Ultrasound Enhances ZD2767P–Carboxypeptidase G2 against Chemoresistant Ovarian Cancer Cells by Altering the Intracellular Pharmacokinetics of ZD2767D

• DOI: 10.1021/acs.molpharmaceut.0c00008
• Publication Date: 2020-04-17T21:04:36Z
• Authors: Qianfen Liu; Xiaocui Zhong; Ying Zhang; Xinya Li; Guanhua Qian; Tinghe Yu
• Keywords: Ovarian Neoplasms; 0303 health sciences; Apoptosis; gamma-Glutamyl Hydrolase; 3. Good health; Mice; 03 medical and health sciences; Drug Resistance, Neoplasm; Cell Line, Tumor; Nitrogen Mustard Compounds; Animals; Humans; Female; HMGB1 Protein; DNA Damage

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