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| Antitumor effect of VEGFR2-targeted microbubble destruction with gemcitabine using an endoscopic ultrasound probe: In vivo mouse pancreatic ductal adenocarcinoma model ? |
| Nana Shimamoto a , ∗, Masaki Ito b , Masafumi Chiba a , Sadamu Honma b , Hiroo Imazu c , Kazuki Sumiyama a |
a Department of Endoscopy, The Jikei University School of Medicine, 3-25-8 Nishi Shinbashi, Minato-ku, Tokyo 105-8461, Japan
b Division of Oncology, Research Center for Medical Science, 3-25-8 Nishi Shinbashi, Minato-ku, Tokyo 105-8461, Japan
c Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchikami-cho, Itabashi-ku, Tokyo 173-8610, Japan
? Notes: This study was selected to receive a poster of distinction at the Digestive Disease Week June 2nd to 6th 2018 in Washington, USA, and the excellence award at the Japan Digestive Disease Week November 1st to 4th 2018 in Kobe, Japan.
∗ Corresponding author.
E-mail address: nanahachinetyou@jikei.ac.jp (N. Shimamoto). |
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Abstract Background: Ultrasound-targeted microbubble destruction (UTMD) induces cellular inflow of drugs at low intensity, while high intensity eradicates tumor vessels. Since vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed in pancreatic ductal adenocarcinoma (PDAC), VEGFR2-targeted microbub- ble (MB) might additionally increase the tissue specificity of drugs and thus improve antitumor effects. In addition, fixing the dual pulse intensity could maximize MB properties. This study evaluated the one-off (experiment 1) and cumulative (experiment 2) treatment effect of UTMD by regulating the dual pulse output applied to PDAC using VEGFR2-targeted MB.
Methods: C57BL/6 mice inoculated with Pan-02 cells were allocated to five groups: VEGFR2-targeted MB + gemcitabine (GEM), VEGFR2-targeted MB, non-targeted MB + GEM, GEM, and control groups. After injection of GEM or GEM and either VEGFR2-targeted or non-targeted MB, UTMD was applied for several minutes at low intensity followed by high intensity application. In experiment 1, mice were treated by the protocol described above and then euthanized immediately or at the tumor diameter doubling time (TDT). In experiment 2, the same protocol was repeated weekly and mice were euthanized at TDT regardless of protocol completion. Histological analysis by CD31 and VEGFR2 staining provided microvascular density (MVD) and VEGFR2 expression along vessels (VEGFR2v) or intra/peripheral cells (VEGFR2c).
Results: In experiment 1, TDT was significantly longer in the VEGFR2-targeted MB + GEM group compared to the non-targeted MB + GEM, GEM, and control groups, while the VEGFR2-targeted MB group showed no statistical significance. MVD and VEGFR2v in the immediate euthanasia was significantly lower in the VEGFR2-targeted MB + GEM and VEGFR2-targeted MB groups than other conditions. In experiment 2, the VEGFR2-targeted MB + GEM group produced significantly longer TDT than the GEM or control groups, whereas the VEGFR2-targeted MB group showed no significant difference. Histology revealed significantly reduced VEGFR2v and VEGFR2c in the VEGFR2-targeted and non-targeted MB + GEM groups, while only VEGFR2v was significantly less in the VEGFR2-targeted MB group.
Conclusions: UTMD-mediated GEM therapy with the dual pulse application using VEGFR2-targeted MB substantially suppresses PDCA growth.
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2020, Vol. 19 
