超声内镜引导下载有吉西他滨的 VEGFR2 靶向微泡破坏的抗肿瘤作用：体内小鼠胰腺导管腺癌模型。
Antitumor effect of VEGFR2-targeted microbubble destruction with gemcitabine using an endoscopic ultrasound probe: In vivo mouse pancreatic ductal adenocarcinoma model.
机构信息
Department of Endoscopy, The Jikei University School of Medicine, 3-25-8 Nishi Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
Division of Oncology, Research Center for Medical Science, 3-25-8 Nishi Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
出版信息
Hepatobiliary Pancreat Dis Int. 2020 Oct;19(5):478-485. doi: 10.1016/j.hbpd.2020.03.004. Epub 2020 Mar 20.
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.
背景
超声靶向微泡破坏（UTMD）在低强度下诱导药物的细胞内流入，而高强度则消除肿瘤血管。由于血管内皮生长因子受体 2（VEGFR2）在胰腺导管腺癌（PDAC）中高度表达，因此 VEGFR2 靶向微泡（MB）可能会额外增加药物的组织特异性，从而提高抗肿瘤效果。此外，固定双脉冲强度可以最大限度地发挥 MB 的特性。本研究通过使用 VEGFR2 靶向 MB 调节施加于 PDAC 的双脉冲输出，评估了 UTMD 的一次性（实验 1）和累积性（实验 2）治疗效果。
方法
将接种 Pan-02 细胞的 C57BL/6 小鼠分为五组：VEGFR2 靶向 MB+吉西他滨（GEM）、VEGFR2 靶向 MB、非靶向 MB+GEM、GEM 和对照组。注射 GEM 或 GEM 与 VEGFR2 靶向或非靶向 MB 后，在低强度下进行几分钟的 UTMD，然后进行高强度应用。在实验 1 中，按照上述方案对小鼠进行治疗，然后立即处死或在肿瘤直径倍增时间（TDT）处死。在实验 2 中，每周重复相同的方案，无论方案完成与否，均在 TDT 时处死小鼠。通过 CD31 和 VEGFR2 染色进行组织学分析，提供微血管密度（MVD）和沿血管（VEGFR2v）或血管内/周围细胞（VEGFR2c）的 VEGFR2 表达。
结果
在实验 1 中，与非靶向 MB+GEM、GEM 和对照组相比，VEGFR2 靶向 MB+GEM 组的 TDT 明显更长，而 VEGFR2 靶向 MB 组则没有统计学意义。立即安乐死的 MVD 和 VEGFR2v 在 VEGFR2 靶向 MB+GEM 和 VEGFR2 靶向 MB 组明显低于其他条件。在实验 2 中，VEGFR2 靶向 MB+GEM 组的 TDT 明显长于 GEM 或对照组，而 VEGFR2 靶向 MB 组则没有显著差异。组织学显示，VEGFR2 靶向和非靶向 MB+GEM 组的 VEGFR2v 和 VEGFR2c 明显减少，而只有 VEGFR2 靶向 MB 组的 VEGFR2v 明显减少。
结论
使用 VEGFR2 靶向 MB 进行 UTMD 介导的 GEM 治疗，采用双脉冲应用，可显著抑制 PDCA 的生长。
Zotero 插件