Effect of Transcatheter Intraarterial Therapies on the Distribution of Doxorubicin in Liver Cancer in a Rabbit Model

Abstract

Background and AimsTranscatheter 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.MethodsVX2 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.ResultsDoxorubicin 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).ConclusionTranscatheter intraarterial therapies improve doxorubicin penetration in liver cancer; nevertheless their effect on drug distribution is somewhat limited.

Lipiodol does not affect the tissue distribution of intravenous doxorubicin infusion in pigs

“…Together with those results, the results of this second part of the study clearly showed that lipiodol alone does not interact directly with DOX membrane transport, and indicate that it is the properties of the complete lipiodol‐based parenteral formulation of DOX that result in its increased tumour‐directed delivery . In fact, it has been demonstrated in other studies that the properties of the formulation may be important for the delivery of DOX to the tumour in vivo . Lipid transport in the body is dependent on lipoproteins, fatty acid binding proteins, lipid transporters (such as ABC transporters), endocytosis and lymphatic drainage .…”

Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer

“…When given systemically, doxorubicin has a poor penetration through cancer tissue due to its avid binding to DNA and sequestration in endosomes by perivascular cells (51, 52). However, intraarterial administration of doxorubicin with TACE demonstrated improved drug penetration into tumor tissue compared to systemic therapy (53). Evofosfamide showed the ability to enhance the activity of commonly used systemic chemotherapeutics agents, notably doxorubicin, in xenograft models (14, 44).…”

Treatment of Intermediate Stage Hepatocellular Carcinoma: A Review of Intrahepatic Doxorubicin Drug-Delivery Systems

“…DOX was mostly distributed only around the tumor blood vessels 4 h after intra-arterial administration [82]. Drug penetration was enhanced with LIP, but adjacent avascular regions were never reached with DOX [82].…”

“…Even though co-administration of DOX with LIP (unknown composition) increased tumor DOX concentrations, the intra-tumor distribution of the iodine component of LIP did not predict the intratumor distribution of DOX [80,81]. DOX was mostly distributed only around the tumor blood vessels 4 h after intra-arterial administration [82]. Drug penetration was enhanced with LIP, but adjacent avascular regions were never reached with DOX [82].…”

“…These factors will influence both the local and systemic concentration-time profiles of DOX and its active metabolite(s). Both DDSs deliver DOX to the proximity of the tumor, but penetration of DOX into the tumor is still diffusion dependent [82,109].…”