Saturation Transfer Magnetic Resonance Imaging Research Articles

Theranostics for MRI‐guided therapy: Recent developments

AbstractRecent advances in bioimaging, biochemistry, and bioinformatics have facilitated the development of personalized and precision medicine. Theranostics, combining imaging modalities and therapeutic agents, have garnered a lot of attention in this context, owing to their potential to monitor and control treatment for individual patients. A promising strategy to achieve this goal involves the development of therapy guided by magnetic resonance imaging (MRI). MRI has a high degree of soft tissue contrast, low invasiveness, high depth of penetration and good spatial resolution. MRI‐guided therapy could thus allow precise and time‐resolved assessment of disease conditions and therapeutic progression. This article will give a brief introduction to the principles of MRI, and describe recently developed strategies to produce MRI‐guided therapies. A number of theranostics based on T1, T2, or chemical exchange saturation transfer (CEST) MRI have been explored to track the route of drug carriers in vivo and image diseased tissue so as to enhance bioavailability, overcome complex delivery barriers, and assess therapeutic responses. In addition, the integration of thermal therapy and MRI imaging offers a strategy to noninvasively identify target areas, plan treatment, and provide real‐time assessment of the efficacy of tumor ablation. We also discuss advances in intelligent nanoparticles combining small molecule drugs, thermal treatment and multimodal imaging, arguing that these multifunctional agents can further improve therapeutic outcomes.

Metabolic Magnetic Resonance Imaging in Neuroimaging: Magnetic Resonance Spectroscopy, Sodium Magnetic Resonance Imaging and Chemical Exchange Saturation Transfer

Magnetic resonance (MR) is a powerful and versatile technique that offers much more beyond conventional anatomic imaging and has the potential of probing in vivo metabolism. Although MR spectroscopy (MRS) predates clinical MR imaging (MRI), its clinical application has been limited by technical and practical challenges. Other MR techniques actively being developed for in vivo metabolic imaging include sodium concentration imaging and chemical exchange saturation transfer. This article will review some of the practical aspects of MRS in neuroimaging, introduce sodium MRI and chemical exchange saturation transfer MRI, and highlight some of their emerging clinical applications.

Accelerated multi-target chemical exchange saturation transfer magnetic resonance imaging of the mouse heart

Cardiac chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) has been used to probe levels of various metabolites that provide insight into myocardial structure and function. However, imaging of the heart using CEST-MRI is prolonged by the need to repeatedly acquire multiple images for a full Z-spectrum and to perform saturation and acquisition around cardiac and respiratory cycles. Compressed sensing (CS) reconstruction of sparse data enables accelerated acquisition, but reconstruction artifacts may bias subsequently derived measures of CEST contrast. In this study, we examine the impact of CS reconstruction of increasingly under-sampled cardiac CEST-MRI data on subsequent CEST contrasts of amine-containing metabolites and amide-containing proteins. Cardiac CEST-MRI data sets were acquired in six mice using low and high RF saturation for single and dual contrast generation, respectively. CEST-weighted images were reconstructed using CS methods at 2–5× levels of under-sampling. CEST contrasts were derived from corresponding Z-spectra and the impact of accelerated imaging on accuracy was assessed via analysis of variance. CS reconstruction preserved myocardial signal to noise ratio as compared to conventional reconstruction. However, greater absolute error and distribution of derived contrasts was observed with increasing acceleration factors. The results from this study indicate that acquisition of radial cardiac CEST-MRI data can be modestly, but meaningfully, accelerated via CS reconstructions with little error in CEST contrast quantification.

Imaging Self-Healing Hydrogels and Chemotherapeutics Using CEST MRI at 3 T.

Imaging hydrogel-based local drug delivery to the brain after tumor resection has implications for refining treatments, especially for brain tumors with poor prognosis and high recurrence rate. Here, we developed a series of self-healing chitosan-dextran (CD)-based hydrogels for drug delivery to the brain. These hydrogels are injectable, self-healing, mechanically compatible, and detectable by chemical exchange saturation transfer magnetic resonance imaging (CEST MRI). CD hydrogels have an inherent CEST contrast at 1.1 ppm, which decreases as the stiffness increases. We further examined the rheological properties and CEST contrast of various chemotherapeutic-loaded CD hydrogels, including gemcitabine (Gem), doxorubicin, and procarbazine. Among these formulations, Gem presented the best compatibility with the rheological (G': 215.3 ± 4.5 Pa) and CEST properties of CD hydrogels. More importantly, the Gem-loaded CD hydrogel generated another CEST readout at 2.2 ppm (11.6 ± 0.1%) for monitoring Gem. This enabled independent and simultaneous imaging of the drug and hydrogel integrity using a clinically relevant 3 T MRI scanner. In addition, the Gem-loaded CD hydrogel exhibited a longitudinal antitumor efficacy of Gem over a week in vitro. Furthermore, the CD hydrogel could be visualized by CEST after brain injection with a contrast of 7.38 ± 2.31%. These natural labels on both the chemotherapeutics and hydrogels demonstrate unique image-guided local drug delivery for brain applications.

In Vivo Imaging of Allografted Glial-Restricted Progenitor Cell Survival and Hydrogel Scaffold Biodegradation

Transplanted glial-restricted progenitor (GRP) cells have potential to focally replace defunct astrocytes and produce remyelinating oligodendrocytes to avert neuronal death and dysfunction. However, most central nervous system cell therapeutic paradigms are hampered by high initial cell death and a host anti-graft immune response. We show here that composite hyaluronic acid-based hydrogels of tunable mechanical strengths can significantly improve transplanted GRP survival and differentiation. Allogeneic GRPs expressing green fluorescent protein and firefly luciferase were scaffolded in optimized hydrogel formulations and transplanted intracerebrally into immunocompetent BALB/c mice followed by serial in vivo bioluminescent imaging and chemical exchange saturation transfer magnetic resonance imaging (CEST MRI). We demonstrate that gelatin-sensitive CEST MRI can be exploited to monitor hydrogel scaffold degradation in vivo for ∼5 weeks post transplantation without necessitating exogenous labeling. Hydrogel scaffolding of GRPs resulted in a 4.5-fold increase in transplanted cell survival at day 32 post transplantation compared to naked cells. Histological analysis showed significant enhancement of cell proliferation as well as Olig2+ and GFAP+ cell differentiation for scaffolded cells compared to naked cells, with reduced host immunoreactivity. Hence, hydrogel scaffolding of transplanted GRPs in conjunction with serial in vivo imaging of cell survival and hydrogel degradation has potential for further advances in glial cell therapy.

Early detection of Alzheimer's disease using creatine chemical exchange saturation transfer magnetic resonance imaging

Detecting Alzheimer's disease (AD) at an early stage brings a lot of benefits including disease management and actions to slow the progression of the disease. Here, we demonstrate that reduced creatine chemical exchange saturation transfer (CrCEST) contrast has the potential to serve as a new biomarker for early detection of AD. The results on wild type (WT) mice and two age-matched AD models, namely tauopathy (Tau) and Aβ amyloidosis (APP), indicated that CrCEST contrasts of the cortex and corpus callosum in the APP and Tau mice were significantly reduced compared to WT counterpart at an early stage (6-7 months) (p < 0.011). Two main causes of the reduced CrCEST contrast, i.e. cerebral pH and creatine concentration, were investigated. From phantom and hypercapnia experiments, CrCEST showed excellent sensitivity to pH variations. From MRS results, the creatine concentration in WT and AD mouse brain was equivalent, which suggests that the reduced CrCEST contrast was dominated by cerebral pH change involved in the progression of AD. Immunohistochemical analysis revealed that the abnormal cerebral pH in AD mice may relate to neuroinflammation, a known factor that can cause pH reduction.

Non-Specific Low Back Pain and Lumbar Radiculopathy: Comparison of Morphologic and Compositional MRI as Assessed by gagCEST Imaging at 3T.

Using glycosaminoglycan Chemical Exchange Saturation Transfer (gagCEST) magnetic resonance imaging (MRI), this study comparatively evaluated the GAG contents of lumbar intervertebral disks (IVDs) of patients with non-specific low back pain (nsLBP), radiculopathy, and asymptomatic volunteers to elucidate the association of clinical manifestation and compositional correlate. A total of 18 patients (mean age 57.5 ± 22.5 years) with radiculopathy, 16 age-matched patients with chronic nsLBP and 20 age-matched volunteers underwent standard morphologic and compositional gagCEST MRI on a 3T scanner. In all cohorts, GAG contents of lumbar IVDs were determined using gagCEST MRI. An assessment of morphologic IVD degeneration based on the Pfirrmann classification and T2-weighted sequences served as a reference. A linear mixed model adjusted for multiple confounders was used for statistical evaluation. IVDs of patients with nsLBP showed lower gagCEST values than those of volunteers (nsLBP: 1.3% [99% confidence intervals (CI): 1.0; 1.6] vs. volunteers: 1.9% [99% CI: 1.6; 2.2]). Yet, IVDs of patients with radiculopathy (1.8% [99% CI: 1.4; 2.1]) were not different from patients with nsLBP or volunteers. In patients with radiculopathy, IVDs directly adjacent to IVD extrusions demonstrated lower gagCEST values than distant IVDs (adjacent: 0.9% [99% CI: 0.3; 1.5], distant: 2.1% [99% CI: 1.7; 2.5]). Advanced GAG depletion in nsLBP and directly adjacent to IVD extrusions in radiculopathy indicates close interrelatedness of clinical pathology and compositional degeneration.

CEST MRI trackable nanoparticle drug delivery systems

Mounting evidence shows the great promise of nanoparticle drug delivery systems (nano-DDSs) to improve delivery efficiency and reduce off-target adverse effects. By tracking drug delivery and distribution, monitoring nanoparticle degradation and drug release, aiding and optimizing treatment planning, and directing the design of more robust nano-DDSs, image guidance has become a vital component of nanomedicine. Recently, chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) has emerged as an attempting imaging method for achieving image-guided drug delivery. One of the unbeatable advantages of CEST MRI is its ability to detect diamagnetic compounds that cannot be detected using conventional MRI methods, making a broad spectrum of bioorganic agents, natural compounds, even nano-carriers directly MRI detectable in a high-spatial-resolution manner. To date, CEST MRI has become a versatile and powerful imaging technology for non-invasive in vivo tracking of nanoparticles and their loaded drugs. In this review, we will provide a concise overview of different forms of recently developed, CEST MRI trackable nano-DDSs, including liposomes, polymeric nanoparticles, self-assembled drug-based nanoparticles, and carbon dots. The potential applications and future perspectives will also be discussed.

MRSI vs CEST MRI to understand tomato metabolism in ripening fruit: is there a better contrast?

Besides structural information, magnetic resonance imaging (MRI) is crucial to reveal the presence and gradients of metabolites in organs constituted of several tissues. In plant science, such knowledge is key to better understand fruit development and metabolism. Routine methods based on fixation for cytological studies or dissection for metabolite measurements induce biases and plant sample destruction. Magnetic resonance spectroscopy imaging (MSRI) leads to one NMR spectrum per pixel while chemical exchange saturation transfer (CEST) MRI allows mapping metabolites having exchangeable protons. As both methods present different advantages and drawbacks, we compared them to map metabolites in ripe tomato fruits. We demonstrated that MRSI was difficult to interpret due to large spatial chemical shift variations while CEST MRI produced promising image mapping of the main carbohydrates and amino acids. It showed that glucose/fructose was mostly located in the locular tissue, whereas glutamate/glutamine/GABA was found inside the columella.Graphical abstract.

Repurposing Clinical Agents for Chemical Exchange Saturation Transfer Magnetic Resonance Imaging: Current Status and Future Perspectives

Molecular imaging is becoming an indispensable tool to pursue precision medicine. However, quickly translating newly developed magnetic resonance imaging (MRI) agents into clinical use remains a formidable challenge. Recently, Chemical Exchange Saturation Transfer (CEST) MRI is emerging as an attractive approach with the capability of directly using low concentration, exchangeable protons-containing agents for generating quantitative MRI contrast. The ability to utilize diamagnetic compounds has been extensively exploited to detect many clinical compounds, such as FDA approved drugs, X-ray/CT contrast agents, nutrients, supplements, and biopolymers. The ability to directly off-label use clinical compounds permits CEST MRI to be rapidly translated to clinical settings. In this review, the current status of CEST MRI based on clinically available compounds will be briefly introduced. The advancements and limitations of these studies are reviewed in the context of their pre-clinical or clinical applications. Finally, future directions will be briefly discussed.

Longitudinal GluCEST MRI Changes and Cerebral Blood Flow in 5xFAD Mice.

Many of the focal neurological symptoms associated with Alzheimer's disease (AD) are due to synaptic loss. Glutamate chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) is a candidate method to assess synaptic dysfunction. We assessed chronological changes in GluCEST in a 5xFAD mouse model of AD, comparing Glucest effects and regional cerebral blood flow (CBF). GluCEST effects and CBF in 5xFAD mice aged 1–15 months and their littermates (WT) were measured. Neurite orientation dispersion and density imaging (NODDI) MRI reflecting dendritic/axonal density was also measured and compared with GluCEST in 7-month-old mice. While regional CBF's decrease began at 7 months, GluCEST-reduction effects preceded hypoperfusion of the temporal cortex and hippocampus. While longitudinal 5xFAD mouse measurements revealed a correlation between the regional GluCEST effects and CBF, a generalized linear mixed model revealed statistically different correlations in cortical and basal brain regions. Further, NODDI-derived neurite density correlated with GluCEST effects in the parietal cortex, but not in the hippocampus, thereby revealing regional differences in pathophysiological mechanisms. Finally, GluCEST's effects correlated with regional synaptophysin. These results demonstrate that GluCEST can reflect subtle synaptic changes and may be a potential imaging method for AD diagnosis as well as serve as a biomarker of AD progression.

Noninvasive Detection of Extracellular pH in Human Benign and Malignant Liver Tumors Using CEST MRI.

PurposeIn this study, we aimed to use 3T magnetic resonance imaging (MRI), which is clinically available, to determine the extracellular pH (pHe) of liver tumors and prospectively evaluate the ability of chemical exchange saturation transfer (CEST) MRI to distinguish between benign and malignant liver tumors.MethodsDifferent radiofrequency irradiation schemes were assessed for ioversol-based pH measurements at 3T. CEST effects were quantified in vitro using the asymmetric magnetization transfer ratio (MTRasym) at 4.3 ppm from the corrected Z spectrum. Generalized ratiometric analysis was conducted by rationing resolved ioversol CEST effects at 4.3 ppm at a flip angle of 60 and 350°. Fifteen patients recently diagnosed with hepatic carcinoma and five patients diagnosed with hepatic hemangioma [1 male; mean age, 48.6 (range, 37–59) years] were assessed.ResultsBy conducting dual-power CEST MRI, the pH of solutions was determined to be 6.0–7.2 at 3T in vitro. In vivo, ioversol signal intensities in the tumor region showed that the extracellular pH in hepatic carcinoma was acidic(mean ± standard deviation, 6.66 ± 0.19), whereas the extracellular pH was more physiologically neutral in hemangioma (mean ± standard deviation, 7.34 ± 0.09).The lesion size was similar between CEST pH MRI and T2-weighted imaging.Conclusiondual-power CEST MRI can detect extracellular pH in human liver tumors and can provide molecular-level diagnostic tools for differentiating benign and malignant liver tumors at 3T.

Signal alterations of glutamate-weighted chemical exchange saturation transfer MRI in lysophosphatidylcholine-induced demyelination in the rat brain

PurposeTo compare in vivo glutamate-weighted chemical exchange saturation transfer (GluCEST-weighted) signal changes between in a rat model of demyelinated multiple sclerosis and control groups. ProceduresUsing a pre-clinical 7 T magnetic resonance imaging (MRI) system, CEST imaging was applied to a toxin (lysophosphatidylcholine; LPC) induced rat (MSLPC) and control (CTRL) groups to compare in vivo glutamate signal changes. The GluCEST-weighted signals were analyzed based on the magnetization transfer ratio asymmetry approach at 3.0 ppm on the region-of-interests (ROIs) in the corpus callosum and hippocampus at each hemispheric region. ResultsGluCEST-weighted signals were significantly changed between the CTRL and MSLPC groups, while higher glutamate signals were indicated in the MSLPC than the CTRL group ([MSLPC / CTRL]; hippocampus: [6.159 ± 0.790 / 4.336 ± 0.446] and corpus callosum: [-3.545 ± 0.945 / -6.038 ± 0.620], all p = 0.001). ConclusionsOur results show increased GluCEST-weighted signals in the LPC-induced demyelination rat brain compared with control. GluCEST-weighted imaging could be a useful tool for defining a biomarker to estimate the glutamate-related metabolism in MS.

Rapid three-dimensional steady-state chemical exchange saturation transfer magnetic resonance imaging.

To make clinically feasible whole-brain chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) by enhancing imaging efficiency. A novel, whole-brain three-dimensional (3D) steady-state CEST MRI method was introduced by utilizing a time-efficient, fat-suppressed excitation followed by rapid, segmented 3D echo-planar-imaging with incoherent undersampling in k-ω space. Missing signals and CEST-specific spectral images were then jointly estimated directly from incomplete measurements using model-based reconstruction and robust spectral analysis. In vivo studies were performed at 3T both retrospectively (using a fully sampled reference) and prospectively to validate the effectiveness of the proposed method in patients with brain cancer. In retrospective studies, the proposed method exhibits superior accuracies to existing methods in estimating images, z-spectra, and APTw relative to the reference. In prospective patient studies, compared with existing methods, the proposed method is statistically significantly different in contrast-to-noise ratio of the APTw contrast between tumor and normal appearing white matter (NAWM) and amide proton transfer weighted contrast (p < 0.05) while not being significantly different in signal-to-noise ratio in an NAWM region. We successfully demonstrated that it is feasible to perform whole-brain CEST MRI roughly within 4 minutes for patients with brain cancer. It is expected that the proposed method widens clinical utilities of CEST MRI.

N-Aryl Amides as Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Contrast Agents.

Chemical exchange saturation transfer (CEST) MRI has recently emerged as a versatile molecular imaging approach in which diamagnetic compounds can be utilized to generate an MRI signal. To expand the scope of CEST MRI applications, herein, we systematically investigated the CEST properties of N-aryl amides with different N-aromatic substitution, revealing their chemical shifts (4.6-5.8 ppm) and exchange rates (up to thousands s-1 ) are favorable to be used as CEST agents as compared to alkyl amides. As the first proof-of-concept study, we used CEST MRI to detect the enzymatic metabolism of the drug acebutolol directly by its intrinsic CEST signal without any chemical labeling. Our study implies that N-aryl amides may enable the label-free CEST MRI detection of the metabolism of many N-aryl amide-containing drugs and a variety of enzymes that act on N-aryl amides, greatly expanding the scope of CEST MR molecular imaging.

Glutamate Chemical Exchange Saturation Transfer (GluCEST) Magnetic Resonance Imaging in Pre-clinical and Clinical Applications for Encephalitis.

BackgroundEncephalitis is a common central nervous system inflammatory disease that seriously endangers human health owing to the lack of effective diagnostic methods, which leads to a high rate of misdiagnosis and mortality. Glutamate is implicated closely in microglial activation, and activated microglia are key players in encephalitis. Hence, using glutamate chemical exchange saturation transfer (GluCEST) imaging for the early diagnosis of encephalitis holds promise.MethodsThe sensitivity of GluCEST imaging with different concentrations of glutamate and other major metabolites in the brain was validated in phantoms. Twenty-seven Sprague–Dawley (SD) rats with encephalitis induced by Staphylococcus aureus infection were used for preclinical research of GluCEST imaging in a 7.0-Tesla scanner. For the clinical study, six patients with encephalitis, six patients with lacunar infarction, and six healthy volunteers underwent GluCEST imaging in a 3.0-Tesla scanner.ResultsThe number of amine protons on glutamate that had a chemical shift of 3.0 ppm away from bulk water and the signal intensity of GluCEST were concentration-dependent. Under physiological conditions, glutamate is the main contributor to the GluCEST signal. Compared with normal tissue, in both rats and patients with encephalitis, the encephalitis areas demonstrated a hyper-intense GluCEST signal, while the lacunar infarction had a decreased GluCEST signal intensity. After intravenous immunoglobulin therapy, patients with encephalitis lesions showed a decrease in GluCEST signal, and the results were significantly different from the pre-treatment signal (1.34 ± 0.31 vs 5.0 ± 0.27%, respectively; p = 0.000).ConclusionGlutamate plays a role in encephalitis, and the GluCEST imaging signal has potential as an in vivo imaging biomarker for the early diagnosis of encephalitis. GluCEST will provide new insight into encephalitis and help improve the differential diagnosis of brain disorders.

CEST MRI detectable liposomal hydrogels for multiparametric monitoring in the brain at 3T.

Adjuvant treatment using local drug delivery is applied in treating glioblastoma multiforme (GBM) after tumor resection. However, there are no non-invasive imaging techniques available for tracking the compositional changes of hydrogel-based drug treatment.Methods: We developed Chemical Exchange Saturation Transfer Magnetic Resonance Imaging (CEST MRI) detectable and injectable liposomal hydrogel to monitor these events in vivo at 3T clinical field. Mechanical attributes of these hydrogels and their in vitro and in vivo CEST imaging properties were systematically studied.Results: The MRI detectable hydrogels were capable of generating multiparametric readouts for monitoring specific components of the hydrogel matrix simultaneously and independently. Herein, we report, for the first time, CEST contrast at -3.4 ppm provides an estimated number of liposomes and CEST contrast at 5 ppm provides an estimated amount of encapsulated drug. CEST contrast decreased by 1.57% at 5 ppm, while the contrast at -3.4 ppm remained constant over 3 d in vivo, demonstrating different release kinetics of these components from the hydrogel matrix. Furthermore, histology analysis confirmed that the CEST contrast at -3.4 ppm was associated with liposome concentrations.Conclusion: This multiparametric CEST imaging of individual compositional changes in liposomal hydrogels, formulated with clinical-grade materials at 3T and described in this study, has the potential to facilitate the refinement of adjuvant treatment for GBM.

Enhanced CEST MRI Using the Residual of Inversed Z-Spectra for Ischemia Detection

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) had shown potential in sensing pH changes that occurs early in ischemic stroke. However, detection of mild acidosis is still challenging. To enhance CEST detection for ischemia, we proposed a quantification approach using the residual of inversed Z-spectra, i.e. MTR Rex VOPVP = 1/Z exp -1/Z ref , where the reference Z-spectra Z ref was calculated using our previously developed Voxel-wise Optimization of Pseudo Voigt Profile (VOPVP). Simulations were performed at two different exchange rates of amide, representing different pH values. Among all tested quantification methods, including MTR asym , Lorentzian Difference (LD), VOPVP residual (ZVOPVP residual), the analytical solution and MTR Rex OPVP , MTR Rex VOPVP exhibited the largest difference between the two exchange rates. In vivo CEST-MRI was performed at 7 Tesla in rat brain, at 2 hours after transient ischemia by middle cerebral artery occlusion. Firstly, Z-spectra images were assessed at multiple offsets using histogram analysis, with 3.5 and -3.5 ppm exhibiting significant changes between normal rats and stroke rats (n = 5 each). For all stroke rats, MTR Rex VOPVP images (3.5 ppm) exhibited a large area of hypointensity in the lesion hemisphere. In contrast, MTR asym and the three-offsets method failed in detecting such changes, particularly for rats with little changes on T 2w and DWI images. Among all tested methods, MTR Rex VOPVP achieved the highest contrast-to-noise ratio between lesion striatum and the contralateral. For amide, amine and NOE, Z residual VOPVP and MTR Rex VOPVP showed significant reduced signals in lesions compared to the contralateral, indicating lower pH with slower exchange. But Z-spectra and MTRasym signal did not show such difference. At later time points (6 hrs and 24 hrs), all methods displayed contrast between two hemispheres and MTR Rex VOPVP still show the largest contrast between the two hemisphere. Histology confirmed the edema and other damage in the ipsilateral hemisphere at 2 hours post transient ischemia. In summary, MTR Rex VOPVP may enhance CEST detection for ischemia.

Analysis of model-based and model-free CEST effect quantification methods for different medical applications.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) holds great potential to provide new metabolic information for clinical applications such as tumor, stroke and Parkinson's Disease diagnosis. Many active research and developments have been conducted to translate this emerging MRI technique for routine clinical applications. In general, there are two CEST quantification techniques: (i) model-free and (ii) model-based techniques. The reliability of these quantification techniques depends heavily on the experimental conditions and quality of the collected data. Errors such as noise may lead to misleading quantification results and thus inaccurate diagnosis when CEST imaging becomes a standard or routine imaging scan in the future. This paper investigates the accuracy and robustness of these quantification techniques under different signal-to-noise (SNR) levels and magnetic field strengths. The quantified CEST effect before and after adding random Gaussian White Noise using model-free and model-based quantification techniques were compared. It was found that the model-free technique consistently yielded larger average percentage error across all tested parameters compared to its model-based counterpart, and that the model-based technique could withstand SNR of about 3 times lower than the model-free technique. When applied on noisy brain tumor, ischemic stroke, and Parkinson's Disease clinical data, the model-free technique failed to produce significant differences between normal and abnormal tissue whereas the model-based technique consistently generated significant differences. Although the model-free technique was less accurate and robust, its simplicity and thus speed would still make it a good approximate when the SNR was high (>50) or when the CEST effect was large and well-defined. For more accurate CEST quantification, model-based techniques should be considered. When SNR was low (<50) and the CEST effect was small such as those acquired from clinical field strength scanners, which are generally 3T and below, model-based techniques should be considered over model-free counterpart to maintain an average percentage error of less than 44% even under very noisy condition as tested in this work.

Furin-mediated intracellular self-assembly of olsalazine nanoparticles for enhanced magnetic resonance imaging and tumour therapy.

One strategy to enhance tumor retention of imaging agents or anti-cancer drugs is rational design of probes that undergo a tumor-specific enzymatic reaction which prevents them from being pumped out of the cell. Here, the anticancer agent olsalazine (Olsa) was conjugated to the cell-penetrating peptide RVRR. Taking advantage of a biologically compatible condensation reaction, single Olsa-RVRR molecules were self-assembled into large intracellular nanoparticles (Olsa-NPs) by the tumor-associated enzyme furin. Both Olsa-RVRR and Olsa-NPs could be readily detected with chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) by virtue of exchangeable olsalazine hydroxyl protons. In vivo studies using HCT116 and LoVo murine xenografts showed that the OlsaCEST signal and anti-tumor therapeutic effect were 6.5-fold and 5.2-fold increased, respectively, compared to olsalazine without RVRR, with an excellent “theranostic correlation” (R2=0.97) between the imaging signal and therapeutic response (normalized tumor size). This furin-targeted MRI-detectable platform has potential for imaging tumor aggressiveness, drug accumulation, and therapeutic response.