A dual-targeted liposomal nanosystem for co-delivery of estrogen receptor β antagonist and disulfiram for the non-hormonal treatment of endometriosis.

Abstract

Endometriosis is an estrogen-dependent disease that severely affects the physical and mental health of women of childbearing age. Due to the significant side effects of traditional hormone therapies, non-hormonal treatment strategies are urgently needed. In this study, a targeted liposomal nanosystem (cRGD/iRGD-LP@DP) was developed, co-loaded with the pyroptosis inhibitor disulfiram and the estrogen receptor β (ERβ) antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP), to synergistically block the positive feedback loop between inflammation and estrogen. By modifying the dual-targeting peptides cRGD and iRGD, the nanocarrier can specifically bind to the integrin αvβ3 receptor, which is highly expressed in the lesions and promote the delivery of drugs to deep tissues with the help of the penetration function of iRGD. In vitro experiments showed that cRGD/iRGD-LP@DP significantly inhibited the proliferation and migration of ectopic endometrial stromal cells and the expression of pyroptosis-related proteins (NLRP3/Caspase-1/GSDMD), and reduced the release of inflammatory factors IL-1β and IL-18. In the mouse model, intraperitoneal injection of this nanomedicine could efficiently accumulate in the ectopic lesions, reducing the volume and weight of the lesions without significantly affecting the normal endometrium and ovarian function. Mechanistically, disulfiram blocks pyroptosis by inhibiting the formation of Gasdermin D pores, while PHTPP inhibits the nuclear translocation of ERβ. The two work synergistically to break the vicious cycle between inflammation and estrogen. In addition, this nanosystem has good biosafety and no hepatotoxicity or nephrotoxicity. This study provides an efficient and targeted non-hormonal treatment platform for endometriosis with potential for clinical translation. STATEMENT OF SIGNIFICANCE: Endometriosis is an estrogen-dependent chronic inflammatory disease, and dual targeting of estrogen and inflammation can effectively inhibit the progression of this disease. However, fibrosis of ectopic lesions impedes drug penetration. Additionally, both the estrogen receptor β antagonist PHTPP and the inflammatory inhibitor disulfiram are lipophilic drugs with limited bioavailability. To address this challenge, researchers have developed a nanomedicine modified with cRGD and iRGD dual-targeting peptides. This nanomedicine can specifically bind to integrin αvβ3 receptors, which are highly expressed in ectopic lesions, allowing for deep penetration into the interior of ectopic lesions, and achieving efficient drug delivery. Results demonstrate that this nanomedicine exerts a favorable therapeutic effect on endometriosis, providing an innovative strategy for the non-hormonal treatment of endometriosis.