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Tuneable Peptide Cross-Linked Nanogels for Enzyme Triggered Protein Delivery

preprint
submitted on 29.04.2020 and posted on 29.04.2020 by Lucia Massi, Adrian Najer, Robert Chapman, Christopher Spicer, Valeria Nele, Marsilea Booth, James J Doutch, Molly Stevens

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.

Funding

Marie Skłodowska-Curie grant agreement (No 642414).

Swiss National Science Foundation Early Postdoc Mobility Fellowship (P2BSP2_168751).

Sir Henry Wellcome Postdoctoral Fellowship (209121_Z_17_Z).

Australian Research Council DECRA (DE170100315).

British Heart Foundation Cardiovascular Regenerative Medicine Centre (RM/13/1/30157)

Ermenegildo Zegna Founder’s Scholarship program.

Rosetrees Trust

New Zealand-Rutherford Foundation (MAB, RFT-ICT 1501-FF).

UK Regenerative Medicine Platform “Acellular Approaches for Therapeutic Delivery” (MR/K026682/1).

Engineering and Physical Science Research Council (EPSRC) grant "Bio-functionalised nanomaterials for ultrasensitive biosensing" (EP/K020641/1).

Wellcome Trust Senior Investigator Award (098411/Z/12/Z).

History

Email Address of Submitting Author

a.najer@imperial.ac.uk

Institution

Imperial College London

Country

UK

ORCID For Submitting Author

0000-0003-4868-9364

Declaration of Conflict of Interest

The authors declare no competing interests.

Version Notes

Preprint before peer review.

Licence

Exports