Deoxycytidine kinase (DCK) is a key enzyme for the activation of a broad spectrum of nucleoside-based chemotherapy drugs (e.g., gemcitabine); low DCK activity is one of the most important causes of cancer drug-resistance. Noninvasive imaging methods that can quantify DCK activity are invaluable for assessing tumor resistance and predicting treatment efficacy. Here we developed a “natural” MRI approach to detect DCK activity using its natural substrate deoxycytidine (dC) as the imaging probe, which can be detected directly by chemical exchange saturation transfer (CEST) MRI without any synthetic labeling. CEST MRI contrast of dC and its phosphorylated form, dCTP, successfully discriminated DCK activity in two mouse leukemia cell lines with different DCK expression. This dC-enhanced CEST MRI in xenograft leukemic cancer mouse models demonstrated that DCK(+) tumors have a distinctive dynamic CEST contrast enhancement and a significantly higher CEST contrast than DCK(−) tumors (AUC0–60 min = 0.47 ± 0.25 and 0.20 ± 0.13, respectively; P = 0.026, paired Student t test, n = 4) at 1 hour after the injection of dC. dC-enhanced CEST contrast also correlated well with tumor responses to gemcitabine treatment. This study demonstrates a novel MR molecular imaging approach for predicting cancer resistance using natural, nonradioactive, nonmetallic, and clinically available agents. This method has great potential for pursuing personalized chemotherapy by stratifying patients with different DCK activity.
Significance: A new molecular MRI method that detects deoxycytidine kinase activity using its natural substrate deoxycytidine has great translational potential for clinical assessment of tumor resistance and prediction of treatment efficacy.
The full text of the article can be found here: http://cancerres.aacrjournals.org/content/79/10/2775.short
Congrats to Zheng for the publication on Bioconjugate Chemistry!
The article can be found at the link: https://pubs.acs.org/doi/abs/10.1021/acs.bioconjchem.9b00161
Sugar‐based biopolymers have been recognized as attractive materials to develop macromolecule‐ and nanoparticle‐based cancer imaging and therapy. However, traditional biopolymer‐based imaging approaches rely on the use of synthetic or isotopic labeling, and because of it, clinical translation often is hindered. Recently, a novel magnetic resonance imaging (MRI) technology, chemical exchange saturation transfer (CEST), has emerged, which allows the exploitation of sugar‐based biopolymers as MRI agents by their hydroxyl protons‐rich nature. In the study, we reviewed recent studies on the topic of CEST MRI detection of sugar‐based biopolymers. The CEST MRI property of each biopolymer was briefly introduced, followed by the pre‐clinical and clinical applications. The findings of these preliminary studies imply the enormous potential of CEST detectable sugar‐based biopolymers in developing highly sensitive and translatable molecular imaging agents and constructing image‐guided biopolymer‐based drug delivery systems.
Sepsis‐induced acute kidney injury (SAKI) is a major complication of kidney disease associated with increased mortality and faster progression. Therefore, the development of imaging biomarkers to detect septic AKI is of great clinical interest. In this study, we aimed to characterize the endogenous chemical exchange saturation transfer (CEST) MRI contrast in the lipopolysaccharide (LPS)‐induced SAKI mouse model and to investigate the use of CEST MRI for detecting such injury. We used a SAKI mouse model that was generated by i.p. injection of 10 mg/kg LPS. The resulting kidney injury was confirmed by the elevation of serum creatinine and histology. MRI assessments were performed 24 h after LPS injection, including CEST MRI at different B1 strengths (1, 1.8 and 3 μT), T1mapping, T2 mapping and conventional magnetization transfer contrast (MTC) MRI. The CEST MRI results were analyzed using Z‐spectra, in which the normalized water signal saturation (Ssat/S0) is measured as a function of saturation frequency. Substantial decreases in CEST contrast were observed at both 3.5 and − 3.5 ppm frequency offset from water at all B1 powers, with the most significant difference obtained at a B1 of 1.8 μT. The average Ssat/S0 differences between injured and normal kidneys were 0.07 (0.55 ± 0.04 versus 0.62 ± 0.04, P = 0.0028) and 0.07 (0.50 ± 0.04 versus 0.57 ± 0.03, P = 0.0008) for 3.5 and − 3.5 ppm, respectively. In contrast, the T1 and T2 relaxation times and MTC contrast in the injured kidneys did not show a significant change compared with the normal control. Our results showed that CEST MRI is more sensitive to the pathological changes in injured kidneys than the changes in T1, T2 and MTC effect, indicating its potential clinical utility for molecular imaging of renal diseases.
Purpose—To develop a new MRI method to detect and characterize brain abscesses using the CEST contrast inherently carried by bacterial cells, namely bacCEST.
Methods—Bacteria S. aureus (ATCC #49775) and F98 glioma cells were injected stereotactically in the brains of F344 rats to form abscesses and tumors. The CEST signals of brain abscesses (n=4) and tumors (n=4) were acquired using two B1 values (i.e., 1 and 3 μT) and compared. The bacCEST signal of the brain abscesses in the rats (n=3) receiving ampicillin (i.p. 40 mg/kg twice daily) was acquired before, 4 and 10 days after the treatment.
Results—The bacCEST signal of S. aureus was characterized in vitro as a strong and broad signal in the range of 1 to 4 ppm, with the maximum contrast occurring at 2.6 ppm. The CEST signal in S. aureus-induced brain abscesses was significantly higher than that of contralateral parenchyma (P=0.003). Moreover, thanks to their different B1-independece, brain abscesses and tumors could be effectively differentiated (P=0.005) using ΔCEST(2.6ppm,3μT-1μT), defined by the difference between the CEST signal (offset=2.6ppm) acquired using B1 = 3 μT and that of 1 μT. In treated rats, bacCEST MRI could detect the response of bacteria as early as 4 days after the antibiotic treatment (P=0.035).
Conclusion—BacCEST MRI provides a new imaging method to detect, discriminate and monitor bacterial infection in deep-seated organs. Because no contrast agent is needed, such an approach has a great translational potential for detecting and monitoring bacterial infection in deep-seated organs.