Development of Novel Tumor-Targeted Theranostic Nanoparticles Activated by Membrane-Type Matrix Metalloproteinases for Combined Cancer Magnetic Resonance Imaging and Therapy
Ansari, C. Tikhomirov, G.A. Hong, S.H. Falconer, Robert A. Gill, Jason H. Castaneda, R. Hazard, F.K. Tong, L. Lenkov, O.D.
Ansari, C.
Tikhomirov, G.A.
Hong, S.H.
Falconer, Robert A.
Gill, Jason H.
Castaneda, R.
Hazard, F.K.
Tong, L.
Lenkov, O.D.
Publication Date
2014-02-04
End of Embargo
Supervisor
Rights
Peer-Reviewed
Yes
Open Access status
closedAccess
Accepted for publication
2013-08-27
Institution
Department
Awarded
Embargo end date
Collections
Additional title
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.
Version
No full-text in the repository
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
Link to published version
Link to Version of Record
Type
Article