Ultrasound Enhances ZD2767P-Carboxypeptidase G2 against Chemoresistant Ovarian Cancer Cells by Altering the Intracellular Pharmacokinetics of ZD2767D.,Molecular Pharmaceutics

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Ultrasound Enhances ZD2767P-Carboxypeptidase G2 against Chemoresistant Ovarian Cancer Cells by Altering the Intracellular Pharmacokinetics of ZD2767D.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-04-17 , DOI: 10.1021/acs.molpharmaceut.0c00008
Qianfen Liu ₁ , Xiaocui Zhong ₁ , Ying Zhang ₁ , Xinya Li ₁ , Guanhua Qian ₁ , Tinghe Yu ₁

Affiliation

Prodrug–carboxypeptidase G2 (e.g., ZD2767P+CPG2) can realize a targeted treatment where the specific advantage is a lack of CPG2 analogues in humans, but it is limited by low efficacy. Here ultrasound was employed to enhance ZD2767P+CPG2 (i.e., ZD2767P+CPG2+US) against chemoresistant human ovarian cancer cells. The release dynamics of ZD2767D (activated drug) by CPG2 were investigated. The in vitro efficacy was explored in SKOV3 and SKOV3/DDP (cisplatin-resistant subline) cells; spectrophotometry was established to quantify ZD2767P and ZD2767D, and then intracellular pharmacokinetics were evaluated. The in vivo efficacy was validated in both subcutaneous and orthotopic tumors. With insonation, the ZD2767D concentration was increased during an early period. Insonation synergized ZD2767P+CPG2 to enhance cell death and apoptosis, and efficacies in SKOV3 and SKOV3/DDP cells were similar. Intracellular pharmacokinetics of ZD2767D were nonproportional, and insonation increased the peak level, area under the level vs time curve, and mean residence time. In subcutaneous xenografts, ZD2767P+CPG2 and ZD2767P+CPG2+US resulted in volume-inhibitory rates of 20.4% and 26.5% in SKOV3 tumors and 36.8% and 81.6% in SKOV3/DDP tumors, respectively. In the orthotopic tumor model, the survival time in group ZD2767P+CPG2 or ZD2767P+CPG2+US was prolonged compared with group control, in SKOV3 (33.0 ± 3.5 or 39.2 ± 1.8 vs 25.0 ± 1.6 days, p < 0.0001) and SKOV3/DDP (16.2 ± 4.8 or 22.3 ± 7.3 vs 8.7 ± 3.9 days, p = 0.0015) tumors. These data indicated that ZD2767P+CPG2+US was effective against resistant ovarian cancer cells.

中文翻译：

超声通过改变ZD2767D的细胞内药代动力学来增强针对化学耐药性卵巢癌细胞的ZD2767P-羧肽酶G2。

前药-羧肽酶G2（例如ZD2767P + CPG2）可以实现靶向治疗，其特定优势是人类缺乏CPG2类似物，但疗效低下。在这里，超声波被用来增强抗化学性人类卵巢癌细胞的ZD2767P + CPG2（即ZD2767P + CPG2 + US）。研究了CPG2对ZD2767D（活化药物）的释放动力学。在SKOV3和SKOV3 / DDP（顺铂抗性亚系）细胞中探索了体外功效；建立了分光光度法以定量ZD2767P和ZD2767D，然后评估了细胞内药代动力学。体内疗效在皮下和原位肿瘤中均得到验证。伴随声波作用，ZD2767D浓度在早期升高。声波作用可协同ZD2767P + CPG2增强细胞死亡和细胞凋亡，并且在SKOV3和SKOV3 / DDP细胞中的功效相似。ZD2767D的细胞内药代动力学是不成比例的，并且声波作用会增加峰水平，水平-时间曲线下的面积以及平均停留时间。在皮下异种移植物中，ZD2767P + CPG2和ZD2767P + CPG2 + US在SKOV3肿瘤中的体积抑制率分别为20.4％和26.5％，在SKOV3 / DDP肿瘤中分别为36.8％和81.6％。在原位肿瘤模型中，与SKOV3组相比，ZD2767P + CPG2或ZD2767P + CPG2 + US组的存活时间延长（33.0±3.5或39.2±1.8 vs 25.0±1.6天，ZD2767P + CPG2和ZD2767P + CPG2 + US在SKOV3肿瘤中的体积抑制率分别为20.4％和26.5％，在SKOV3 / DDP肿瘤中的体积抑制率分别为36.8％和81.6％。在原位肿瘤模型中，与SKOV3组相比，ZD2767P + CPG2或ZD2767P + CPG2 + US组的存活时间延长（33.0±3.5或39.2±1.8 vs 25.0±1.6天，ZD2767P + CPG2和ZD2767P + CPG2 + US在SKOV3肿瘤中的体积抑制率分别为20.4％和26.5％，在SKOV3 / DDP肿瘤中的体积抑制率分别为36.8％和81.6％。在原位肿瘤模型中，与SKOV3组相比，ZD2767P + CPG2或ZD2767P + CPG2 + US组的存活时间延长（33.0±3.5或39.2±1.8 vs 25.0±1.6天，p <0.0001）和SKOV3 / DDP（16.2±4.8或22.3±7.3对8.7±3.9天，p = 0.0015）肿瘤。这些数据表明ZD2767P + CPG2 + US对抵抗性卵巢癌细胞有效。

更新日期：2020-04-17

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