Understanding the distribution and embolization effects of ultrasmall doxorubicin eluting beads in a rodent model of hepatocellular carcinoma

To evaluate the distribution and embolization effect of ultrasmall 40-60 µm doxorubicin eluting beads (DEBs) versus small 70-150 µm DEBs after intra-arterial administration in the N1S1 rat model of hepatocellular carcinoma (HCC). All studies were approved by our institutional animal care and use committee and were performed in accordance with institutional guidelines. Twenty adult male Sprague-Dawley rats underwent hepatic arterial chemoembolization using a left transcarotid approach and were randomly assigned to receive a fixed dose of 4x10*4 of ultrasmall or small DEBs. The embolization endpoint was the injection of the entire dose. After 3 or 7 days, five animals per group were euthanized. Each tumor was sectioned in three equidistant regions along axial planes (cranial, middle and caudal). Bead number, spatial distribution, and percentage of tumor necrosis were measured on histology section. Mann-Whitney and Wilcoxon test were used to evaluate differences between groups. The overall percentage of necrosis was 33% and 56% for the ultrasmall DEBs at 3 and 7 days, and 10% and 28% for the small group, respectively (P<0.001). The effect of the treatment with ultrasmall DEBs was similar across different areas of the same tumor (p>0.05). Small DEBs showed necrosis predominantly in the cranial (34%) and central (25%) regions at day 7 (p = 0.004). No significant differences in the total number of beads were observed between the groups at any of the time points (p>0.05). Significant differences in bead distribution were observed in the ultrasmall size group, at both time points, by comparing tumor versus normal parenchyma regions (p<0.05). Small beads aggregate more frequently within the tumor, whereas the ultrasmall beads were equally distributed across normal liver and tumor. Higher rates of tumor necrosis were observed after ultrasmall DEB chemoembolization using equivalent bead dose. Small beads demonstrated a more heterogeneous tumor necrosis pattern with certain tumor regions consistently spared after embolization. Ultrasmall beads tend to be evenly distributed across both normal liver and tumor, whereas small beads distribute preferentially within tumor.