免疫调节小分子JQ1可以阻断其下游效应PD-L1通路，有效逆转阿霉素（DOX）诱导的PD-L1上调。因此化疗药物DOX与JQ1的协同给药有望增加肿瘤对免疫检查点治疗的敏感性，共同增强机体自身免疫力，从而有效杀伤肿瘤细胞。因此，本研究设计了一种负载DOX和JQ1的药物递送系统。通过自发聚合合成聚多巴胺纳米颗粒（PDA NPs）。在适当的pH条件下，将DOX和JQ1负载到PDA NPs的表面，并使用UV-Vis或高效液相色谱（HPLC）测量DOX和JQ1的释放。通过细胞摄取实验、细胞活力测定、细胞凋亡测定和蛋白质印迹分析研究了体外制备的纳米复合物的机制。最后利用荷瘤小鼠模型评价其抑瘤效果和体内生物安全性。JQ1和DOX成功负载到PDA NPs上。 PDA-DOX/JQ1 NPs 在体外抑制前列腺癌细胞的生长，降低凋亡相关蛋白的表达并诱导细胞凋亡。体内生物分布表明PDA-DOX/JQ1 NPs可以通过EPR效应在肿瘤部位积累。在荷瘤小鼠中，JQ1 与 PDA-DOX/JQ1 NP 一起递送可降低肿瘤部位的 PD-L1 表达，从而产生显着的肿瘤抑制作用。此外，PDA-DOX/JQ1 NPs可以减少副作用，并在体内产生良好的协同治疗效果。我们已经成功制备了一个用于协同前列腺癌治疗的多功能平台。© 2024 Hu et al.

Immune regulatory small molecule JQ1 can block its downstream effector PD-L1 pathway and effectively reverse the PD-L1 upregulation induced by doxorubicin (DOX). So the synergistic administration of chemotherapeutic drug DOX and JQ1 is expected to increase the sensitivity of tumors to immune checkpoint therapy and jointly enhance the body's own immunity, thus effectively killing tumor cells. Therefore, a drug delivery system loaded with DOX and JQ1 was devised in this study.Polydopamine nanoparticles (PDA NPs) were synthesized through spontaneous polymerization. Under appropriate pH conditions, DOX and JQ1 were loaded onto the surface of PDA NPs, and the release of DOX and JQ1 were measured using UV-Vis or high performance liquid chromatography (HPLC). The mechanism of fabricated nanocomplex in vitro was investigated by cell uptake experiment, cell viability assays, apoptosis assays, and Western blot analysis. Finally, the tumor-bearing mouse model was used to evaluate the tumor-inhibiting efficacy and the biosafety in vivo.JQ1 and DOX were successfully loaded onto PDA NPs. PDA-DOX/JQ1 NPs inhibited the growth of prostate cancer cells, reduced the expression of apoptosis related proteins and induced apoptosis in vitro. The in vivo biodistribution indicated that PDA-DOX/JQ1 NPs could accumulated at the tumor sites through the EPR effect. In tumor-bearing mice, JQ1 delivered with PDA-DOX/JQ1 NPs reduced PD-L1 expression at tumor sites, generating significant tumor suppression. Furthermore, PDA-DOX/JQ1 NPs could reduce the side effects, and produce good synergistic treatment effect in vivo.We have successfully prepared a multifunctional platform for synergistic prostate cancer therapy.© 2024 Hu et al.