Matrix Metalloproteinase Responsive, Proximity-activated Polymeric Nanoparticles for siRNA Delivery
| Autor: | Martina Miteva, Thomas A. Werfel, Todd D. Giorgio, Hongmei Li, Craig L. Duvall, Shann S. Yu, Christopher E. Nelson |
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| Rok vydání: | 2014 |
| Předmět: |
Gene knockdown
Small interfering RNA Materials science media_common.quotation_subject Nanotechnology Gene delivery Matrix metalloproteinase Condensed Matter Physics Article Electronic Optical and Magnetic Materials Cell biology Biomaterials RNA interference Electrochemistry Luciferase Internalization Intracellular media_common |
| Zdroj: | Advanced functional materials. 23(24) |
| ISSN: | 1616-301X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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