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: Celina Ansari, Grigory A Tikhomirov, Su Hyun Hong, Robert A Falconer, Paul M Loadman, Jason H Gill, Rosalinda Castaneda, Florette K Hazard, Ling Tong, Olga D Lenkov, Dean W Felsher, Jianghong Rao, Heike E Daldrup-Link
• Journal: Small (Weinheim an der Bergstrasse, Germany) (Small) Vol. 10 Issue 3 Pg. 566-75, 417 (Feb 12 2014) ISSN: 1613-6829 [Electronic] Germany
• PMID: 24038954 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Caspases
• Matrix Metalloproteinases, Membrane-Associated

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Caspases (metabolism)
• Chemical Phenomena (drug effects)
• Female
• Fibroblasts (drug effects, enzymology, pathology)
• Humans
• Magnetic Resonance Imaging
• Matrix Metalloproteinases, Membrane-Associated (metabolism)
• Mice
• Nanoparticles
• Neoplasms (diagnosis, therapy)