Tuneable Peptide Cross-Linked Nanogels for Enzyme Triggered Protein Delivery
2020
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 °C, 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 enzyme-specific 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.
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