The objective of these investigations was to test the hypothesis that a rapid cytoplasmic release profile from nanoparticles would potentiate the anticancer activity of cisplatin. Cisplatin-loaded nanoparticles with pH-responsive poly [2-(N,N-diethylamino)ethyl methacrylate] (PDEA) cores were synthesized from PDEA-block-poly(ethylene glycol) (PDEA-PEG) copolymer using a solventdisplacement (acetone-water) method. Nanoparticles with pH-nonresponsive poly(ε-caprolactone) (PCL) cores made from PCL-block-PEG (PCL-PEG) were used for comparison. Nanoparticle sizes, zeta-potentials, drug-loading capacities, and pH responsiveness were characterized. The cellular uptakes and localization in lysosomes were visualized using confocal fluorescence microscopy. Cytostatic effects of free and encapsulated cis-diammineplatinum(II) dichloride (cisplatin) toward human SKOV-3 epithelial ovarian cancer cells were estimated using the MTT assay. Intraperitoneal tumor responses to cisplatin and cisplatin/PDEA-PEG were evaluated in athymic mice at 4-6 weeks post-inoculation of SKOV-3 cells. PDEA-PEG nanoparticles dissolved at pH < 6, and rapidly internalized and transferred to lysosomes; it therefore was predicted that the PDEA nanoparticles would rapidly release cisplatin into cytoplasm upon integration into acidic lysosomes and thereby overwhelm the chemoresistant properties of SKOV-3 cells. Indeed, relative proportions of viable cells were diminished to a greater extent by exposure in vitro to fast-releasing nanoparticles compared to slow-releasing nanoparticles or an equivalent dose of free cisplatin. Incidences of cellular pyknosis (a morphological indicator of apoptosis) were most evident within intestinal/mesentery tumors of mice treated with cisplatin/PDEA-PEG; tumor burdens were correspondingly reduced.

The lethality of common (surface) epithelial ovarian cancer is contingent on its metastatic capacity. Dissemination of the neoplasia throughout the abdominal cavity has been associated with secretion of proteolytic enzymes from vesicles shed by ovarian cancer cells. We report that the lipophilic steroid hormone progesterone decreases the fluid dynamics of plasma membranes of human SKOV-3 adenocarcinoma cells. The decrease in membrane fluidity was related to an inhibition in vitro of exocytotic vesicle release, cellular invasiveness into Matrigel, and colony formation in three-dimensional collagen matrix. Tumorigenesis was suppressed by progesterone in immunocompromised nude mice inoculated intraperitoneally with SKOV-3 cells. Progestins could therefore be of benefit in the prevention and(or) treatment of early-stage ovarian carcinomatosis.

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Objectives-The underlying premise of these investigations was that the lipophilic hormone progesterone, which partitions into and (at relatively high concentrations) impedes the fluid mechanics of the plasmalemma, would perturb integral associations between membrane lipids and exporter pumps that otherwise confer drug resistance. That progesterone can affect susceptibility of ovarian adenocarcinoma cells and xenografts to cisplatin was tested.Methods-The cisplatin-resistant human cell lines SKOV-3 and OVCAR-3 were treated for 24 hours with cisplatin (0.1 μg/ml) ± progesterone (0.01, 0.1 μg/ml). Cytotoxicity and platinum were measured by MTT assay and inductively coupled plasma mass spectrometry, respectively. Athymic mice were inoculated intraperitoneal (ip) with SKOV-3 cells. Cisplatin (2 mg/kg/week) ± progesterone (25 mg sustained-release pellet) regimens were initiated ip at one week (when micrometastases were present) and continued to six weeks post-xenograft. Tumor burdens, histopathology, and platinum concentrations were assessed upon necropsy at 24 hours after the final injection of cisplatin.Results-There were no significant in vitro/vivo anticancer effects of cisplatin alone. High-dose progesterone enhanced platinum accretion and induced drug toxicity in both cell lines. Tumorigenesis was suppressed by cisplatin + progesterone. The treatment synergy was related to elevated tumor platinum and morphological evidence of apoptosis.Conclusion-It appears that the addition of progesterone to ovarian cancer therapeutic modalities represents a step in improving responses.