Abstract
Simple SummaryIntraperitoneal chemotherapy (IPC) is a locoregional treatment option in patients with peritoneal metastases (PM). Small animal models are valuable research tools allowing for rapid, reproducible, and inexpensive study and optimization of different forms of IPC. Here, we present a mouse model of ovarian cancer-derived PM and demonstrate its suitability for various modes of IPC, including pressurized intraperitoneal chemotherapy (PIPAC) using a micro-nozzle for aerosolized drug delivery.Intraperitoneal chemotherapy (IPC) is a locoregional treatment option in patients with peritoneal metastases (PM). Here, we present an ovarian cancer (OC)-derived PM mouse model for the study of different forms of IPC. Xenograft cell proliferation (luciferase-transfected OVCAR3 and SKOV3 clones) and growth kinetics were assessed using PET scan, bioluminescence imaging (BLI), and histological tumor analysis. Liquid IPC was achieved by intraperitoneal injection with/without capnoperitoneum (6–7 mmHg). Pressurized intraperitoneal aerosol chemotherapy (PIPAC) was mimicked using an intratracheal drug aerosol administration system (micro-nozzle), which, as demonstrated by ex vivo granulometric analysis using laser diffraction spectrometry, produced a polydisperse, bimodal aerosol with a volume-weighted median diameter of (26.49 ± 2.76) µm. Distribution of Tc-99m-labeled doxorubicin in mice was characterized using SPECT and was dependent on the delivery mode and most homogeneous when the micro-nozzle was used. A total of 2 mg doxorubicin per kg body weight was determined to be the optimally effective and tolerable dose to achieve at least 50% tumor reduction. Repeated PIPAC (four times at seven-day-intervals) with doxorubicin in SKOV3-luc tumor-bearing mice resulted in halted tumor proliferation and tumor load reduced after the second round of PIPAC versus controls and the number of tumor nodules was significantly reduced (27.7 ± 9.5 vs. 57.3 ± 9.5; p = 0.0003). Thus, we established the first mouse model of OC PM for the study of IPC using a human xenograft with SKOV3 cells and an experimental IPC setup with a miniaturized nozzle. Repeated IPC was feasible and demonstrated time-dependent anti-tumor activity.
Highlights
Ovarian cancer (OC) is a deadly disease with high morbidity and mortality affecting between 3 and 11 per 100,000 women worldwide [1]
HES staining confirmed the presence of tumor cells in the nodules (Figure 1D), with characteristics similar to those observed in peritoneal metastases of ovarian high-grade serous carcinoma in humans, i.e., significant nuclear atypia and pleomorphism, a solid growth pattern, a scattered invasion front, and necrosis
We describe the development of a feasible, reproducible, and reliable mouse model using a human xenograft ovarian cancer (OC) cell line and an experimental intraperitoneal chemotherapy (IPC) setup mimicking human liquid IPC and IPC based on capnoperitoneum such as Pressurized intraperitoneal aerosol chemotherapy (PIPAC)
Summary
Ovarian cancer (OC) is a deadly disease with high morbidity and mortality affecting between 3 and 11 per 100,000 women worldwide [1]. OC is typically diagnosed at a late stage with peritoneal metastases (PM) being diagnosed in around 75% of cases [2]. The high proportion of women with PM at initial diagnosis results in a poor prognosis with 5-year and 10-year survival rates of only 40% and. PM is the key element in the locoregional growth and progression of OC resulting in a cascade of symptoms including ascites, malnutrition, bowel obstruction, cachexia, and death [4,5]. Many aspects of OC treatment focus on the peritoneal cavity in order to clear the peritoneum from tumor cells and to prevent PM growth and re-growth. Surgery, systemic chemotherapy, and intraperitoneal chemotherapy (IPC) are the available means of treating
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