Effect of Inhibiting Tumor Angiogenesis After Embolization in the Treatment of HCC with Apatinib-Loaded p(N-Isopropyl-Acrylamide-co-Butyl Methyl Acrylate) Temperature-Sensitive Nanogel

摘要

Background:Transcatheter arterial embolization (TAE) is widely used in hepatocellular carcinoma (HCC) therapy. Tumor hypoxia often correlates with the recurrence and metastasis of the tumor and is the critical factor limiting the treatment effect of TAE.Purpose:To investigate the underlying mechanism and therapeutic potential of TAE combined with apatinib-loaded p(N-isopropyl-acrylamide-co-butyl methyl acrylate) temperature-sensitive (PIB) nanogel for the suppression of rabbit VX2 liver tumor growth.Materials and Methods:Sixty-five VX2 tumor-burdened rabbits were randomly divided into five groups and treated transarterially with apatinib-loaded PIB (Group PA, 0.4 mL, n=13), PIB alone (Group P, 0.4 mL, n=13), iodized oil alone (Group I, 0.4 mL, n=13), apatinib solution (Group A, 0.4 mL, n=13) or saline (Group NS, 0.4 mL, n=13). The dose of apatinib was 2 mg/kg. Tumors were harvested, sectioned and immunohistochemically stained, and the tumor growth rates and survival times in each group were measured. Blood samples and liver tissues were collected for pharmacokinetic analysis.Results:The tumor growth rate in Group PA was considerably lower than the other four groups (P=0.0000.01), and the survival time was significantly prolonged (P=0.0000.01). The immunohistochemistry results showed that CD31 expression was significantly lower in Group PA than that of the other four groups (P=0.0000.01). The apatinib concentration in the blood fell below 10 ng/mL within 10 min after TAE and dropped below 1 ng/mL after 8 h. The drug was released continuously in the liver for 36 days, with the highest concentration at the tumor junction (P=0.0450.05).Conclusion:PIB effectively targeted apatinib to HCC tissues, achieved a slow and sustained release of the drug in the tumor and considerably reduced the systemic drug concentration. Further experiments showed significantly prolonged survival times and an inhibitory effect on tumor growth.? 2020 Zhou et al.