Abstract Targeted delivery of therapeutics to the uterus is an important goal in the treatment of obstetric complications, such as preterm labour, postpartum hemorrhage, and dysfunctional labour. Current treatment for these obstetric complications is challenging, as there are limited effective and safe therapeutic options available. We have developed a targeted drug delivery system for the uterus by conjugating anti-oxytocin receptor (OTR) antibodies to the surface of PEGylated liposomes (OTR-PEG-ILs). The functionality of the OTR-PEG-ILs has previously been evaluated on human and murine myometrial tissues as well as in vivo in a murine model of preterm labour. The aim of this study was to report the pharmaceutical synthesis and characterization of the OTR-PEG-ILs and investigate their specific cellular interaction with OTR-expressing myometrial cells in vitro. Immunoliposomes composed of 1,2-distearoyl-sn-glycero-2-phosphocholine (DSPC) and cholesterol were prepared using an optimized method for the coupling of low concentrations of antibody to liposomes. The liposomes were characterized for particle size, antibody conjugation, drug encapsulation, liposome stability, specificity of binding, cellular internalization, mechanistic pathway of cellular uptake, and cellular toxicity. Cellular association studies demonstrated specific binding of OTR-PEG-ILs to OTRs and significant cellular uptake following binding. Evaluation of the mechanistic pathway of cellular uptake indicated that they undergo internalization through both clathrin- and caveolin-mediated mechanisms. Furthermore, cellular toxicity studies have shown no significant effect of OTR-PEG-ILs or the endocytotic inhibitors on cell viability. This study further supports oxytocin receptors as a novel pharmaceutical target for drug delivery to the uterus.

中文翻译：

---

用于向子宫输送药物的催产素受体靶向聚乙二醇化免疫脂质体的合成和体外表征

摘要 将治疗药物靶向子宫是治疗早产、产后出血和功能障碍等产科并发症的重要目标。目前对这些产科并发症的治疗具有挑战性，因为可用的有效和安全的治疗选择有限。我们通过将抗催产素受体 (OTR) 抗体结合到聚乙二醇化脂质体 (OTR-PEG-IL) 的表面，开发了一种用于子宫的靶向给药系统。OTR-PEG-ILs 的功能先前已在人和小鼠子宫肌层组织以及小鼠早产模型体内进行了评估。本研究的目的是报告 OTR-PEG-ILs 的药物合成和表征，并在体外研究它们与表达 OTR 的子宫肌层细胞的特异性细胞相互作用。使用优化的方法制备由 1,2-二硬脂酰-sn-甘油-2-磷酸胆碱 (DSPC) 和胆固醇组成的免疫脂质体，用于将低浓度抗体与脂质体偶联。脂质体的特征在于粒径、抗体偶联、药物包封、脂质体稳定性、结合特异性、细胞内化、细胞摄取的机制途径和细胞毒性。细胞结合研究证明了 OTR-PEG-ILs 与 OTRs 的特异性结合以及结合后显着的细胞摄取。对细胞摄取机制途径的评估表明，它们通过网格蛋白和小窝蛋白介导的机制进行内化。此外，细胞毒性研究表明 OTR-PEG-ILs 或内吞抑制剂对细胞活力没有显着影响。该研究进一步支持催产素受体作为将药物输送到子宫的新型药物靶点。