T-VISA-miR-200纳米系统靶向治疗三阴乳腺癌及其作用机制的研究

Triple negative breast cancer (TNBC) is the most aggressive subgroup with the highest metastasis rate and poorest survival, accounting for about 20% of all cases of breast cancer. Owing to the absence of estrogen-receptor (ER), progesterone-receptor (PR) and human epidermal growth factor receptor type 2 (HER2), the patients with TNBC could benefit neither from endocrine therapy nor from HER-2-targeted therapy. With numerous studies of microRNAs profiles in recent years, miR-200 is identified to be down-regulated in TNBC. The over-expression of miR-200 could inhibit the proliferation, metastasis and chemotherapy resistance in TNBC significantly, through targeting multiple oncogenes. Therefore, we anticipate the potential of miR-200 for being developed as a targeted drug of TNBC. Based on VISA Integrated Systemic Amplifier (u.s. patent no. US 7723104 B2) and nanoparticle XM001 technology, we constructed the TNBC specific T (hTERT)-VISA nanoparticle vector system. Now we want to synthetize T-VISA-miR-200 nanoparticle targeted system, which initiates the over-expression of miR-200 in TNBC efficiently and specifically. Then the safety and effectiveness of T-VISA-miR-200 nanoparticle targeted system will be evaluated. Furthermore, the mechanism of miR-200 regulating TNBC will be explored by using analysis software such as GO and Pathway, and there will be more new molecular targets unrevealed, which lays a theoretical foundation for targeted therapy of TNBC.

三阴乳腺癌（Triple Negative Breast Cancer, TNBC）是一种预后极差的特殊类型乳腺癌，约占所有乳腺癌的20%，因其ER、PR及HER2均为阴性，内分泌治疗和抗HER2靶向治疗均无效。近年研究发现miR-200可明显抑制TNBC增殖、转移，并可同时降低其干细胞活性，因此我们认为miR-200具备开发成为TNBC靶向药物的潜质。本课题前期在VISA基因扩增系统（美国专利号：US7723104B2）及脂质体纳米颗粒的基础上，建立了三阴乳腺癌特异性T-VISA 纳米靶向载体（中国专利申请号: 2011103300441.X），现欲构建T-VISA-miR-200纳米系统，将miR-200高效特异的表达于TNBC中，评价其治疗的安全性及有效性。探索miR-200作用于TNBC的分子机制，利用GO、Pathway等软件绘制信号通路网络，为靶向治疗TNBC奠定基础。

乳腺癌病人致死性转移中最为常见的是肺转移。三阴乳腺癌（Triple Negative Breast Cancer, TNBC）的远处转移率明显高于其他类型乳腺癌，尤其是肺转移率最高（40%-50%）。TNBC因其ER、PR及HER2均为阴性，内分泌治疗和抗HER2靶向治疗均无效，一旦出现复发转移，目前尚无有效药物控制。因此防治TNBC肺转移是提高该类型乳腺癌生存率的关键。TNBC的异质性极强，而microRNA具有多靶向性，可同时参与多个信号通路调节，因此也成为多靶点治疗TNBC的研究热点。本研究利用microRNA芯片等分析发现miR-629-3p为TNBC肺转移特异性miRNA，其高表达对TNBC肺转移有较强的预测及诊断意义。体外、体内试验均提示miR-629-3p可显著促进TNBC细胞增殖、侵袭、转移的能力。通过靶基因预测联合KEGG pathway分析，我们进一步验证了LIFR为miR-629-3p的直接靶基因。下一步研究我们将探索miR-629-3p/LIFR的相关信号传导通路，为其作为生物学标记、治疗靶点提供理论依据。最终我们将构建TV-antagomir-629-3p及TV-LIFR靶向纳米颗粒，评价其治疗TNBC肺转移的安全性及有效性，为靶向药物的开发及临床研究奠定基础。