Arimoclomol-loaded Pluronic F127 nanomicelles in experimental endometriosis: drug incorporation, in vitro release, and early morphological and histological responses.

چکیده اصلی

Endometriosis is a chronic, estrogen-dependent inflammatory disease characterized by ectopic endometrial-like glands and stroma, persistent pelvic inflammation, pain, infertility, and frequent recurrence. The limited availability of nonhormonal and lesion-directed therapies supports the investigation of alternative pharmacological mechanisms and regional drug-delivery strategies. Arimoclomol is a co-inducer of the endogenous heat-shock response with the capacity to amplify stress-dependent proteostasis, whereas Pluronic F127 is an amphiphilic PEO-PPO-PEO copolymer that forms drug-associated micellar assemblies in aqueous media. This exploratory study evaluated the physicochemical properties, in vitro release profile, and early biological response to arimoclomol-loaded Pluronic F127 nanomicelles in an autologous-transplantation rat model of endometriosis. The formulation was prepared by dispersing 30 mg of arimoclomol in 2 mL of Pluronic F127 at 20% (w/v), followed by stirring and ultrasonication under cooling. Because no centrifugation, filtration, dialysis, lyophilization, or other drug-removal step was applied after incorporation, the nominal process loading efficiency was 100%, based on formulation mass balance. The corresponding theoretical drug content was 6.98% w/w of total formulation solids and 7.5% w/w relative to the polymer mass. Drug-polymer association was supported by scanning electron microscopy coupled to energy-dispersive X-ray spectroscopy, Raman spectroscopy, and UV-Vis spectroscopy. In vitro dialysis at 37 °C showed a rapid increase in acceptor-medium arimoclomol concentration, reaching 14.33 ± 0.18 µg/mL at 2 h, followed by a progressive decline, with arimoclomol remaining detectable at 72 h (2.76 ± 0.04 µg/mL). Endometriosis was induced in ten female Wistar rats. On day 16, animals received a single intraperitoneal administration of arimoclomol-loaded nanomicelles (n = 4), empty nanomicelles (n = 3), or free arimoclomol (n = 3). The arimoclomol dose was 3 mg/animal, equivalent to approximately 14.7-16.8 mg/kg according to the recorded body-weight range. Twenty-four hours after treatment, representative lesions from the loaded-nanomicelle group appeared smaller macroscopically and showed mildly atrophic glands, stromal disorganization, and less prominent inflammatory infiltration than representative lesions from the empty-carrier and free-drug groups. All clinical welfare scores remained zero, and no overt short-term intolerance was observed. These findings demonstrate nominal quantitative drug retention based on process mass balance, a biphasic in vitro release pattern, and an early treatment-associated morphological and histological response. These preliminary findings require confirmation in larger, blinded, power-calculated studies with quantitative lesion endpoints, mechanistic biomarkers, lesion-specific pharmacokinetics, and longitudinal safety assessment.

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