Noninvasive ¹H/¹³C magnetic resonance spectroscopic imaging of the intratumoral distribution of temozolomide

Among the primary reasons for failure of anticancer chemotherapy are insufficient drug delivery to the tumor because of inadequate tumor vascularization and/or the antivascular effects of chemotherapy. Thus, determining the spatial intratumoral distribution of anticancer agents by noninvasive methods such as MRI/MRSI is important for monitoring cancer chemotherapy. We therefore studied the distribution of the ¹³C- labeled anticancer agent temozolomide ([¹³C]TMZ) in MCF-7 tumor-bearing mice using ¹H/¹³C MRSI. In phantom studies inverse ¹³C detection with heteronuclear multiple quantum coherence (HMQC) provided a 2.3-fold gain in signal-to-noise ratio (SNR) over direct nuclear overhauser effect (NOE)-enhanced ¹³C-MRS. This enabled detection of [¹³C]TMZ in the micromolar range. Three-dimensional (3D) maps of drug distribution with a nominal 2.5-mm isotropic resolution were obtained following intraperitoneal administration of [¹³C]TMZ, for a total dose of 200 mg/kg. The status of the blood supply of tumors was assessed by gadolinium (Gd)-enhanced dynamic MRI. Nonuniform distributions of the drug and the contrast agent were detected in the tumors. Although carbon-13 MIRSI has an inherently low sensitivity for detection, the novel technique described here demonstrates the feasibility of studying the delivery of ¹³C-labeled drugs and contrast uptake during the course of chemotherapy.