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Tuneable peptide cross-linked nanogels for enzyme-triggered protein delivery

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Title: Tuneable peptide cross-linked nanogels for enzyme-triggered protein delivery
Authors: Massi, L
Najer, A
Chapman, R
Spicer, C
Nele, V
Che, J
Booth, MA
Doutch, JJ
Stevens, M
Item Type: Journal Article
Abstract: Many diseases are associated with the dysregulated activity of enzymes, such as matrix metalloproteinases (MMPs). This dysregulation can be leveraged in drug delivery to achieve disease- or site-specific cargo release. Self-assembled polymeric nanoparticles are versatile drug carrier materials due to the accessible diversity of polymer chemistry. However, efficient loading of sensitive cargo, such as proteins, and introducing functional enzyme-responsive behaviour remain challenging. Herein, peptide-crosslinked, temperature-sensitive nanogels for protein delivery were designed to respond to MMP-7, which is overexpressed in many pathologies including cancer and inflammatory diseases. The incorporation of N-cyclopropylacrylamide (NCPAM) into N-isopropylacrylamide (NIPAM)-based copolymers enabled us to tune the polymer lower critical solution temperature from 33 to 44 1C, allowing the encapsulation of protein cargo and nanogel-crosslinking at slightly elevated temperatures. This approach resulted in nanogels that were held together by MMP-sensitive peptides for enzymespecific protein delivery. We employed a combination of cryogenic transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS), small angle neutron scattering (SANS), and fluorescence correlation spectroscopy (FCS) to precisely decipher the morphology, self-assembly mechanism, enzyme-responsiveness, and model protein loading/release properties of our nanogel platform. Simple variation of the peptide linker sequence and combining multiple different crosslinkers will enable us to adjust our platform to target specific diseases in the future.
Issue Date: 3-Sep-2020
Date of Acceptance: 22-Aug-2020
URI: http://hdl.handle.net/10044/1/82302
DOI: 10.1039/D0TB01546F
ISSN: 2050-750X
Publisher: Royal Society of Chemistry
Start Page: 8894
End Page: 8907
Journal / Book Title: Journal of Materials Chemistry B
Volume: 8
Issue: 38
Copyright Statement: © The Royal Society of Chemistry 2020. Open Access Article. Published on 03 September 2020. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence
Sponsor/Funder: British Heart Foundation
Medical Research Council (MRC)
Engineering & Physical Science Research Council (EPSRC)
Wellcome Trust
Commission of the European Communities
Wellcome Trust
Funder's Grant Number: RM/13/1/30157
MR/R015651/1
EP/K020641/1
098411/Z/12/Z
642414
209121/Z/17/Z
Keywords: 0303 Macromolecular and Materials Chemistry
0903 Biomedical Engineering
Publication Status: Published
Online Publication Date: 2020-09-03
Appears in Collections:Materials
Bioengineering
Faculty of Natural Sciences
Faculty of Engineering



This item is licensed under a Creative Commons License Creative Commons