Herein, we describe an enzyme-responsive, paclitaxel-loaded nanoparticle and assess its safety and efficacy in vivo in a human fibrosarcoma murine xenograft. The material was generated via graft-through block copolymerization of norbornene monomers with hydrophilic targeting peptides together with hydrophobic paclitaxel prodrugs. In this system, an enzymatic signal endogenous to tumor tissue directs a build-up of material selectively at the tumor site. Specifically, we utilize matrix metalloproteinases (MMPs), overexpressed in an array of cancer types and present as catalytic, extracellular or membrane-bound tumor markers. In this strategy, nanoparticles have shells decorated with peptides containing a substrate for MMPs. Upon exposure to the enzyme, the materials undergo a nano- to microscale change in size, coupled with a change in morphology. In this way, the tumor guides the accumulation process through MMP expression patterns resulting in active accumulation through catalytic amplification. 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. 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. Additionally, it demonstrates the utility of enzyme-responsive nanoscale drug carriers capable of targeted accumulation and retention in tumor tissue in response to overexpressed endogenous enzymes.

Enzyme-responsive polymeric nanomaterials for paclitaxel delivery to tumor tissue

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.