Tuneable peptide cross-linked nanogels for enzyme-triggered protein delivery
File(s)
Published version
Author(s)
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.
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.
Date Issued
2020-09-03
Date Acceptance
2020-08-22
Citation
Journal of Materials Chemistry B, 2020, 8 (38), pp.8894-8907
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
License URL
Sponsor
British Heart Foundation
Medical Research Council (MRC)
Engineering & Physical Science Research Council (EPSRC)
Wellcome Trust
Commission of the European Communities
Wellcome Trust
Identifier
https://pubs.rsc.org/en/content/articlelanding/2020/TB/D0TB01546F#!divAbstract
Grant Number
RM/13/1/30157
MR/R015651/1
EP/K020641/1
098411/Z/12/Z
642414
209121/Z/17/Z
Subjects
0303 Macromolecular and Materials Chemistry
0903 Biomedical Engineering
Publication Status
Published
Date Publish Online
2020-09-03