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

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Author(s)

  • Lucia Massi
  • Adrian Najer
  • Robert Chapman
  • Christopher D Spicer
  • Valeria Nele
  • Junyi Che
  • Marsilea A Booth
  • James J Doutch
  • Molly M Stevens

Department/unit(s)

Publication details

JournalJournal of Materials Chemistry B
DateAccepted/In press - 22 Aug 2020
DateE-pub ahead of print - 3 Sep 2020
DatePublished (current) - 14 Oct 2020
Issue number38
Volume8
Number of pages14
Pages (from-to)8894-8907
Early online date3/09/20
Original languageEnglish

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.

Bibliographical note

© The Royal Society of Chemistry 2020

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