Department of Pharmacy, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
Clinical Pharmacology Center, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
Acta Biomater. 2024 Nov;189:505-518. doi: 10.1016/j.actbio.2024.09.037. Epub 2024 Sep 26.
Endometriosis seriously affects 6-10 % of reproductive women globally and poses significant clinical challenges. The process of ectopic endometrial cell colonization shares similarities with cancer, and a dysfunctional immune microenvironment, characterized by non-classically polarized macrophages, plays a critical role in the progression of endometriosis. In this study, a targeted nano delivery system (BSA@Mif NPs) was developed using bovine serum albumin (BSA) as the carrier of mifepristone. The BSA@Mif NPs were utilized to selectively target M2 macrophages highly enriched in ectopic endometrial tissue via the SPARC receptor. This targeting strategy increases drug concentration at ectopic lesions while minimizing its distribution to normal tissue, thereby reducing side effects. In vitro studies demonstrated that BSA@Mif NPs not only enhanced the cellular uptake of M2-type macrophages and ectopic endometrial cells but also improved the cytotoxic effect of mifepristone on ectopic endometrial cells. Furthermore, the BSA@Mif NPs effectively induced immunogenic cell death (ICD) in ectopic endometrial cells and repolarized M2-type macrophages toward the M1 phenotype, resulting in a synergistic inhibition of ectopic endometrial cell growth. In vivo experiments revealed that BSA@Mif NPs exhibited significant therapeutic efficacy in endometriosis-bearing mice by increasing drug accumulation in the endometriotic tissues and modulating the immune microenvironment. This targeted biomimetic delivery strategy presents a promising approach for the development of endometriosis-specific therapies based on existing drugs. STATEMENT OF SIGNIFICANCE: Macrophages play an essential role in immune dysfunctional microenvironment promoting the occurrence and progression of endometriosis and can be a crucial target for developing immune microenvironment regulation strategies for the unmet long-term management of endometriosis. The albumin nanoparticles constructed based on SPARC overexpression in macrophages and endometrial cells and albumin biosafety can achieve the targeted therapy of endometriosis by increasing the passive- and active-mediated drug accumulation in ectopic endometrium and remodeling the immune microenvironment based on macrophage regulation. This study has the following implications: i) overcoming the inherent shortcomings of clinical drugs by nanotechnology is an alternative way of developing medication; ii) developing microenvironment modulation strategies based on macrophage regulation for endometriosis management is feasible.
子宫内膜异位症严重影响全球 6-10%的育龄妇女，带来严重的临床挑战。异位子宫内膜细胞定植的过程与癌症相似，功能失调的免疫微环境（其特征为非经典极化的巨噬细胞）在子宫内膜异位症的进展中起着关键作用。在这项研究中，使用牛血清白蛋白（BSA）作为米非司酮的载体，开发了一种靶向纳米递药系统（BSA@Mif NPs）。BSA@Mif NPs 通过富含 SPARC 受体的异位子宫内膜组织中的巨噬细胞来选择性地靶向 M2 型巨噬细胞。这种靶向策略增加了异位病变处的药物浓度，同时减少了其向正常组织的分布，从而降低了副作用。体外研究表明，BSA@Mif NPs 不仅增强了 M2 型巨噬细胞和异位子宫内膜细胞的细胞摄取，还提高了米非司酮对异位子宫内膜细胞的细胞毒性作用。此外，BSA@Mif NPs 有效地诱导了异位子宫内膜细胞的免疫原性细胞死亡（ICD），并将 M2 型巨噬细胞重新极化为 M1 表型，从而协同抑制异位子宫内膜细胞的生长。体内实验表明，BSA@Mif NPs 通过增加药物在子宫内膜异位组织中的积累并调节免疫微环境，在子宫内膜异位症荷瘤小鼠中表现出显著的治疗效果。这种基于生物模拟的靶向递药策略为基于现有药物的子宫内膜异位症特异性治疗的发展提供了一种有前途的方法。
巨噬细胞在促进子宫内膜异位症发生和进展的免疫功能失调的微环境中发挥着重要作用，是开发免疫微环境调节策略的关键靶点，用于治疗子宫内膜异位症的长期管理需求。基于巨噬细胞调控构建的基于 SPARC 在巨噬细胞和子宫内膜细胞中过表达的白蛋白纳米颗粒以及白蛋白的生物安全性，可以通过增加药物在异位子宫内膜中的被动和主动介导的积累，并基于巨噬细胞调控重塑免疫微环境，实现子宫内膜异位症的靶向治疗。本研究具有以下意义：i）通过纳米技术克服临床药物的固有缺点是开发药物的另一种方法；ii）开发基于巨噬细胞调控的子宫内膜异位症管理的微环境调节策略是可行的。
