Antitumor effect of VEGFR2-targeted microbubble destruction with gemcitabine using an endoscopic ultrasound probe: In vivo mouse pancreatic ductal adenocarcinoma model
| Autor: | Nana Shimamoto, Masaki Ito, Kazuki Sumiyama, Sadamu Honma, Hiroo Imazu, Masafumi Chiba |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Endoscopic ultrasound
CD31 Antimetabolites Antineoplastic endocrine system diseases Iron Ultrasonic Therapy Contrast Media Deoxycytidine Ferric Compounds Endosonography 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor medicine Animals Doubling time Microbubbles Hepatology medicine.diagnostic_test business.industry Gastroenterology Microvascular Density Oxides Kinase insert domain receptor Histology respiratory system Vascular Endothelial Growth Factor Receptor-2 Gemcitabine Tumor Burden Mice Inbred C57BL Pancreatic Neoplasms 030220 oncology & carcinogenesis cardiovascular system Cancer research Female 030211 gastroenterology & hepatology business Carcinoma Pancreatic Ductal circulatory and respiratory physiology medicine.drug |
| Zdroj: | Hepatobiliary & Pancreatic Diseases International. 19:478-485 |
| ISSN: | 1499-3872 |
| DOI: | 10.1016/j.hbpd.2020.03.004 |
| Popis: | 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 microbubble (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. |
| Databáze: | OpenAIRE |
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