Three-dimensional structure micelles of heparin-poloxamer improve the therapeutic effect of 17β-estradiol on endometrial regeneration for intrauterine adhesions in a rat model

Si‐Si Zhang, Weiting Xia, Jie Xu, Helin Xu, Cui‐Tao Lu, Ying-Zheng Zhao, Xueqing Wu
In: International Journal of Nanomedicine · 2017 · vol. Volume 12 , pp. 5643–5657 · doi:10.2147/ijn.s137237 · PMID:28848344 · W2743933331
article OA: gold CC0 ⤵ 9 in-corpus citations
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Heparin-poloxamer micelles encapsulating 17β-estradiol improved endometrial regeneration and reduced fibrosis in a rat model of intrauterine adhesions by suppressing endoplasmic reticulum stress.

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Abstract

Abstract: Intrauterine adhesions (IUA) frequently occur after infectious or mechanical injury to the endometrium, which may lead to infertility and/or pregnancy complications. There are few effective treatments due to the complex function of endometrium and shortage of native materials. 17β-estradiol (E 2 ) is commonly used as an ancillary treatment in IUA patients, but it is limited by its poor solubility in aqueous solutions and low concentrations at the injured sites. In this research, a mini-endometrial curette was used to injure the rat’s endometrium to form an IUA model. 17β-estradiol was encapsulated into the micelles of heparin-poloxamer and a thermosensitive hydrogel (E 2 -HP hydrogel) was formed. This sustained releasing system was applied to restore the structure and function of the injured uterus. E 2 -HP hydrogel was constructed and relevant characteristics including gelation temperature and micromorphology were evaluated. Sustained release of 17β-estradiol from HP hydrogel was performed both in vitro and in vivo. Ultrasonography measurement and pathologic characteristics on the IUA rats were performed to evaluate the therapeutic effect of E 2 -HP hydrogel. Endoplasmic reticulum (ER) stress-related apoptosis was analyzed to explore the possible mechanisms in IUA recovery. E 2 -HP hydrogel showed a prolonged release of E 2 at the targeting region and more effective endometrium regeneration in IUA rats. Significant improvements in both gland numbers and fibrosis area were observed in the E 2 -HP hydrogel group. We also demonstrated that E 2 -HP hydrogel in the recovery of IUA was closely related to the suppression of ER stress signals via the activation of downstream signals, PI3K/Akt and ERK1/2. HP hydrogel might be an effective approach to deliver E 2 into the injured endometrium. Therapeutic strategies targeting ER stress using E 2 -HP hydrogel might be a promising solution for the treatment of women with intrauterine adhesions. Keywords: intrauterine adhesions, 17β-estradiol, heparin-poloxamer hydrogel, endometrium regeneration, endoplasmic reticulum stress

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