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

Area of Science:

• Biomaterials Science
• Nanotechnology
• Cancer Biology

Background:

• Extracellular matrix metalloproteinase-9 (MMP-9) is upregulated in tumors.
• Nanogels offer potential for targeted drug delivery.
• Stimuli-responsive materials can enhance therapeutic efficacy.

Purpose of the Study:

• To design and synthesize a nanogel platform for MMP-9-mediated surface conversion.
• To enhance tumor-specific cellular uptake via enzyme-triggered dePEGylation.
• To investigate the effect of poly(ethylene glycol) corona length on nanogel responsiveness.

Main Methods:

• Synthesis of modular polymeric nanogels with MMP-9-cleavable motifs.
• Characterization of dePEGylation using MALDI, fluorescamine assay, and zeta potential measurements.
• Confocal microscopy to assess cellular uptake in HeLa cells with and without MMP-9 exposure.

Main Results:

• Nanogels with shorter poly(ethylene glycol) (PEG) length (mPEG350-NG) showed greater MMP-9-induced surface conversion than those with longer PEG (mPEG750-NG).
• MMP-9 activation significantly increased cellular uptake of mPEG350-NG compared to the non-activated form.
• Demonstrated stimuli-responsive uptake dependent on cancer-relevant protease concentrations.

Conclusions:

• Developed a versatile nanogel system for stimuli-responsive, tumor-specific cellular uptake.
• MMP-9-mediated dePEGylation effectively enhances nanogel internalization.
• This platform holds promise for targeted cancer therapy by exploiting the tumor microenvironment.