Development and Validation of Sorafenib-eluting Microspheres to Enhance Therapeutic Efficacy of Transcatheter Arterial Chemoembolization in a Rat Model of Hepatocellular Carcinoma.

Purpose: To validate the therapeutic efficacy of sorafenib-eluting embolic microspheres (SOR-EMs) used in combination with transarterial chemoembolization (TACE) for treatment of hepatocellular carcinoma (HCC) in a preclinical animal model. Materials and Methods: SOR-EMs were prepared with poly(d,l-lactide-co-glycolide), iron oxide nanoparticles, and sorafenib. The morphology of the prepared SOR-EMs was confirmed by using optical microscopy. Drug release from the SOR-EMs was quantified in vitro by using high-performance liquid chromatography. In an orthotopic rat model of HCC, embolic doxorubicin-Lipiodol (ethiodized oil) emulsion (DLE) and SOR-EMs were sequentially injected into the hepatic artery of the rats: The rats in group 1 were injected with DLE; group 2 was injected with DLE plus unloaded embolic microspheres (DLE + EM); group 3, with DLE plus SOR-EMs (DLE + SOR-EM); and group 4, with saline solution. The SOR-EM and tumor size changes in each group (of six rats each) over time were measured by using MRI. Tissues were assessed by using immunohistochemistry, with hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated dUTP (2'-deoxyuridine 5'-triphosphate) nick-end labeling staining used for dead cells and CD34 staining used for new microvessel formation. Results: The SOR-EMs were a mean size of 6.6 µm ± 2.3 (standard deviation) and showed 53.7% ± 8.3 sorafenib loading efficiency with T2-weighted MRI capability. In the HCC rat model, the intra-arterially injected SOR-EMs were successfully monitored by using MRI. The DLE + SOR-EM-treated rats showed a superior tumor growth-inhibitory effect compared with the rats treated with DLE only (P < .05). Immunohistochemical assessment of tissue specimens showed that compared with the other treatment groups, the DLE + SOR-EM treatment group had the lowest number of microvessels, as quantified by using the percentage of CD34-positive stained area (P < .01 for all comparisons). Conclusion: In a preclinical rat HCC model, SOR-EMs used in combination with DLE TACE were effective in treating HCC.Keywords: Chemoembolization, Experimental Investigations, Laboratory Tests, Liver, Technology Assessment Supplemental material is available for this article. © RSNA, 2021See also the commentary by Yamada and Gayed in this issue.

Iron-Oxide Nanocluster Labeling of Clostridium novyi-NT Spores for MR Imaging-Monitored Locoregional Delivery to Liver Tumors in Rat and Rabbit Models.

PURPOSE: To label Clostridium novyi-NT spores (C. novyi-NT) with iron oxide nanoclusters and track distribution of bacteria during magnetic resonance (MR) imaging-monitored locoregional delivery to liver tumors using intratumoral injection or intra-arterial transcatheter infusion. MATERIALS AND METHODS: Vegetative state C. novyi-NT were labeled with iron oxide particles followed by induction of sporulation. Labeling was confirmed with fluorescence microscopy and transmission electron microscopy (TEM). T2 and T2* relaxation times for magnetic clusters and magnetic microspheres were determined using 7T and 1.5T MR imaging scanners. In vitro assays compared labeled bacteria viability and oncolytic potential to unlabeled controls. Labeled spores were either directly injected into N1-S1 rodent liver tumors (n = 24) or selectively infused via the hepatic artery in rabbits with VX2 liver tumors (n = 3). Hematoxylin-eosin, Prussian blue, and gram staining were performed. Statistical comparison methods included paired t-test and ANOVA. RESULTS: Both fluorescence microscopy and TEM studies confirmed presence of iron oxide labels within the bacterial spores. Phantom studies demonstrated that the synthesized nanoclusters produce R2 relaxivities comparable to clinical agents. Labeling had no significant impact on overall growth or oncolytic properties (P >.05). Tumor signal-to-noise ratio (SNR) decreased significantly following intratumoral injection and intra-arterial infusion of labeled spores (P <.05). Prussian blue and gram staining confirmed spore delivery. CONCLUSIONS: C. novyi-NT spores can be internally labeled with iron oxide nanoparticles to visualize distribution with MR imaging during locoregional bacteriolytic therapy involving direct injection or intra-arterial transcatheter infusion.