本研究描述了合理的工程方法来制备多柔比星前药负载的肽靶向脂质体纳米粒子，以选择性地靶向体内转移性乳腺癌细胞。葡萄糖调节蛋白78 (GRP78) 是一种通常定位在健康细胞内质网的热休克蛋白，在某些癌症中已被发现定位在细胞表面，因此成为一个有前途的治疗靶点。最近的报告表明，GRP78表达在一种具有转移潜力的乳腺癌干细胞亚群的细胞表面。本研究优化了一个带有GRP78结合肽（结合常数Kd为7.4 ± 1.0 μM）的靶向纳米粒子配方，以选择性地靶向此亚群。体外研究使用乳腺癌细胞系显示，与对照组相比，靶向纳米粒子配方（TNPGRP78pep）具有增强的细胞摄取能力，并且仍然保持选择性。体内使用肽靶向纳米粒子负载多柔比星前药在肺转移小鼠模型中评估，并且显示抑制了乳腺癌细胞种植到肺的能力，达到了阴性对照组的水平。综合而言，本研究证实了特异性靶向表面GRP78表达的具有侵袭性的乳腺癌细胞亚群能够抑制乳腺癌转移到肺的能力，并强调了GRP78在乳腺癌转移中的重要性。

Here, rational engineering of doxorubicin prodrug loaded peptide-targeted liposomal nanoparticles to selectively target metastatic breast cancer cells in vivo is described. Glucose-regulated protein 78 (GRP78), a heat shock protein typically localized in the endoplasmic reticulum in healthy cells, has been identified to home to the cell surface in certain cancers, and thus has emerged as a promising therapeutic target. Recent reports indicated GRP78 to be expressed on the cell surface of an aggressive subpopulation of stem-like breast cancer cells that exhibit metastatic potential. In this study, a targeted nanoparticle formulation with a GRP78-binding peptide (Kd of 7.4 ± 1.0 μM) was optimized to selectively target this subpopulation. In vitro studies with breast cancer cell lines showed the targeted nanoparticle formulation (TNPGRP78pep) achieved enhanced cellular uptake, while maintaining selectivity over the control groups. In vivo, TNPGRP78pep loaded with doxorubicin prodrug was evaluated using a lung metastatic mouse model and demonstrated inhibition of breast cancer cell seeding to lungs down at the level of negative control groups. Combined, this study established that specific-targeting of surface GRP78 expressing a subpopulation of aggressive breast cancer cells was able to inhibit breast cancer metastasis to lungs, and underpinned the significance of GRP78 in breast cancer metastasis.