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 °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.
Highlights
Many diseases are associated with the dysregulated activity of enzymes, such as matrix metalloproteinases (MMPs)
With respect to temperature-triggered systems, poly(N-isopropylacrylamide) (PNIPAM) remains one of the most studied polymers incorporated in the design of temperature-responsive materials for biomedical applications due to its fast temperature-induced phase transition at a lower critical solution temperature (LCST) of B32 1C.10,11
Via copolymerisation of NIPAM with NCPAM we could tune the thermal behaviour of the resulting copolymers resulting in a range of Tcp values around body temperature
Summary
Many diseases are associated with the dysregulated activity of enzymes, such as matrix metalloproteinases (MMPs). 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. To yield high level of control of drug loading and triggered release, temperature and/or enzyme-responsive motifs can be incorporated in polymer-based drug delivery.[9] With respect to temperature-triggered systems, poly(N-isopropylacrylamide) (PNIPAM) remains one of the most studied polymers incorporated in the design of temperature-responsive materials for biomedical applications due to its fast temperature-induced phase transition at a lower critical solution temperature (LCST) of B32 1C.10,11. Fine-tuning of the transition temperature using a library of copolymers, with precise control of the LCST around body temperature, enables application-dependent selection of a certain copolymer from the library to create customised vehicles for loading and release of sensitive therapeutic protein cargoes
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