Customizing Morphology, Size, and Response Kinetics of Matrix Metalloproteinase-Responsive Nanostructures by Systematic Peptide Design

Abstract

Over-expression and activation of matrix metalloproteinase-9 (MMP-9) is associated with multiple diseases, and can serve as a stimulus to activate nanomaterials for sensing and controlled release. In order to achieve autonomous therapeutics with improved space-time targeting capabilities, several features need to be considered beyond the introduction of an enzyme-cleavable linker into a nanostructure. We introduce guiding principles for a customizable platform using supramolecular peptide nanostructures with three modular components to achieve tunable kinetics and morphology changes upon MMP-9 exposure. This approach enables: (1) fine-tuning of kinetics through introduction of ordered/disordered structures, (2) a 12-fold variation in hydrolysis rates achieved by electrostatic (mis) matching of particle and enzyme charge, and (3) selection of enzymatic reaction products that are either cell-killing nanofibers or that disintegrate. These guiding principles, which can be rationalized and involve exchange of just a few amino acids, enable systematic customization of enzyme-responsive peptide nanostructures for general use in performance optimization of enzyme-responsive materials.

Inhibiting cancer metabolism by aromatic carbohydrate amphiphiles that act as antagonists of the glucose transporter GLUT1

“…in close proximity of cancer cells. 2,6,[12][13][14][15][16][17][18][19][20] Several studies suggested a mechanism that involves an initial internalization of the precursor by the cells, followed by intracellular enzymatic transformation and assembly that leads to cellular death. 6,18,21 Most of the described precursors are based on short self-assembling peptides that are functionalized with enzymatic sensitive moieties.…”

Tuning the matrix metalloproteinase-1 degradability of peptide amphiphile nanofibers through supramolecular engineering

“…23,24 Recently, Ulijn and coworkers reported a peptide design approach to tune the degradation kinetics of supramolecular peptide nanostructures by MMP-9. 25 Peptides were designed with systematically modified amino acid sequences to control overall charge and order in the MMP-9 substrate region. As result of this systematic design, nanostructures with different secondary structures and morphologies (nanofibers, elongated worm-like micelles and spherical micelles) were formed by self-assembly, not being possible to isolate the effect of nanostructure morphology on MMP cleavability.…”

Ultrashort Peptide Self-Assembly: Front-Runners to Transport Drug and Gene Cargos

“…Recently, guiding principles to customize the kinetics and morphological changes in supramolecular peptide nanostructures have been introduced by Son et al (2019) upon exposure of matrix metalloproteinase. These guiding principles enumerate systematic customization of enzyme-responsive peptide nanostructures by exchange of just a few amino acids, for general use in performance optimization of enzymeresponsive materials (Son et al, 2019). The advantages of enzyme-instructed self-assembly (EISA) in triggering the molecular self-assembly in situ, by overexpression, to prepare supramolecular biofunctional materials and hydrogels has been reviewed by Gao et al (2019).…”