title: Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy.
abstract: A major drawback with current cancer therapy is the prevalence of unrequired dose-limiting 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-specific 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 CLIO-ICTs (TNPs). Significant cell death is observed in TNP-treated MMP-14 positive MMTV-PyMT breast cancer cells in vitro, but not MMP-14 negative fibroblasts or cells treated with ferumoxytol alone. Intravenous administration of TNPs to MMTV-PyMT tumor-bearing mice and subsequent MRI demonstrates significant tumor selective accumulation of the TNP, an observation confirmed 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 findings demonstrate proof of concept for a new nanotemplate that integrates tumor specificity, 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 significantly improve targeted cancer therapies, and ultimately enable personalized therapy regimens.
authors.affiliation: Molecular Imaging Program at Stanford and Department of Radiology, Stanford University, 725 Welch Road, Rm 1665, Stanford, CA, 94305-5614, USA.
authors.forename: Celina
authors.initials: C
authors.lastname: Ansari
authors.forename: Grigory A
authors.initials: GA
authors.lastname: Tikhomirov
authors.forename: Su Hyun
authors.initials: SH
authors.lastname: Hong
authors.forename: Robert A
authors.initials: RA
authors.lastname: Falconer
authors.forename: Paul M
authors.initials: PM
authors.lastname: Loadman
authors.forename: Jason H
authors.initials: JH
authors.lastname: Gill
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Castaneda
authors.forename: Florette K
authors.initials: FK
authors.lastname: Hazard
authors.forename: Ling
authors.initials: L
authors.lastname: Tong
authors.forename: Olga D
authors.initials: OD
authors.lastname: Lenkov
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
authors.forename: Jianghong
authors.initials: J
authors.lastname: Rao
authors.forename: Heike E
authors.initials: HE
authors.lastname: Daldrup-Link
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D055598:Chemical Phenomena / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000378:metabolism*; D051379:Mice; D053758:Nanoparticles; D009369:Neoplasms / Q000175:diagnosis* / Q000628:therapy*
chemical_list: D000970:Antineoplastic Agents; D020169:Caspases; D053504:Matrix Metalloproteinases, Membrane-Associated
keywords: MMP-14; MR imaging; cancer therapy; iron oxide; nanoparticles; theranostic
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