Clinical magnetic hyperthermia requires integrated magnetic particle imaging.

Magnetic nanomaterials that respond to clinical magnetic devices have significant potential as cancer nanotheranostics. The complexities of their physics, however, introduce challenges for these applications. Hyperthermia is a heat-based cancer therapy that improves treatment outcomes and patient survival when controlled energy delivery is combined with accurate thermometry. To date, few technologies have achieved the needed evolution for the demands of the clinic. Magnetic fluid hyperthermia (MFH) offers this potential, but to be successful it requires particle-imaging technology that provides real-time thermometry. Presently, the only technology having the potential to meet these requirements is magnetic particle imaging (MPI), for which a proof-of-principle demonstration with MFH has been achieved. Successful clinical translation and adoption of integrated MPI/MFH technology will depend on successful resolution of the technological challenges discussed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Multifunctional Theranostic Graphene Oxide Nanoflakes as MR Imaging Agents with Enhanced Photothermal and Radiosensitizing Properties.

The integration of multiple therapeutic and diagnostic functions into a single nanoplatform for image-guided cancer therapy has been an emerging trend in nanomedicine. We show here that multifunctional theranostic nanostructures consisting of superparamagnetic iron oxide (SPIO) and gold nanoparticles (AuNPs) scaffolded within graphene oxide nanoflakes (GO-SPIO-Au NFs) can be used for dual photo/radiotherapy by virtue of the near-infrared (NIR) absorbance of GO for photothermal therapy (PTT) and the Z element radiosensitization of AuNPs for enhanced radiation therapy (RT). At the same time, this nanoplatform can also be detected by magnetic resonance (MR) imaging because of the presence of SPIO NPs. Using a mouse carcinoma model, GO-SPIO-Au NF-mediated combined PTT/RT exhibited a 1.85-fold and 1.44-fold higher therapeutic efficacy compared to either NF-mediated PTT or RT alone, respectively, resulting in a complete eradication of tumors. As a sensitive multifunctional theranostic platform, GO-SPIO-Au NFs appear to be a promising nanomaterial for enhanced cancer imaging and therapy.

Label-free CEST MRI Detection of Citicoline-Liposome Drug Delivery in Ischemic Stroke.

Citicoline (CDPC) is a natural supplement with well-documented neuroprotective effects in the treatment of neurodegenerative diseases. In the present study, we sought to exploit citicoline as a theranostic agent with its inherent chemical exchange saturation transfer (CEST) MRI signal, which can be directly used as an MRI guidance in the citicoline drug delivery. Our in vitro CEST MRI results showed citicoline has two inherent CEST signals at +1 and +2 ppm, attributed to exchangeable hydroxyl and amine protons, respectively. To facilitate the targeted drug delivery of citicoline to ischemic regions, we prepared liposomes encapsulating citicoline (CDPC-lipo) and characterized the particle properties and CEST MRI properties. The in vivo CEST MRI detection of liposomal citicoline was then examined in a rat brain model of unilateral transient ischemia induced by a two-hour middle cerebral artery occlusion. The results showed that the delivery of CPDC-lipo to the brain ischemic areas could be monitored and quantified by CEST MRI. When administered intra-arterially, CDPC-lipo clearly demonstrated a detectable CEST MRI contrast at 2 ppm. CEST MRI revealed that liposomes preferentially accumulated in the areas of ischemia with a disrupted blood-brain-barrier. We furthermore used CEST MRI to detect the improvement in drug delivery using CDPC-lipo targeted against vascular cell adhesion molecule (VCAM)-1 in the same animal model. The MRI findings were validated using fluorescence microscopy. Hence, liposomal citicoline represents a prototype theranostic system, where the therapeutic agent can be detected directly by CEST MRI in a label-free fashion.

Non-invasive temperature mapping using temperature-responsive water saturation shift referencing (T-WASSR) MRI.

We present a non-invasive MRI approach for assessing the water proton resonance frequency (PRF) shifts associated with changes in temperature. This method is based on water saturation shift referencing (WASSR), a method first developed for assessing B0 field inhomogeneity. Temperature-induced water PRF shifts were determined by estimating the frequency of the minimum intensity of the water direct saturation spectrum at each temperature using Lorentzian line-shape fitting. The change in temperature was then calculated from the difference in water PRF shifts between temperatures. Optimal acquisition parameters were first estimated using simulations and later confirmed experimentally. Results in vitro and in vivo showed that the temperature changes measured using the temperature-responsive WASSR (T-WASSR) were in good agreement with those obtained with MR spectroscopy or phase-mapping-based water PRF measurement methods,. In addition, the feasibility of temperature mapping in fat-containing tissue is demonstrated in vitro. In conclusion, the T-WASSR approach provides an alternative for non-invasive temperature mapping by MRI, especially suitable for temperature measurements in fat-containing tissues.

Noninvasive imaging of infection after treatment with tumor-homing bacteria using Chemical Exchange Saturation Transfer (CEST) MRI.

PURPOSE: To develop a noninvasive MRI method for determining the germination and infection of tumor-homing bacteria in bacteriolytic cancer therapy using endogenous CEST contrast. METHODS: The CEST parameters of the anaerobic gram-positive bacterium Clostridium novyi-NT (C. novyi-NT) were first characterized in vitro, then used to detect C. novyi-NT germination and infection in subcutaneous CT26 colorectal tumor-bearing mice (n = 6) after injection of 300 million bacterial spores. Lipopolysacharide (LPS) injected mice were used to exclude that the changes of CEST MRI were due to inflammation. RESULTS: CEST contrast was observed over a broad frequency range for bacterial suspensions in vitro, with the maximum contrast around 2.6 ppm from the water resonance. No signal could be detected for bacterial spores, demonstrating the specificity for germination. In vivo, a significant elevation of CEST contrast was identified in C. novyi-NT infected tumors as compared to those before bacterial germination and infection (P < 0.05; n = 6). No significant change was observed in tumors with LPS-induced sterile inflammation (P > 0.05; n = 4). CONCLUSION: Endogenous bacterial CEST contrast (bacCEST) can be used to monitor the germination and proliferation of the therapeutic bacterium C. novyi-NT without a need for exogenous cell labeling probes.

Science to practice: can stem cells be labeled inside the body instead of outside?

Instead of conventional labeling ex vivo in cell culture, mesenchymal stem cells (MSCs) were labeled in vivo with intravenous injection of ferumoxytol (Feraheme; AMAG Pharmaceuticals, Lexington, Mass), a Food and Drug Administration (FDA)-approved intravenous iron supplement. After their isolation and processing from bone marrow, the same MSCs were injected in rats with an osteochondral defect, allowing MR monitoring of their engraftment for at least 4 weeks. This straightforward labeling approach, avoiding several regulatory issues, may accelerate clinical translation of magnetic resonance (MR) imaging for stem cell tracking.

Magnetovaccination as a novel method to assess and quantify dendritic cell tumor antigen capture and delivery to lymph nodes.

A major parameter limiting immune responses to vaccination is the number of activated antigen-presenting cells (APC) that capture antigen and migrate to draining lymph nodes (LN). Currently, a quantitative noninvasive technique for monitoring in vivo antigen capture and delivery is lacking. The use of cellular magnetic resonance (MR) imaging (MRI) is a promising approach for this purpose; however, cellular imaging currently requires ex vivo prelabeling of cells with contrast agents followed by reintroduction of cells into the subject being monitored. Here, we describe an in vivo labeling method, which relies upon cell-to-cell transfer of superparamagnetic iron oxide (SPIO) from tumor cells to endogenous APCs, in situ, to quantify APC delivery to LNs in a tumor vaccine model. Mice were immunized with a tumor cell-based vaccine that was irradiated and labeled with SPIO. APCs that had captured SPIO were imaged over time as they accumulated in LNs. We show here that MRI is capable of monitoring, in vivo, the trafficking of magnetically labeled APCs inducing a tumor-specific immune response, and that these cells can be magnetically recovered ex vivo. Excellent correlation was observed between in vivo and ex vivo quantification of APCs, with resolution sufficient to detect increased APC trafficking elicited by an adjuvant. This study shows the potential of magnetovaccination and MRI cell tracking to systematically evaluate a key parameter relevant to the optimization of vaccine therapies through noninvasive MRI-based quantification of APC numbers.