Our lab has developed a novel drug delivery system to overcome significant limitations facing traditional cytotoxic drug delivery, namely the frequently narrow therapeutic indexes and significant off-target toxicities. Our materials are generated via graft-through polymerization of hydrophilic, enzyme-responsive peptides with hydrophobic therapeutics to generate diblock copolymer amphiphiles that assemble into nanoparticles upon dialysis. The function of these materials is mediated by overexpressed enzymes in diseased tissue that elicit a morphology change of the nanoparticles and results in enhanced accumulation of material at disease sites. Specifically, we utilize matrix metalloproteinases (MMPs) overexpressed in tumor tissue to guide the in vivo accumulation of our materials. The peptides on our system are cleaved at their recognitions sequences, which disrupts the nanoparticle structure and induces a nano- to micro-scale morphology change in the material. This translates to long retention times (on the order of days to weeks) of material in the tissue of interest, making it possible to deliver therapeutic cargo at high concentrations (&gt;60% drug loading, by mass) for extended periods through this mechanism. Herein, we describe the general strategy for the preparation and in vivo analysis of our enzyme-responsive drug delivery systems that contain chemotherapeutics (paclitaxel), as well as small molecule immune activators (TLR-7 agonists). We demonstrate the capacity of these systems to significantly delay primary tumor growth in an HT-1080 xenograft model and reduce the number of lung nodules in a metastatic 4T1 orthotopic syngeneic model. Further, we demonstrate exceptionally low systemic drug toxicity through our delivery system, as compared to the parent compounds.

Enzyme-responsive nanomaterials for targeted delivery of chemo- and immunotherapeutics

253rd National Meeting (2017)

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