Development of a new therapy for endometriosis using biodegrative drug delivery system

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Endometriosis has been treated using systemic administration of hormonal modulators such as GnRH agonists, oral contraceptives and danazol (DZ). These treatments improve symptoms and reduce lesion size, but effectiveness is limited and prolonged treatment often provokes serious adverse effects. We devised a novel drug delivery system comprising DZ-loaded hyaluronic acid (HA) for local application to endometriosis. Hydrogels of hydrophobically modified HA with DZ loaded at concentrations of 1 or 10 mg/ml (DZ-HA gel) were prepared and injected aseptically into a rat model of endometriosis. Changes in cyst size, DZ concentrations in cyst walls and blood, histology of treated cysts, and estrous cycles were examined. Proliferative activity of endometrial epithelial cells was evaluated immunohistologically and using [^3H]-thymidine incorporation assay. Treatment with 10^<-5> M DZ inhibited [^3H]-thymidine incorporation in cultured endometrial epithelial cells, even in the presence of estradi … More ol (10^<-8> M), suggesting direct inhibition by DZ. Size of treated cysts decreased to 72.2 ±10.9% for HA hydrogel without DZ (n=8), 71.3 ±8.4% for 1 mg/ml DZ-HA gel (n=8), 89.2 ±8.8% for 10 mg/ml DZ-HA gel (n=8), and 12.7 ±2.5% for ovariectomized rats (n=8) at 4 weeks after injection. Histologically, DZ-HA gel-treated cysts displayed marked atrophy of the endometrial epithelium. Increased numbers of apoptotic cells and decreased numbers of proliferative cells were noted with 10 mg/ml DZ-HA gel. DZ concentrations in cysts treated using 10 mg/ml DZ-HA gel were 3000〜13,300 ng/g tissue at 3 weeks after injection, but plasma levels of DZ never exceeded 5.0 ng/ml. Regular estrous cycles were maintained in all DZ-HA gel-treated rats (n=16). Local injection of DZ-HA gel achieved regression of an experimental model of endometriosis without disturbing the sexual cycle. These results suggest that local application of DZ using this novel drug delivery system may prove useful for treating endometriosis. Less