Ovarian cancer is the most lethal gynecological
malignancy, characterized by a high rate of chemoresistance. Current treatment strategies for
ovarian cancer focus on novel
drug combinations of
cytotoxic agents and molecular targeted agents or novel
drug delivery strategies that often involve intraperitoneal (IP) injection. Poly(
ethylene glycol)-block-poly(ε-
caprolactone) (
PEG-b-PCL)
micelles were loaded with
paclitaxel (
cytotoxic agent),
cyclopamine (hedgehog inhibitor), and
gossypol (Bcl-2 inhibitor). After physicochemical studies focusing on
combination drug solubilization, 3-drug
PEG-b-PCL micelles were evaluated in vitro in 2-D and 3-D cell culture and in vivo in xenograft models of
ovarian cancer, tracking bioluminescence signals from ES-2 and SKOV3 human
ovarian cancer cell lines after IP injection. 3-Drug
PEG-b-PCL micelles were not significantly more potent in 2-D cell culture in comparison to
paclitaxel; however, they disaggregated ES-2
tumor spheroids, whereas single drugs or 2-drug combinations only slowed growth of ES-2
tumor spheroids or had no noticeable effects. In ES-2 and SKOV3 xenograft models, 3-drug
PEG-b-PCL micelles had significantly less
tumor burden than
paclitaxel based on bioluminescence imaging, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET imaging, and overall survival. (18)F-FLT-PET images clearly showed that 3-drug
PEG-b-PCL micelles dramatically reduce
tumor volumes over
paclitaxel and vehicle controls. In summary,
PEG-b-PCL micelles enable the IP
combination drug delivery of
paclitaxel,
cyclopamine and
gossypol, resulting in
tumor growth inhibition and prolonged survival over
paclitaxel alone. These results validate a novel treatment strategy for
ovarian cancer based on
drug combinations of
cytotoxic agents and molecular targeted agents, delivered concurrently by a nanoscale drug delivery system, e.g.
PEG-b-PCL micelles.