Abstract No. 4: High resolution quantitative MRI-guided nano-embolization enhances drug delivery to liver tumors

Abstract

There is a critical unmet need to monitor intratumoral drug uptake non-invasively. Superparamagnetic iron oxide nanoparticles (SPIOs) are agents with dual diagnostic and therapeutic properties that may meet this need. However, systemic (IV) administration results in unfavorable biodistribution with minimal tumor delivery. To overcome this limitation we propose nano-embolization (NE) as the image-guided delivery of SPIOs and embolic agents directly into the blood supply of tumors. It remains unknown if MRI can quantify the amount of NPs delivered to tumors during NE. Using VX2 liver tumors, we tested the hypotheses that a) NE increases uptake of therapeutic SPIOs over IV administration and b) 7T MRI can quantify intratumoral drug delivery. We induced VX2 liver tumors in 20 rabbits, evenly dividing them into NE and control (IV) groups. Both groups received doxorubicin-loaded therapeutic SPIOs at 0.56 mg/kg body weight. For the NE group, SPIOs and ethiodol were delivered into the hepatic artery under fluoroscopy. T2*-weighted gradient echo imaging (Bruker 7T ClinScan MRI) was performed on both groups pre and post-treatment to quantify SPIO delivery and uptake using T2*W mapping. After necropsy, we used ICP-MS as the gold standard to measure SPIO concentrations in normal liver and tumor pathological specimens. We compared SPIO uptake between the groups using ANOVA with post-hoc Tukey analysis, with p<0.05 considered significant. NE significantly increased tumor SPIO uptake 240% over IV delivery alone (340 vs. 140 μg Fe/mg, p<0.05). This correlated with T2*W MRI, which showed a significant T2 signal drop in NE tumors over controls (ΔT2: 47.4 ms vs. 18.9 ms, p<0.05). Furthermore, NE resulted in 75% less off target delivery to healthy liver tissue than IV delivery (p<0.05). NE improves tumor uptake of therapeutic SPIOs over conventional IV administration, with significantly less off-target delivery. 7T MRI can also quantify SPIO uptake non-invasively. To determine the optimal dose of therapeutic nanoparticles to inject, future studies should correlate SPIO delivery with tumor response.