Matrix Metalloproteinase-9-Responsive Nanogels for Proximal Surface Conversion and Activated Cellular Uptake

Abstract

Here, we have exploited the heightened extracellular concentration of matrix metalloproteinase-9 (MMP-9) to induce surface-conversional properties of nanogels with the aim of tumor-specific enhanced cellular uptake. A modular polymeric nanogel platform was designed and synthesized for facile formulation and validation of MMP-9-mediated dePEGylation and generation of polyamine-type surface characteristics through peptide N-termini. Nanogels containing MMP-9-cleavable motifs and different poly(ethylene glycol) corona lengths (350 and 750 g/mol) were prepared, and enzymatic surface conversional properties were validated by MALDI characterization of cleaved byproducts, fluorescamine assay amine quantification, and zeta potential. The nanogel with a shorter PEG length, mPEG350-NG, exhibited superior surface conversion in response to extracellular concentrations of MMP-9 compared to that of the longer PEG length, mPEG750-NG. Confocal microscopy images of HeLa cells incubated with both fluorescein-labeled nanogels and DiI-encapsulated nanogels demonstrated greater uptake following MMP-9 "activation" for mPEG350-NG compared to its nontreated "passive" mPEG350-NG parent, demonstrating the versatility of such systems to achieve stimuli-responsive uptake in response to cancer-relevant proteases.

DePEGylation strategies to increase cancer nanomedicine efficacy

“…Liposomes [139][140][141][142][143][144][145] Quantum dots (QDs) [157] Polymersomes [158] Magnetic nanoparticles [159] Micelles [146][147][148][149][150][151][152][153][154][155][156] [ 160,161] External Light Liposomes [163] MSN [164] Micelles [168] [ 63,[165][166][167]169]…”

Recent advances in drug delivery systems for enhancing drug penetration into tumors

“…However, when placing the PEAGA-CPT drug-loaded system in an environment with high GGT expression, charge reversal did not occur and in subsequent animal experiments, a therapeutic effect inferior to that of PBEAGA-CPT was observed. Gordon et al (2018) proposed a simplified protease activation strategy to explore the generation of peptide N-termini on the surface of particles, for the promotion of cellular uptake (Figure 9). This can be achieved by attaching a protease-cleavable peptide to a nanogel at its C-and N-termini which is shielded by PEG.…”

“…Gordon et al. ( 2018 ) proposed a simplified protease activation strategy to explore the generation of peptide N-termini on the surface of particles, for the promotion of cellular uptake ( Figure 9 ). This can be achieved by attaching a protease-cleavable peptide to a nanogel at its C- and N-termini which is shielded by PEG.…”

“… MMP-9 response charge reversal gel system showing a more rapid rate of endocytosis rate and representing a passive PEGylated gel system (Gordon et al., 2018 ). …”

An Insight into Structural and Mechanical Properties of Ideal‐Networked Poly(Ethylene Glycol)–Peptide Hydrogels from Molecular Dynamics Simulations

“…Several factors including molecular weight and solution concentration of the monomers/macromers, synthesis technique, cross‐linking time, temperature, pH, viscosity, and the specificity of bioactive molecules incorporated can modify the network structure and thereby the macroscopic gel properties, including stiffness, volumetric swelling, and diffusivity of drug molecules through the network. Stimuli‐responsive PEG–peptide hydrogels that respond to the presence of proteolytic enzymes, such as matrix‐metalloproteinases (MMPs) have been synthesized . MMPs degrade the extra‐cellular matrix, which is an essential cellular structure for adhesion, migration, proliferation, and differentiation.…”