Transarterial Chemoembolization Using Sorafenib in a Rabbit VX2 Liver Tumor Model: Pharmacokinetics and Antitumor Effect

Kim, Gyoung Min; Kim, Man Deuk; Kim, Do Young; Kim, Se Hoon; Won, Jong Yun; Park, Sung Il; Lee, Do Yun; Shin, Wan Seon; Shin, Minwoo

doi:10.1016/j.jvir.2016.02.032

Cited by 9 publications

(6 citation statements)

References 16 publications

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“…Compared with lipiodol, the drugs can remain in the tumor foci longer due to the sustained release profiles of DEBs. 41 , 42 Furthermore, lipiodol loading targeted drugs damaged liver function more severely than lipiodol alone, 23 , 38 , 39 while targeted drugs loaded with DEBs will not aggravate liver damage, 19 , 28 which agrees with our experimental results. This finding could be explained by the fact that DEBs are solid embolic materials, 43 , 44 resulting in less ectopic embolism.…”

Section: Discussionsupporting

confidence: 88%

“… 50 In this study, we compared the effectiveness and safety of DCBs and ACBs (conventional TACE) embolization in a preclinical cancer model and proved that replacing the chemotherapeutic drugs with antivascular drugs can achieve better treatment effect. 19 , 39 More importantly, we observed a decrease in the expression of VEGF and MVD in the DCB group, both of which are related to the prognosis of patients. 51 , 52 …”

Section: Discussionmentioning

confidence: 62%

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Donafenib-Loaded Callispheres Beads Embolization in a VX2 Liver Tumor: Investigating Efficacy, Safety, and Improvement of Tumor Angiogenesis After Embolization

Li¹,

Shi²,

Liu³

et al. 2021

JHC

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Objective To investigate the efficiency and safety of callispheres beads loaded with donafenib (DCBs) for embolization in a VX2 liver tumor, as well as the improvement of tumor angiogenesis following embolization. Methods Forty New Zealand white rabbit VX2 liver tumors were treated with four different drugs via the hepatic artery: NS (normal saline), CB (blank callispheres beads), ACB (adriamycin-loaded callispheres beads) and DCB (DCBs). Hematoxylin-eosin staining was performed to assess tumor necrosis, while MRI was employed to detect the changes in tumor size. The safety was evaluated by the liver and kidney function parameters, and the immunofluorescence and immunohistochemical staining were performed to reflect the tumor hypoxia and tumor angiogenesis following embolization. Results The DCB group had the smallest tumor growth rate, but the tumor necrosis rate was the highest of the four groups. Compared to the CB and ACB groups, the DCB group did not aggravate the liver damage and had no influence on kidney function. The staining results showed that, although the tumor hypoxia deteriorated after DCBs embolization, the expression of VEGF (vascular endothelial growth factor) reduced, thus inhibiting tumor angiogenesis. Conclusion DCB administration via hepatic artery is an effective and safe treatment for a preclinical liver cancer model, with the unique benefit of suppressing tumor angiogenesis following embolization.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 62%

Donafenib-Loaded Callispheres Beads Embolization in a VX2 Liver Tumor: Investigating Efficacy, Safety, and Improvement of Tumor Angiogenesis After Embolization

Li¹,

Shi²,

Liu³

et al. 2021

JHC

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“…It has been confirmed that sorafenib can reduce the tumor angiogenesis by inhibiting the VEGF and Raf kinase signaling pathways, regardless of the systemic or local administration. 30 , 32 Similarly, our study showed that the LD group had a lower CD31 expression compared to LE group on day 3 and 7 after treatment. In the LE group, the CD31 expression gradually increased after treatment and peaked on day 7, while it has a negligible growth in the LD group.…”

Section: Discussionsupporting

confidence: 68%

“…Previous data had reported the local use of sorafenib and apatinib, the results of tumor response were like ours. 30,31 The tumor necrosis rate increased after combined treatment over time. This may be because tumor necrosis is a continuous rather than immediate pathological process, and donafenib plays an important role in the late stage of necrosis.…”

Section: Discussionmentioning

confidence: 99%

Transcatheter Arterial Embolization Containing Donafenib Induces Anti-Angiogenesis and Tumoricidal CD8+ T-Cell Infiltration in Rabbit VX2 Liver Tumor

Shi¹,

Li²,

Huang³

et al. 2021

CMAR

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To evaluate the effect and immune response of transcatheter arterial embolization (TAE) combined with donafenib in rabbit VX2 liver tumor model. Materials and Methods: Thirty-six New Zealand white rabbits with VX2 liver tumor were randomly divided into three groups. The LD group was treated with the emulsion of 0.5 mL lipiodol and 4 mg donafenib via hepatic arterial administration. The LE group was treated with the emulsion of 0.5 mL lipiodol and 4 mg epirubicin. The control group was treated with the equal volume of saline. Four rabbits were euthanized in each group on day 1, 3 and 7 after treatment. The tumor growth, histological markers associated with angiogenesis and immune response were assessed by imaging and histopathology. In addition, immune modulatory cytokines included interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and biochemical hepatorenal function were measured. Results: Compared to other groups, LD group achieved lower tumor growth rate, fewer metastatic lesions, and higher tumor necrosis rate on day 7 after treatment. The percentage of CD31-positive area in the LD group was significantly lower than that in the LE group on day 3 and 7 after treatment. In addition, CD8 + lymphocytes infiltration was more pronounced in LD group than in LE group on day 7 after treatment, regardless of in the tumor or adjacent liver tissue. Serum cytokines including IL-6, TNF-α and IFN-γ were strongly upregulated in the LD group on day 1 after treatment. And there was no significant difference in the hepatorenal function between LD group and LE group after treatment. Conclusion:The combination of TAE and angiogenesis inhibitor donafenib resulted in a potentiated tumoricidal effect, anti-angiogenesis and antitumour T cell response in rabbit VX2 liver tumor model. This may provide a potential basis for exploring the immune-related mechanisms of embolization in liver cancer.

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“…However, due to the lack of tumor specificity, oralsystemic administration of these anti-angiogenesis agents often lead to high toxicity and severe side effects [9]. Some researchers then proved that local administration through transcatheter arterial embolization (TAE) not only inhibited tumor angiogenesis but also reduced the side effects of these anti-angiogenesis agents in animal models [10][11][12]. Thus, many methods have emerged to improve the therapeutic effect of TACE such as the application of different inhibitors to disrupt VEGF or HIF-1α signal pathways, or combination with novel nanomaterials to change the hypoxia environment [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy

Wang

Liu

et al. 2022

Cell Death Discov.

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Transcatheter arterial chemoembolization (TACE) has become the preferred therapy for unresectable advanced hepatocellular carcinoma (HCC). However, the embolization of tumor-feeding arteries by TACE always leads to hypoxia-related tumor angiogenesis, which limited the therapeutic effect for HCC. In this paper, we used a VEGFR targeting peptide VEGF125 − 136 (QKRKRKKSRYKS) to conjugate with a lytic peptide (KLUKLUKKLUKLUK) to form a peptide-drug conjugate (PDC). We used cell affinity assay to detect the peptide binding ability to VEGFR highly expressed cell lines, and CCK8, cell apoptosis to confirm the cellular toxicity for different cell lines. Meanwhile, we created a VX2 tumor-bearing rabbit model to assess the in vivo anti-tumor effect of the peptide conjugate in combination with TAE. HE staining was used to verify the in vivo safety of the peptide conjugate. IHC was used to assess the anti-angiogenesis and cell toxicity of the peptide conjugate in tumor tissues. The peptide conjugate could not only target VEGFR in cell surface and inhibit VEGFR function, but also have potent anti-cancer effect. We luckily found the peptide conjugate showed potent cytotoxicity for liver cancer cell Huh7 (IC50 7.3 ± 0.74 μM) and endothelial cell HUVEC (IC50 10.7 ± 0.292 μM) and induced cell apoptosis of these two cell lines. We also found the peptide conjugate inhibited cell migration of HUVEC through wound healing assay. Besides, these peptides also showed better in vivo anti-tumor effect than traditional drug DOX through TACE in VX2 rabbit tumor model, and efficiently inhibit angiogenesis in tumor tissues with good safety. In conclusion, our work may provide an alternative option for clinical HCC therapy via TACE combination.

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Transarterial Chemoembolization Using Sorafenib in a Rabbit VX2 Liver Tumor Model: Pharmacokinetics and Antitumor Effect

Cited by 9 publications

References 16 publications

Donafenib-Loaded Callispheres Beads Embolization in a VX2 Liver Tumor: Investigating Efficacy, Safety, and Improvement of Tumor Angiogenesis After Embolization

Donafenib-Loaded Callispheres Beads Embolization in a VX2 Liver Tumor: Investigating Efficacy, Safety, and Improvement of Tumor Angiogenesis After Embolization

Transcatheter Arterial Embolization Containing Donafenib Induces Anti-Angiogenesis and Tumoricidal CD8+ T-Cell Infiltration in Rabbit VX2 Liver Tumor

A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy

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