Metastatic
ovarian cancer (OvCa) frequently recurs due to chemoresistance, highlighting the need for nonoverlapping combination
therapies that mechanistically synergize to eradicate residual disease.
Photodynamic therapy (
PDT), a photochemistry-based cytotoxic modality, sensitizes ovarian
tumors to
platinum agents and biologics and has shown clinical promise against ovarian
carcinomatosis. We introduce a three-dimensional (3D) model representing adherent ovarian
micrometastases and high-throughput quantitative imaging methods to rapidly screen the order-dependent effects of combining benzoporphyrin-derivative (BPD) monoacid A-based
PDT with low-dose
carboplatin. 3D ovarian micronodules grown on
Matrigel were subjected to BPD-
PDT either before or after
carboplatin treatment. We developed custom fluorescence image analysis routines to quantify
residual tumor volume and viability.
Carboplatin alone did not eradicate ovarian
micrometastases at a dose of 400 mg/m2, leaving surviving cores that were nonsensitive or impermeable to
chemotherapy. BPD-
PDT (1.25 μmol/L·J/cm2) created punctate cytotoxic regions within
tumors and disrupted micronodular structure. Treatment with BPD-
PDT prior to low-dose
carboplatin (40 mg/m2) produced a significant synergistic reduction [P<0.0001, analysis of covariance (ANCOVA)] in
residual tumor volume [0.26; 95% confidence interval (95% CI), 0.19-0.36] compared with
PDT alone (0.76; 95% CI, 0.63-0.92) or
carboplatin alone (0.95; 95% CI, 0.83-1.09), relative to controls. This synergism was not observed with the reverse treatment order. Here, we demonstrate for the first time the use of a 3D model for micrometastatic OvCa as a rapid and quantitative reporter to optimize sequence and dosing regimens of clinically relevant combination strategies. This approach combining
biological modeling with high-content imaging provides a platform to rapidly screen therapeutic strategies for a broad array of metastatic
tumors.