Effect of transcatheter intraarterial therapies on the distribution of Doxorubicin in liver cancer in a rabbit model

Abstract

Background and aims: Transcatheter intraarterial techniques can effectively deliver chemotherapeutic agents to tumor and improve the efficacy of chemotherapy. The present study is designed to evaluate the effect of transcatheter intraarterial techniques on the distribution of doxorubicin in relation to blood vessels in liver cancer.

Methods: VX2 tumors were implanted in the livers of 32 rabbits. The animals were divided into 4 groups of 8 animals each. Group 1 (doxo iv) animals received doxorubicin intravenous injection; group 2 (doxo ia) received doxorubicin hepatic intraarterial infusion; group 3 (doxo ia + E) received doxorubicin hepatic intraarterial infusion followed by embolization; group 4 (doxo + L ia + E) received hepatic intraarterial infusion of doxorubicin mixed with Lipiodol followed by embolization. Ten minutes or 4 hours after treatment, the animals were sacrificed and tumors were sampled. Immunofluorescence techniques were used to evaluate the distribution of doxorubicin in relation to blood vessels.

Results: Doxorubicin fluorescence was distributed around tumor blood vessels and decreased with distance from the blood vessels. Tumor cells in avascular and adjacent regions were not exposed to detectable concentrations of doxorubicin. Tumors in the group 2, 3 and 4 had a significant increase in doxorubicin penetration compared with the group 1 tumors (P<0.05). Among the three groups of transcatheter therapies, doxorubicin penetration distance in group 3 was significantly larger than that in group 2 and 4 (P<0.05), and no significant difference was found between group 2 and 4 tumors (P>0.05) at 10 minutes. In contrast, at 4 hours and in total, both group 3 and 4 tumors had significant increases in drug penetration compared with group 2 (P<0.05), and no significant difference was noted between group 3 and 4 tumors (P>0.05).

Conclusion: Transcatheter intraarterial therapies improve doxorubicin penetration in liver cancer; nevertheless their effect on drug distribution is somewhat limited.

Figure 1. MR image of a VX2 tumor.

T2-weighted MR image shows a hyper-intensity VX2 tumor in the left liver lobe (arrow).

Figure 2. DSA image of a VX2 tumor.

Selective left hepatic artery angiogram shows a hypervascular tumor (arrow) receiving its blood supply from the left hepatic artery (arrowhead).

Figure 3. Immunofluorescence image of anti-CD31 stain.

Photomicrograph of a representative VX2 tumor shows numerous blood vessels (green, recognized by CD31) at the edge of the tumor.

Figure 4. Immunofluorescence image of doxorubicin.

Photomicrograph of a representative VX2 tumor shows doxorubicin auto-fluorescence (red) at the edge of the tumor.

Figure 5. Histology images of a VX2 tumor.

Hematoxylin-eosin (A), immunofluorescence (B, nucleus; C, doxorubicin; D, blood vessels) and composite (E, original composite; F, modified composite) images show the distribution of doxorubicin (red) in relation to tumor blood vessels (green).

Figure 6. Composite images of doxorubicin and blood vessels.

Images shows the difference in doxorubicin penetration between group 1 (A, E), 2 (B, F), 3 (C, G) and 4 (D, H) tumors at 10-minute (A–D) and 4-hour (E–H) time point.