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    Development of Novel Tumor-Targeted Theranostic Nanoparticles Activated by Membrane-Type Matrix Metalloproteinases for Combined Cancer Magnetic Resonance Imaging and Therapy

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    Publication date
    2014-02-04
    Author
    Ansari, C.
    Tikhomirov, G.A.
    Hong, S.H.
    Falconer, Robert A.
    Loadman, Paul M.
    Gill, Jason H.
    Castaneda, R.
    Hazard, F.K.
    Tong, L.
    Lenkov, O.D.
    Felsher, D.W.
    Rao, J.
    Daldrup-Link, H.E.
    Show allShow less
    Keyword
    Nanoparticles; Iron oxide; Cancer therapy; MR imaging; Theranostic; MMP-14; REF 2014
    Peer-Reviewed
    Yes
    
    Metadata
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    Abstract
    A major drawback with current cancer therapy is the prevalence of unrequired doselimiting toxicity to non-cancerous tissues and organs, which is further compounded by a limited ability to rapidly and easily monitor drug delivery, pharmacodynamics and therapeutic response. In this report, the design and characterization of novel multifunctional “theranostic” nanoparticles (TNPs) is described for enzyme-specifi c drug activation at tumor sites and simultaneous in vivo magnetic resonance imaging (MRI) of drug delivery. TNPs are synthesized by conjugation of FDA-approved iron oxide nanoparticles ferumoxytol to an MMP-activatable peptide conjugate of azademethylcolchicine (ICT), creating CLIOICTs (TNPs). Signifi cant cell death is observed in TNP-treated MMP-14 positive MMTVPyMT breast cancer cells in vitro, but not MMP-14 negative fi broblasts or cells treated with ferumoxytol alone. Intravenous administration of TNPs to MMTV-PyMT tumor-bearing mice and subsequent MRI demonstrates signifi cant tumor selective accumulation of the TNP, an observation confi rmed by histopathology. Treatment with CLIO-ICTs induces a significant antitumor effect and tumor necrosis, a response not observed with ferumoxytol. Furthermore, no toxicity or cell death is observed in normal tissues following treatment with CLIO-ICTs, ICT, or ferumoxytol. These fi ndings demonstrate proof of concept for a new nanotemplate that integrates tumor specifi city, drug delivery and in vivo imaging into a single TNP entity through attachment of enzyme-activated prodrugs onto magnetic nanoparticles. This novel approach holds the potential to signifi cantly improve targeted cancer therapies, and ultimately enable personalized therapy regimens.
    URI
    http://hdl.handle.net/10454/8822
    Version
    published version paper
    Citation
    Ansari C,,Tikhomirov GA, Hong SH, Falconer RA, Loadman PM, Gill JH, Castaneda R, Hazard FK, Tong L, Lenkov OD, Felsher DW, Rao J and Daldrup-Link HE (2014) Development of Novel Tumor-Targeted Theranostic Nanoparticles Activated by Membrane-Type Matrix Metalloproteinases for Combined Cancer Magnetic Resonance Imaging and Therapy. Small, 10 (3): 566–575.
    Link to publisher’s version
    http://onlinelibrary.wiley.com/doi/10.1002/smll.201301456/full
    Type
    Article
    Collections
    Life Sciences Publications

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