Controlling the pharmacokinetics and targeting of small molecule drugs is at the core of medicinal chemistry and pharmaceutical science. This work utilizes enzyme-responsive, drug-conjugated, peptide-polymer amphiphiles that assemble into micellar nanoparticles with a surface comprised of enzyme-susceptible peptides and a hydrophobic paclitaxel core. Notably, the drug is polymerized directly (<i>i.e.,</i> in a graft-through fashion) and is covalently bound via a degradable linkage. Paclitaxel (PTX) is the therapeutic moiety in this motif, as it is a potent microtubule-stabilizing agent and standard component of chemotherapy regimes for many malignant and metastatic cancers. The hydrophilic peptide shell contains a substrate for matrix metalloproteinases (MMPs), which are overexpressed in an array of cancer types and present as catalytic, extracellular or membrane-bound tumor markers. Upon exposure to the enzyme, these materials undergo a nano- to micro-scale change in size, coupled with a change in morphology (from spherical micelles to aggregates). In this way, the tumor guides the accumulation process through MMP expression patterns resulting in active accumulation through catalytic amplification.<br/><br/>This work represents a proof-of-concept study demonstrating the utility of enzyme-responsive nanoscale drug carriers capable of targeted accumulation and retention in tumor tissue in response to overexpressed endogenous enzymes. Critically, we observed low systemic toxicity in healthy mice following intravenous (IV) administration, with the maximum tolerated dose (MTD) exceeding 240 mg/kg with respect to paclitaxel (16 times the MTD of the free drug). Furthermore, we observed efficacy against tumorigenesis paralleling that of paclitaxel at equivalent intravenous dosing, and near complete tumor growth suppression when administered intratumorally. This work represents a significant departure from traditional targeted drug delivery systems and presents a new avenue of exploration for nanomedicine.

Therapeutic enzyme-responsive nanoparticles for targeted delivery and accumulation in tumors

251st National Meeting (2016)

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