Controlled release of G AG-binding e nhanced t ransduction (GET) peptides for sustained and highly efficient intracellular delivery

Abu-Awwad, Hosam Al-Deen M.; Thiagarajan, Lalitha; Dixon, James E.

Abstract

Controlled release systems for therapeutic molecules are vital to allow the sustained local delivery of their activities which direct cell behaviour and enable novel regenerative strategies. Direct programming of cells using exogenously delivered transcription factors can by-pass growth factor signalling but there is still a requirement to deliver such activity spatio-temporally. We previously developed a technology termed GAG-binding enhanced transduction (GET) to efficiently deliver a variety of cargoes intracellularly, using GAG-binding domains which promote cell targeting, and cell penetrating peptides (CPPs) which allow cell entry. Herein we demonstrate that GET system can be used in controlled release systems to mediate sustained intracellular transduction over one week. We assessed the stability and activity of GET peptides in poly(dl-lactic acid-co-glycolic acid) (PLGA) microparticles (MPs) prepared using a S/O/W double emulsion method. Efficient encapsulation (∼65%) and tailored protein release profiles could be achieved, however intracellular transduction was significantly inhibited post-release. To retain GET peptide activity we optimized a strategy of co-encapsulation of l-Histidine, which may form a complex with the PLGA degradation products under acidic conditions. Simulations of the polymer microclimate showed that hydrolytic acidic PLGA degradation products directly inhibited GET peptide transduction activity, and use of l-Histidine significantly enhanced released protein delivery. The ability to control the intracellular transduction of functional proteins into cells will facilitate new localized delivery methods and allow approaches to direct cellular behaviour for many regenerative medicine applications.

Citation

Abu-Awwad, H. A.-D. M., Thiagarajan, L., & Dixon, J. E. (2017). Controlled release of G AG-binding e nhanced t ransduction (GET) peptides for sustained and highly efficient intracellular delivery. Acta Biomaterialia, 57, 225-237. https://doi.org/10.1016/j.actbio.2017.04.028

• Journal Article Type: Article
• Acceptance Date: Apr 24, 2017
• Online Publication Date: Apr 27, 2017
• Publication Date: 2017-07
• Deposit Date: Jun 6, 2017
• Publicly Available Date: Jun 6, 2017
• Journal: Acta Biomaterialia
• Print ISSN: 1742-7061
• Electronic ISSN: 1878-7568
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 57
• Pages: 225-237
• DOI: https://doi.org/10.1016/j.actbio.2017.04.028
• Keywords: Intracellular transduction; Controlled release; GAG-binding enhanced transduction (GET); CPP; PLGA; l-Histidine
• Public URL: https://nottingham-repository.worktribe.com/output/872600
• Publisher URL: http://www.sciencedirect.com/science/article/pii/S1742706117302751
• Additional Information: This article is maintained by: Elsevier; Article Title: Controlled release of GAG-binding enhanced transduction (GET) peptides for sustained and highly efficient intracellular delivery; Journal Title: Acta Biomaterialia; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.actbio.2017.04.028; Content Type: article; Copyright: © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
• Contract Date: Jun 6, 2017