title: Matrix Metalloproteinase Responsive, Proximity-activated Polymeric Nanoparticles for siRNA Delivery.
abstract: Small interfering RNA (siRNA) has significant potential to evolve into a new class of pharmaceutical inhibitors, but technologies that enable robust, tissue-specific intracellular delivery must be developed before effective clinical translation can be achieved. A pH-responsive, smart polymeric nanoparticle (SPN) with matrix metalloproteinase (MMP)-7-dependent proximity-activated targeting (PAT) is described here. The PAT-SPN was designed to trigger cellular uptake and cytosolic delivery of siRNA once activated by MMP-7, an enzyme whose overexpression is a hallmark of cancer initiation and progression. The PAT-SPN is composed of a corona-forming PEG block, an MMP-7-cleavable peptide, a cationic siRNA-condensing block, and a pH-responsive, endosomolytic terpolymer block that drives self-assembly and forms the PAT-SPN core. With this novel design, the PEG corona shields cellular interactions until it is cleaved in MMP-7-rich environments, shifting SPNζ-potential from +5.8 to +14.4 mV and triggering a 2.5 fold increase in carrier internalization. The PAT-SPN exhibited pH-dependent membrane disruptive behavior that enabled siRNA escape from endo-lysosomal pathways. Efficient intracellular siRNA delivery and knockdown of the model enzyme luciferase in R221A-Luc mammary tumor cellssignificantly depended on MMP-7 pre-activation. These combined data indicate that the PAT-SPN provides a promising new platform for tissue-specific, proximity-activated siRNA delivery to MMP-rich pathological environments.
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, VU Station B, Box 351631, Nashville, TN, USA; Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt University, Nashville, TN, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, VU Station B, Box 351631, Nashville, TN, USA.
authors.forename: Shann S
authors.initials: SS
authors.lastname: Yu
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, VU Station B, Box 351631, Nashville, TN, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Miteva
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, VU Station B, Box 351631, Nashville, TN, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Nelson
authors.affiliation: Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt University, Nashville, TN, USA; Department of Engineering and Physics, Murray State University, Murray, KY, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Werfel
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, VU Station B, Box 351631, Nashville, TN, USA; Department of Cancer Biology, Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Giorgio
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, VU Station B, Box 351631, Nashville, TN, USA; Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt University, Nashville, TN, USA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Duvall
keywords: MMP-7; Matrix metalloproteinase-responsive; Proximity-activated targeting; RNA interference; endosome escape; environmental targeting; gene delivery; pH responsive; smart polymer