Non-surgical treatment options for low-grade endometrial cancer and precancerous lesions are a critical unmet need for women who wish to preserve fertility or are unable to undergo hysterectomy. The PI3K/AKT/mTOR pathway is frequently activated in endometrial cancers and has been associated with resistance to endocrine therapy, making it a compelling target for early stage disease. Oral everolimus, an inhibitor against mTORC1, has shown clinical benefit in advanced or recurrent disease but has severe adverse effects that may lead to treatment interruption or dose reduction. To overcome this, we developed a polymer-based intrauterine delivery system to achieve persistent, local delivery of everolimus without systemic exposure. In vivo studies, using a rat model, showed that a poly(propylene fumarate)-based rod loaded with everolimus achieved everolimus delivery to the endometrium with levels similar to oral administration, but with limited systemic exposure and up to 84 days of release. Biological activity of everolimus delivered with this system was confirmed, measured by reduced lumen epithelial cell height and PI3K pathway biomarkers. This study shows a promising new delivery approach for anti-cancer drugs for non-surgical treatment of low-grade endometrial cancer.

对于希望保留生育能力或无法进行子宫切除术的女性来说，低级别子宫内膜癌和癌前病变的非手术治疗方案是一项未得到满足的关键需求。PI3K/AKT/mTOR 通路在子宫内膜癌中经常被激活，并且与内分泌治疗的耐药性有关，使其成为早期疾病的一个引人注目的目标。口服依维莫司是一种 mTORC1 抑制剂，已在晚期或复发性疾病中显示出临床益处，但具有可能导致治疗中断或剂量减少的严重不良反应。为了克服这个问题，我们开发了一种基于聚合物的宫内给药系统，以实现依维莫司的持续局部给药，而无需全身暴露。体内使用大鼠模型的研究表明，基于聚（富马酸丙二醇酯）的棒装载依维莫司可实现依维莫司向子宫内膜的递送，其水平与口服给药相似，但全身暴露有限且释放时间长达 84 天。通过降低的管腔上皮细胞高度和 PI3K 通路生物标志物测量，证实了用该系统递送的依维莫司的生物活性。这项研究显示了一种有前途的新的抗癌药物递送方法，用于非手术治疗低级别子宫内膜癌。