Deuterium oxide as a contrast medium for real-time MRI-guided endovascular neurointervention

Rationale: Endovascular intervention plays an important role in the treatment of various diseases, in which MRI-guidance can potentially improve precision. However, the clinical applications of currently available contrast media, including Gadolinium-based contrast agents and superparamagnetic iron oxide particles (SPIO), are hindered by safety concerns. In the present study, we sought to develop D(2)O as a novel contrast agent for guiding endovascular neurointervention. Methods: Animal studies were approved by institutional ACUC and conducted using an 11.7 T Bruker Biospec system and a 3T Siemens Trio clinical scanner for rodent and canine imaging, respectively. The locally selective blood brain barrier opening (BBBO) in rat brains was obtained by intraarterial (IA) injection of mannitol. The dynamic T(2w)* EPI MRI sequence was used to study the trans-catheter perfusion territory by IA administered SPIO before mannitol administration, whereas a dynamic T(1w) FLASH sequence was used to acquire Gd contrast-enhanced MRI for assessing BBBO after injection of mannitol. The contrast generated by D(2)O assessed by either EPI or FLASH methods was compared with the corresponding results assessed by SPIO or Gd. The utility of D(2)O MRI was also demonstrated to guide drug delivery to glioma in a mouse model. Finally, the clinical utility of D(2)O-MRI was demonstrated in a canine model. Results: Our study has shown that the contrast generated by D(2)O can be used to precisely delineate trans-catheter perfusion territory in both small and large animals. The perfusion territories determined by D(2)O-MRI show moderate correlation with those by SPIO-MRI (Spearman coefficient r = 0.5234, P < 0.001). Moreover, our results show that the perfusion territory determined by D(2)O-MRI can successfully predict the areas with BBBO after mannitol treatment similar to that assessed by Gd-MRI (Spearman coefficient r = 0.6923, P < 0.001). Using D(2)O-MRI as imaging guidance, the optimal infusion rate in the mouse brain was determined to be 150 µL/min to maximize the delivery efficacy to the tumor without serious off-target delivery to the brain parenchyma. The enhanced drug delivery of antibodies to the brain tumor was confirmed by fluorescence imaging. Conclusion: Our study demonstrated that D(2)O can be used as a negative MRI contrast medium to guide endovascular neurointervention. The established D(2)O -MRI method is safe and quantitative, without the concern of contrast accumulation. These qualities make it an attempting approach for a variety of endovascular procedures.