Overexpression of caveolin-1 in inflammatory breast cancer cells enables IBC-specific gene delivery and prodrug conversion using histone-targeted polyplexes.
Overexpression of caveolin-1 in inflammatory breast cancer cells enables IBC-specific gene delivery and prodrug conversion using histone-targeted polyplexes.
复制标题
炎症性乳腺癌细胞中小窝蛋白-1的过表达可以使用靶向组蛋白的息肉群来实现IBC特异性基因递送和前药转化。
DOI：
10.1002/bit.26022
复制
发表时间：
2016-12
影响因子：
3.8
通讯作者：
Sullivan MO
中科院分区：
文献类型：
--
作者：
Ross NL;Sullivan MO
基因治疗平台为开发可用于癌症治疗的靶向药物提供了多种潜在有效的解决方案。纳米载体的物理化学性质可以被调整以增强其在肿瘤中的定位，并且细胞特异性也可以通过适当选择基因靶点来增加。增强癌症组织中的治疗选择性的相对未充分开发的方法是使用纳米载体，其核靶向和摄取由癌细胞中特异性内膜运输蛋白的改变表达触发。以前，我们表明，组蛋白3（H3）肽靶向的DNA复合物交通有效地通过细胞膜小窝内吞，然后通过高尔基体和内质网（ER）转移到细胞核。我们假设这些复合物在炎性乳腺癌（IBC）细胞中表现出增强的活性，IBC细胞过度表达小窝蛋白-1作为其侵袭性表型的一部分，我们还假设这种靶向作用可用于促进正常乳腺上皮细胞存在下的IBC特异性转染和前药转化。在IBC SUM 149细胞单一培养物和IBC SUM 149与MCF 10A正常乳腺上皮细胞共培养物中使用细胞转染实验、功能阻断测定和共聚焦成像，我们发现我们的H3靶向复合物以比正常乳腺上皮细胞高4倍的水平选择性转染IBC SUM 149细胞。这种选择性和增加的转染是由IBC SUM 149细胞中小窝蛋白-1的2.2倍过表达引起的，这导致通过高尔基体和ER向细胞核运输的多聚物增加。当用自杀基因/前药组合转染细胞时，我们还看到细胞选择性和转染的类似增强，因为IBC SUM 149细胞中自杀基因表达的增加导致IBC SUM 149细胞中存活率降低55%，而MCF 10A细胞中存活率降低25%。这些研究结果表明，内吞膜蛋白小窝蛋白-1的表达差异可以用于细胞选择性基因递送，最终，这些基于基因的靶向方法可能用于侵袭性癌症类型的潜在治疗。
Gene therapy platforms offer a variety of potentially effective solutions for development of targeted agents that can be exploited for cancer treatment. The physicochemical properties of nanocarriers can be tuned to enhance their localization in tumors, and cell specificity can also be increased by appropriate selection of gene targets. A relatively underexploited approach to enhance therapeutic selectivity in cancer tissues is the use of nanocarriers whose nuclear targeting and uptake are triggered by the altered expression of specific endomembrane trafficking proteins in cancer cells. Previously, we showed that histone 3 (H3) peptide-targeted DNA polyplexes traffic to the nucleus efficiently through caveolar endocytosis followed by transfer through the Golgi and endoplasmic reticulum (ER). We hypothesized that these polyplexes would exhibit enhanced activity in inflammatory breast cancer (IBC) cells, which overexpress caveolin-1 as part of their invasive phenotype, and we also posited that this targeting effect could be exploited to facilitate IBC-specific transfection and prodrug conversion in the presence of normal breast epithelial cells. Using cellular transfection experiments, function-blocking assays, and confocal imaging in both IBC SUM149 cell monocultures and IBC SUM149 co-cultures with MCF10A normal breast epithelial cells, we found that our H3-targeted polyplexes selectively transfected IBC SUM149 cells at a 4-fold higher level than normal breast epithelial cells. This selectivity and increased transfection were caused by a 2.2-fold overexpression of caveolin-1 in IBC SUM149 cells, which led to increased polyplex trafficking to the nucleus through the Golgi and ER. We also saw similar enhancements in cell selectivity and transfection when cells were transfected with a suicide gene/prodrug combination, as the increased expression of the suicide gene in IBC SUM149 cells led to a 55% decrease in viability in IBC SUM149 cells as compared to a 25% decrease in MCF10A cells. These findings demonstrate that differences in the expression of the endocytic membrane protein caveolin-1 can be exploited for cell-selective gene delivery, and ultimately, these gene-based targeting approaches may be useful in potential treatments for aggressive cancer types.