CEST theranostics: label-free MR imaging of anticancer drugs

Abstract

Image-guided drug delivery is of great clinical interest. Here, we explored a direct way, namely CEST theranostics, to detect diamagnetic anticancer drugs simply through their inherent Chemical Exchange Saturation Transfer (CEST) MRI signal, and demonstrated its application in image-guided drug delivery of nanoparticulate chemotherapeutics. We first screened 22 chemotherapeutic agents and characterized the CEST properties of representative agents and natural analogs in three major categories, i.e., pyrimidine analogs, purine analogs, and antifolates, with respect to chemical structures. Utilizing the inherent CEST MRI signal of gemcitabine, a widely used anticancer drug, the tumor uptake of the i.v.-injected, drug-loaded liposomes was successfully detected in CT26 mouse tumors. Such label-free CEST MRI theranostics provides a new imaging means, potentially with an immediate clinical impact, to monitor the drug delivery in cancer.

Molecular Imaging of Deoxycytidine Kinase Activity Using Deoxycytidine-Enhanced CEST MRI

“…As shown in Fig. 2A, dCTP exhibits maximum CEST MRI signal (in terms of the parameter MTR asym ) at around 2.0 ppm, ascribed to its amine protons (18). Similar to previously reported dC data (18), the magnitude of the CEST signal of dCTP also depends on the RF saturation power (B 1 ) and pH ( Supplementary Fig.…”

“…Using clinically available agents as imaging probes would be a practical strategy to overcome this challenge and allow quick translation of the preclinically validated MR molecular imaging technologies. Demonstrated in recent studies by others and us, natural biocompatible agents, such as sugars (15,16), amino acids (17), and drugs (18,19), can be imaged directly using a relatively new MRI contrast mechanism, chemical exchange saturation transfer (CEST) MRI, a technique that detects small amounts of contrast agent through the saturation of rapidly exchanging protons on these agents (20). Using this approach, enzyme detection has been accomplished using its natural substrates as MRI reporters (21).…”

Clinical applications of chemical exchange saturation transfer (CEST) MRI

“…Derivatives of these agents can undergo enzyme‐catalyzed modification of a ligand, so that the comparison of enzyme‐responsive and unresponsive CEST signals of the agent can then robustly detect enzyme catalysis, which is known as catalyCEST MRI . Some drugs have been shown to generate similar CEST effects, providing potential to directly detect drug delivery with theranostic CEST MRI . Although the toxicity of these agents must be thoroughly evaluated to gain approval for clinical use, high concentrations of these agents have been administered to small animal models of human cancers without acute effects, hinting that these agents may be safe.…”

“…137,138 Some drugs have been shown to generate similar CEST effects, providing potential to directly detect drug delivery with theranostic CEST MRI. 139 Although the toxicity of these agents must be thoroughly evaluated to gain approval for clinical use, 140 high concentrations of these agents have been administered to small animal models of human cancers without acute effects, 141 hinting that these agents may be safe. These new diamagnetic CEST agents show the versatility offered by CEST MRI for molecular imaging.…”

Detection and Quantification of Hydrogen Peroxide in Aqueous Solutions Using Chemical Exchange Saturation Transfer

“…, k ex < Δω , where Δω is the chemical shift difference between the proton and water). 24–26 The CEST principle can be applied to the detection of H 2 O 2 because, in aqueous solution, H 2 O 2 forms a hydrogen bonding network, 27 where each H in H 2 O 2 interacts with two O atoms from neighboring H 2 O 2 and OH − , resulting in exchangeable protons with a chemical shift at ~11 ppm, or Δω ~ 6.3 ppm, making it quite suitable for CEST detection. 28 It should be noted that, different from NMR convention, the chemical shift offset by CEST MRI convention is defined as the frequency difference ( Δω ) between a proton pool and water protons, which will be used in the rest of this work.…”