Zhou Yu, Zhang Shenqi, Chen Zeming, Bao Youmei, Chen Ann T, Sheu Wendy C, Liu Fuyao, Jiang Zhaozhong, Zhou Jiangbing
Department of Neurosurgery Yale University New Haven CT 06511 USA.
Department of Neurosurgery The Second Xiangya Hospital of Central South University Changsha Hunan 410011 China.
Adv Sci (Weinh). 2020 Jan 19;7(5):1901866. doi: 10.1002/advs.201901866. eCollection 2020 Mar.
Breast cancer brain metastases (BCBM) is a devastating disease with dismal prognosis. Although chemotherapy is widely used for clinical management of most tumors, it is often ineffective for BCBM. Therefore, alternative approaches for improved treatment of BCBM are in great demand. Here, an innovative gene therapy regimen is reported that is designed for effective treatment of BCBM. First, poly(lactone--β-amino ester) nanoparticles that are capable of efficient gene delivery are synthesized and are engineered for targeted delivery to BCBM through surface conjugation of AMD3100, which interacts with CXCR4 enriched in the tumor microenvironment. Next, an artificial gene, , is designed for the expression of secretory promelittin protein, which has limited toxicity on its own but releases cytolytic melittin after activation by MMP-2 accumulated in tumors. It is demonstrated that delivery of the via the AMD3100-conjugated nanoparticles effectively inhibits tumor progression in a BCBM mouse model. This study suggests a new direction to treat BCBM through targeted delivery of promelittin-mediated gene therapy.
乳腺癌脑转移（BCBM）是一种预后极差的毁灭性疾病。尽管化疗广泛用于大多数肿瘤的临床治疗，但它对BCBM往往无效。因此，迫切需要改进BCBM治疗的替代方法。在此，报道了一种创新的基因治疗方案，旨在有效治疗BCBM。首先，合成了能够高效递送基因的聚（内酯-β-氨基酯）纳米颗粒，并通过与肿瘤微环境中富集的CXCR4相互作用的AMD3100进行表面偶联，将其设计用于靶向递送至BCBM。接下来，设计了一种人工基因用于分泌前蜂毒肽蛋白的表达，该蛋白本身毒性有限，但在肿瘤中积累的MMP-2激活后会释放细胞溶解蜂毒肽。结果表明，通过AMD3100偶联的纳米颗粒递送该基因可有效抑制BCBM小鼠模型中的肿瘤进展。这项研究为通过靶向递送前蜂毒肽介导的基因治疗来治疗BCBM指明了新方向。
