多药物疗法在癌症患者中很少见到明显的效果，这是因为癌症的复杂性和肿瘤环境的原因。这种失败的主要原因之一是药物在肿瘤部位的不足积累。我们的研究表明，利用唾液酸（SAL）作为配体，设计制备硒（Se）修饰的硼替佐米（BTZ）前药纳米粒子（NPs）是改善乳腺癌治疗的一种有希翼的策略。BTZ与SAL和羟丙基甲基丙烯酰胺（HPMA）结合，形成前药结合物BTZ-SAL-HPMA（BSAL-HP），然后制备成具有Se的前药NPs（Se_BSAL-HP前药NPs）。利用动态光散射（DLS）实验测得了Se功能化的前药NPs的尺寸（204.13±0.02 nm）和电位（-31.0±0.11 mV），并通过透射电子显微镜（TEM）和扫描电子显微镜（SEM）分析得到了球形形状。Se_BSAL-HP前药NPs表现出良好的稳定性和低pH药物释放特性。BTZ的靶向肿瘤的硼酯酯基前药NPs与Se的协同作用显示出卓越的抗癌效果。与前药结合物相比，Se_BSAL-HP前药NPs显示出更高的细胞毒性和增强的细胞内摄取，在线粒体内膜电位（MMP）方面有明显变化。与BTZ相比，Se_BSAL-HP前药NPs在细胞周期的G2/M期显示出升高的细胞凋亡程度（2.7倍）。在大鼠斯普拉格-道利（Sprague-Dawley）上进行的体内研究表明，Se_BSAL-HP前药NPs具有显著的疗效。在4T1肿瘤携带的小鼠中，Se_BSAL-HP前药NPs抑制了原发性肿瘤的生长，并且其肿瘤体积较对照组减少了43.05倍。Se_BSAL-HP前药NPs的令人惊讶和杰出的结果可能是由于硼酯酯基和硒共同起到了诱发ROS效应的作用。

Most cancer patients rarely benefit from monodrug therapy because of both cancer complexity and tumor environment. One of the main reasons for this failure is insufficient accumulation of the optimal dose at the tumorous site. Our investigation implies a promising strategy to engineer prodrug nanoparticles (NPs) of bortezomib (BTZ) and selenium (Se) using sialic acid (SAL) as a ligand to improve breast cancer therapy. BTZ was conjugated with SAL and HPMA (N-2-hydroxypropyl methacrylamide) to prepare a prodrug conjugate; BTZ-SAL-HPMA (BSAL-HP) and then fabricated into prodrug NPs with Se (Se_BSAL-HP prodrug NPs). The self-assembly of prodrug NPs functionalized with Se showed size (204.13 ± 0.02 nm) and zeta potential (-31.0 ± 0.11 mV) in dynamic light scattering (DLS) experiments and spherical shape in TEM and SEM analysis. Good stability and low pH drug release profile were characterized by Se_BSAL-HP prodrug NPs. The tumor-selective boronate-ester-based prodrug NPs of BTZ in combination with Se endowed a synergistic effect against cancer cells. Compared to prodrug conjugate, Se_BSAL-HP prodrug NPs exhibited higher cell cytotoxicity and enhanced cellular internalization with significant changes in mitochondria membrane potential (MMP). Elevated apoptosis was observed in the (G2/M) phase of the cell cycle for Se_BSAL-HP prodrug NPs (2.7-fold) higher than BTZ. In vivo studies were performed on Sprague-Dawley rats and resulted in positive trends. The increased therapeutic activity of Se_BSAL-HP prodrug NPs inhibited primary tumor growth and showed 43.05 fold decrease in tumor volume than the control in 4T1 tumor bearing mice. The surprising and remarkable outcomes for Se_BSAL-HP prodrug NPs were probably due to the ROS triggering effect of boronate ester and selenium given together.