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.
Lipid-polymer hybrid materials have the potential to exhibit enhanced stability and loading capabilities in comparison to parent liposome or polymer materials. However, complexities lie in formulating and characterizing such complex nanomaterials. Here we describe a lipid-coated polymer gel (lipogel) formulated using a single-pot methodology, where self-assembling liposomes template a UV-curable polymer gel core. Using fluorescently labeled lipids, protein, and hydrophobic molecules, we characterized their formation, purification, stability, and encapsulation efficiency via common instrumentation methods such as dynamic light scattering (DLS), matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS), UV-vis spectroscopy, fluorescence spectroscopy, and single-particle total internal reflection fluorescence (TIRF) microscopy. In addition, we confirmed that these dual-guest-loaded lipogels are stable in solution for several months. The simplicity of this complete aqueous formation and noncovalent dual-guest encapsulation holds potential as a tunable nanomaterial scaffold.
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