Pharmacokinetics and anti-tumor efficacy of transarterial chemoembolization using small-particle lenvatinib-loaded beads in a rabbit VX2 liver tumor model.

BACKGROUND

Transarterial chemoembolization (TACE) is a standard treatment for intermediate-stage hepatocellular carcinoma (HCC); however, post-embolization hypoxia may induce vascular endothelial growth factor (VEGF)-mediated angiogenesis, thereby promoting tumor progression and recurrence. Lenvatinib (LEN) is an effective anti-angiogenic agent for unresectable HCC; however, its systemic administration is limited by adverse events. This study aimed to evaluate the feasibility, pharmacokinetics, safety, and anti-tumor efficacy of 75-150 µm LEN-loaded CalliSpheres® Beads (LEN-LCBs) for TACE in a rabbit VX2 liver tumor model.

METHODS

The loading efficiency of LEN-LCBs with particle sizes of 100-300 and 75-150 µm was evaluated at different concentrations and time points, and the drug release rate was measured under maximum loading conditions. Eighteen rabbits with VX2 liver tumors were randomly allocated in equal numbers to two groups to receive TACE with LEN-LCBs of 100-300 or 75-150 µm. LEN concentrations in tumor tissue, adjacent liver tissue, and plasma were measured on days 1, 3, and 7 after TACE in both groups. To further assess different treatment regimens, 38 rabbits with VX2 liver tumors were randomly assigned to four groups: a control group [normal saline (NS); n=5], an oral LEN group (n=14), a blank CalliSpheres® Beads (CB) group (75-150 µm; n=5), and a LEN-LCB group (75-150 µm; n=14). LEN concentrations in tumor, peritumoral liver tissue, and plasma were measured at 1, 3, 7, and 14 days post-treatment in the LEN and LCB groups, while liver function, relative tumor volume (RTV), cluster of differentiation 31 (CD31) staining, and VEGF expression were evaluated across all groups.

RESULTS

The 75-150 µm beads showed higher loading and release efficiency than the 100-300 µm beads, and achieved higher LEN concentrations in tumor and peritumoral tissues after TACE. Compared with oral LEN, 75-150 µm LEN-LCB embolization resulted in higher local drug concentrations at 1-, 3-, and 7-days post-treatment despite lower plasma exposure. This treatment also produced marked tumor necrosis, and the lowest RTV at day 14 (142.1%±17.3% in the LCB group vs. 402.0%±36.9% in the NS group, 320.8%±31.1% in the LEN group, and 205.4%±29.7% in the CB group; P<0.05), without additional liver injury. CD31 staining showed reduced microvessel density, and Western blot analysis showed decreased VEGF expression, indicating inhibition of tumor angiogenesis.

CONCLUSIONS

Compared with the 100-300 µm CBs, the 75-150 µm CBs achieved more efficient LEN loading and higher local drug exposure in rabbit VX2 liver tumors. Small-particle LEN-LCB beads demonstrated favorable preclinical feasibility, with enhanced anti-tumor and anti-angiogenic effects after embolization.