整合素α6作为鼻咽癌新靶向基因研究

Previously we screened a nasopharyngeal carcinoma targeting peptide by phage display and identified its targeting protein as integrin α6 which was found to be overexpressed in several nasopharyngeal carcinoma tissues. This integrin α6 targeting peptide bound and penetrated into nasopharyngeal carcinoma cells in vitro and homed to nasopharyngeal carcinoma tissue in vivo. Suppression of integrin α6 expression in nasopharyngeal carcinoma cells reduced their colony formation, inhibited their migration and invasion and decreased their sphere formation. These results show that integrin α6 is potential therapeutic target of nasopharyngeal carcinoma and the new identified integrin α6 targeting peptide is a potential targeting therapeutic vehicle. Based on these results, here we will detect integrin α6 expression in more nasopharyngeal carcinoma tissues and link the expression level of integrin α6 to nasopharyngeal carcinoma patient prognosis. We also will investigate the tumor-promoting function of integrin α6 in nasopharyngeal carcinoma and its related molecular mechanism. Importantly, based on the integrin α6 targeting peptide, we will develop therapeutic nanoparticles targeting to nasopharyngeal carcinoma and examine the efficacy and toxicity of these nanoparticles.

本研究前期应用噬菌体展示技术筛选一条以整合素α6为结合靶点的多肽；发现整合素α6在鼻咽癌中过表达；体外实验，发现该多肽可以结合和内化进入鼻咽癌细胞；体内实验，发现多肽在鼻咽癌组织中富集；干扰整合素α6可以抑制鼻咽癌细胞克隆形成，迁移，侵袭和成球。这些结果表明整合素α6是鼻咽癌的潜在靶点，以其为靶点的多肽是鼻咽癌靶向性治疗的潜在载体。本研究拟在前期研究基础上，首先通过免疫组化检测整合素α6在鼻咽癌病人组织切片中的表达情况，结合临床预后数据分析整合素α6表达水平与鼻咽癌临床预后之间的关系；然后通过体内外实验，研究整合素α6在鼻咽癌中的作用及其分子机制；最后将整合素α6靶向多肽与顺铂药物纳米颗粒偶联，形成以整合素α6为靶点的多肽纳米药物，评价该药物对鼻咽癌的疗效。

本项目前期研究发现整合素a6在鼻咽癌过表达，是鼻咽癌预后不良的标志物。本研究进一步研究发现整合素a6是鼻咽癌细胞干性分子标志物，是鼻咽癌靶向治疗的潜在靶点；在前期研发整合素a6靶向多肽RWY基础上，研发一种包裹顺铂前体药物的整合素a6靶向纳米药物RWY-NP/Pt(IV)；发现该纳米药物的疗效约为目前临床应用的顺铂疗效的100倍；相对于顺铂使小鼠体重降低，该纳米药物对小鼠体重无明显影响。因此，本项目研发整合素a6靶向多肽纳米药物不仅可以增强顺铂的疗效，而且可以降低顺铂的毒副作用，对鼻咽癌治疗具有潜在转化应用价值。