title: Enzyme-responsive multistage vector for drug delivery to tumor tissue.
abstract: Various nanodelivery systems have been designed to release therapeutic agents upon contact with specific enzymes. However, enzyme-triggered release typically takes place in the tissue interstitium, thereby resulting in the extracellular delivery of drugs. Here, we have designed an enzyme-stimulated multistage vector (ESMSV), which enables stimulus-triggered release of drug-encapsulated nanoparticles from a microparticle. Specifically, polymeric nanoparticles with a surface matrix metalloproteinase-2 (MMP2) peptide substrate were conjugated to the surface of porous silicon microparticles. In the presence of MMP2, the polymeric nanoparticles were released into the tumor interstitium. This platform can be used to attain triggered drug release, while simultaneously facilitating the cellular internalization of drugs. The results indicate that nanoparticle release was MMP2-specific and resulted in improved intracellular uptake of hydrophobic agents in the presence of MMP2. Furthermore, in a mouse model of melanoma lung metastasis, systemic delivery of ESMSVs caused a substantial increase in intracellular accumulation of agents in cancer cells in comparison to delivery with non-stimulus-responsive particles.
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Mi
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA; CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience & Technology of China, University of Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Joy
authors.initials: J
authors.lastname: Wolfram
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Mu
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA.
authors.forename: Xuewu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA.
authors.forename: Elvin
authors.initials: E
authors.lastname: Blanco
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA; Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA. Electronic address: mferrari@houstonmethodist.org.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D004798:Enzymes / Q000737:chemistry*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy*; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D004798:Enzymes; D004364:Pharmaceutical Preparations; D011108:Polymers; D011092:Polyethylene Glycols; D020778:Matrix Metalloproteinase 2
keywords: Enzyme-responsive release; Lung metastasis; MMP2; Multistage vector; Porous silicon