pages (from-to)718-723
Number of pages6
JournalACS Central Science
Volume4
Issue number6
Early online date16 May 2018
Publication statusPublished - 27 Jun 2018