1] Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA [2] Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, California, USA.
Mol Ther. 2013 Dec;21(12):2195-204. doi: 10.1038/mt.2013.191. Epub 2013 Aug 20.
Antiangiogenic therapy is a promising new treatment modality for cancer, but it generally produces only transient tumor regression. We have previously devised a tumor-targeted nanosystem, in which a pentapeptide, CGKRK, delivers a proapoptotic peptide into the mitochondria of tumor blood vessel endothelial cells and tumor cells. The treatment was highly effective in glioblastoma mouse models completely refractory to other antiangiogenic treatments. Here, we identify p32/gC1qR/HABP, a mitochondrial protein that is also expressed at the cell surface of activated (angiogenic) endothelial cells and tumor cells, as a receptor for the CGKRK peptide. The results demonstrate the ability of p32 to cause internalization of a payload bound to p32 into the cytoplasm. We also show that nardilysin, a protease capable of cleaving CGKRK, plays a role in the internalization of a p32-bound payload. As p32 is overexpressed and surface displayed in breast cancers, we studied the efficacy of the nanosystem in this cancer. We show highly significant treatment results in an orthotopic model of breast cancer. The specificity of cell surface p32 for tumor-associated cells, its ability to carry payloads to mitochondria, and the efficacy of the system in important types of cancer make the nanosystem a promising candidate for further development.
抗血管生成治疗是癌症治疗的一种很有前途的新方法，但它通常只能产生短暂的肿瘤消退。我们之前设计了一种肿瘤靶向纳米系统，其中五肽 CGKRK 将促凋亡肽递送到肿瘤血管内皮细胞和肿瘤细胞的线粒体中。该治疗方法在对其他抗血管生成治疗完全耐药的胶质母细胞瘤小鼠模型中非常有效。在这里，我们鉴定出 p32/gC1qR/HABP 是一种线粒体蛋白，也在激活（血管生成）内皮细胞和肿瘤细胞的细胞表面表达，是 CGKRK 肽的受体。结果表明 p32 能够将与 p32 结合的有效载荷内吞到细胞质中。我们还表明，能够切割 CGKRK 的蛋白酶 nardilysin 在 p32 结合的有效载荷的内化中起作用。由于 p32 在乳腺癌中过度表达并在表面表达，我们研究了该纳米系统在这种癌症中的疗效。我们在乳腺癌的原位模型中显示出非常显著的治疗效果。细胞表面 p32 对肿瘤相关细胞的特异性、将有效载荷携带到线粒体的能力以及该系统在重要类型癌症中的疗效使该纳米系统成为进一步开发的有前途的候选物。
