Thermosensitive Hydroxybutyl Polyvinyl Alcohol Hydrogel for Vaginal Delivery of Progesterone Microcrystals to Treat Endometrial Hyperplasia

Endometrial hyperplasia (EH), a common precursor lesion to endometrial carcinoma, represents a major gynecological challenge. Current noninvasive vaginal treatments are severely hampered by poor retention and inadequate mucosal adhesion. Herein, we developed a novel thermosensitive hydroxybutyl polyvinyl alcohol (HBPVA) hydrogel for efficient localized vaginal delivery of progesterone. By grafting hydrophobic hydroxybutyl groups onto the hydrophilic PVA backbone, the resulting HBPVA hydrogel exhibited good flowability at 4 °C and a rapid sol-gel transition at 37 °C. Progesterone microcrystals were directly incorporated into the HBPVA solution via simple physical mixing, yielding a stable formulation (Pro@HBPVA) without the need for organic solvents or purification. The thermosensitive hydrogel, once gelled at body temperature, leveraged its abundant surface hydroxyl groups to achieve superior mucoadhesion compared to commercial F127 hydrogel (mucosal adhesion duration >10 times that of the F127 control). Ex vivo fluorescence imaging revealed that the fluorescein-labeled HBPVA hydrogel was retained in the vaginal tract 4-fold longer and at significantly higher levels than a fluorescein sodium solution. Furthermore, the HBPVA formulation enabled preferential uterine accumulation with prolonged therapeutic exposure (>24 h). In an estrogen-induced EH rat model, Pro@HBPVA demonstrated superior therapeutic efficacy to intramuscular progesterone oil injection (positive control), effectively reducing uterine wet weight, restoring endometrial thickness and apoptosis balance, suppressing excessive endometrial angiogenesis and proliferation, and attenuating local inflammation to levels comparable to healthy controls. Collectively, with proven biocompatibility, this mucoadhesive platform offers an effective and noninvasive strategy for EH treatment.