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, we describe the design and characterization of novel multifunctional “theranostic” nanoparticles (TNPs) for enzyme-specific drug activation at tumor sites and simultaneous in vivo magnetic resonance imaging (MRI) of drug delivery. TNPs were 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 was 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 demonstrated significant tumor selective accumulation of the TNP, an observation confirmed by histopathology. Treatment with CLIO-ICTs induced a significant antitumor effect and tumor necrosis, a response not observed with ferumoxytol. Furthermore, no toxicity or cell death was observed in normal tissues following treatment with CLIO-ICTs, ICT, or ferumoxytol. Our 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.

Light/magnetic hyperthermia triggered drug released from multi-functional thermo-sensitive magnetoliposomes for precise cancer synergetic theranostics

“…It is applied widely in biomedical fields [25,26]. For instance, MNPs can be used in magnetic targeting, thermal therapy, and magnetic resonance imaging (MRI) [27,28], which allow to monitor the biodistribution in vivo non-invasively. Magnetic TSLs (MagTSLs, magnetic nanoparticles encapsulated within TSLs) appear to realize magnetocaloric mediated triggered drug release based on Brown and Neel relaxations [29,30].…”

Human mesenchymal stem cell-derived iron oxide exosomes allow targeted ablation of tumor cells via magnetic hyperthermia

“…42 Furthermore, MSCs/Fe cells and/or MSCs/Fe exosomes can be regarded as nanotheranostics. 43,44 They can help visualize tumor localization by magnetic resonance imaging and eradicate tumors using hyperthermia, and the modified yCD::UPRT-MSCs/ Fe cells might inhibit tumor growth via the expression of the prodrug suicide gene. All of these procedures mentioned are minimally invasive and do not produce systemic toxicity.…”

New approaches to selectively target cancer-associated matrix metalloproteinase activity

“…The injection of the iron oxide conjugated MMP-14 activatable prodrug into a mouse model of mammary tumorigenesis (MMTV-polyoma virus middle t antigen model) allowed for the MR imaging of MMP-14 activity in the tumor-microenvironment due to the accumulation of iron oxide and indirectly, as readout for the disruption of tumorassociated vasculature [110]. Importantly, these approaches focus on a "selectively" cleavable amino acid sequences but while these peptides may be selective in an in vitro setting it is possible that multiple proteases may have the ability to activate the nanoparticles in vivo.…”