Cryogel microcarriers for sustained local delivery of growth factors to the brain

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Abrar Hakami - , Cardiff University, King Abdulaziz University (Author)
  • Kaushik Narasimhan - , University of Galway (Author)
  • Giulia Comini - , University of Galway (Author)
  • Julian Thiele - , Leibniz Institute of Polymer Research Dresden, Otto von Guericke University Magdeburg (Author)
  • Carsten Werner - , Chair of Biofunctional Polymer Materials, Leibniz Institute of Polymer Research Dresden (Author)
  • Eilís Dowd - , University of Galway (Author)
  • Ben Newland - , Cardiff University (Author)

Abstract

Neurotrophic growth factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) have been considered as potential therapeutic candidates for neurodegenerative disorders due to their important role in modulating the growth and survival of neurons. However, clinical translation remains elusive, as their large size hinders translocation across the blood-brain barrier (BBB), and their short half-life in vivo necessitates repeated administrations. Local delivery to the brain offers a potential route to the target site but requires a suitable drug-delivery system capable of releasing these proteins in a controlled and sustained manner. Herein, we develop a cryogel microcarrier delivery system which takes advantage of the heparin-binding properties of GDNF and BDNF, to reversibly bind/release these growth factors via electrostatic interactions. Droplet microfluidics and subzero temperature polymerization was used to create monodisperse cryogels with varying degrees of negative charge and an average diameter of 20 μm. By tailoring the inclusion of 3-sulfopropyl acrylate (SPA) as a negatively charged moiety, the release duration of these two growth factors could be adjusted to range from weeks to half a year. 80% SPA cryogels and 20% SPA cryogels were selected to load GDNF and BDNF respectively, for the subsequent biological studies. Cell culture studies demonstrated that these cryogel microcarriers were cytocompatible with neuronal and microglial cell lines, as well as primary neural cultures. Furthermore, in vivo studies confirmed their biocompatibility after administration into the brain, as well as their ability to deliver, retain and release GDNF and BDNF in the striatum. Overall, this study highlights the potential of using cryogel microcarriers for long-term delivery of neurotrophic growth factors to the brain for neurodegenerative disorder therapeutics.

Details

Original languageEnglish
Pages (from-to)404-419
Number of pages16
JournalJournal of controlled release
Volume369
Publication statusPublished - May 2024
Peer-reviewedYes

External IDs

PubMed 38508528
ORCID /0000-0003-0189-3448/work/161890253

Keywords

ASJC Scopus subject areas

Keywords

  • Cryogel microcarrier, Growth factors, Microfluidics, Sustained release, Brain-Derived Neurotrophic Factor/administration & dosage, Humans, Rats, Male, Rats, Sprague-Dawley, Glial Cell Line-Derived Neurotrophic Factor/administration & dosage, Drug Delivery Systems, Drug Carriers/chemistry, Animals, Drug Liberation, Cryogels/chemistry, Delayed-Action Preparations, Brain/metabolism