Hybrid Programmable Peptide Crosslinkers as Enzyme-Regulated Drug Delivery Vehicles

J.L. Rouge
University of Connecticut,
United States

Keywords: nanocapsules, drug delivery, therapeutic oligonucleotides, peptides, micelles


Biology has evolved the quintessential nucleic acid delivery vehicle, the virus, using proteins built from self-assembled peptide subunits. These viral protein coats are then degraded by specific enzymes, depending on their location, releasing their contents at just the right moment for optimal gene delivery. Our lab seeks to mimic not only the assembly but the programmed disassembly of biomolecule-based vectors for the delivery of therapeutic oligonucleotides and small molecule drugs into cellular and extracellular environments. Using a hybrid surfactant and peptide-based self assembly method, we have built a series of peptide crosslinked micelle systems that breakdown and release their cargo in response to the presence of specific enzyme targets. The nanocapsule displays highly specific release in the presence of closely related proteases (MMPs) and can be modified with electron dense tags such as gold nanoparticles for monitoring its assembly and disassembly using electron microscopy. We have shown through a combination of dynamic light scattering, fluorescence release assays, and cell viability studies that the location and enzyme expression levels in the vicinity of the peptide crosslinked nanocapsules can be used to specifically regulate the degradation of the nanocapsules shell for the controlled release of an internalized drug or cargo. Using drugs such as PMA for inducing MMP9 secretion in cell culture, we have also shown that we can trigger the release of an internalized cargo that would normally not occur, highlighting the relationship between enzyme expression level and the target peptides sequence. Integrating such natural biochemical ques for assembly and degradation into nanomaterials brings us one step closer to enabling more precise therapeutic delivery and effect.