Materializing the potential of small interfering RNA via a tumor-targeting nanodelivery system
Materializing the potential of small interfering RNA via a tumor-targeting nanodelivery system
复制标题
DOI：
10.1158/0008-5472.can-06-4535
复制
发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Chang, Esther H.
中科院分区：
文献类型：
--
作者：
Pirollo, Kathleen F.;Rait, Antonina;Chang, Esther H.
小干扰RNA(SiRNA)作为一种有效的序列选择性转录抑制因子正在迅速发展。然而，到目前为止，体内注射的siRNAs的低转染率、组织穿透性差以及非特异性免疫刺激已经推迟了它们的治疗应用。它们作为抗癌治疗药物的潜力取决于是否有一种载体可以系统地、安全地和重复地给药，并将siRNA特异性和高效地输送到肿瘤，包括原发肿瘤和转移瘤。我们已经开发出一种基于免疫脂质体的纳米递送复合体(SCL)，当系统给药时，它将优先靶向并将基因药物中有用的分子，包括质粒DNA和反义寡核苷酸，输送到发生在体内的肿瘤细胞中。这种肿瘤靶向纳米颗粒递送载体还可以将siRNA递送到原发和转移疾病。我们还通过在复合体中加入对pH敏感的组氨酸-赖氨酸肽(scl-HoKC)和通过传递修饰的杂化(DNA-RNA)抗HER-2 siRNA分子来提高该复合体的效率。扫描探针显微镜证实，这种修饰的复合体保持了其纳米级的尺寸。更重要的是，我们发现这种纳米脂质体抗HER-2 siRNA复合体可以使人肿瘤细胞对化疗药物敏感，在体内沉默靶基因并影响其下游通路成分，并在胰腺癌模型中显著抑制肿瘤生长。因此，这种复合体有可能帮助将siRNA的强大作用转化为临床上可行的抗癌治疗方法。
The field of small interfering RNA (siRNA) as potent sequence-selective inhibitors of transcription is rapidly developing. However, until now, low transfection efficiency, poor tissue penetration, and nonspecific immune stimulation by in vivo administered siRNAs have delayed their therapeutic application. Their potential as anticancer therapeutics hinges on the availability of a vehicle that can be systemically administered, safely and repeatedly, and will deliver the siRNA specifically and efficiently to the tumor, both primary tumors and metastases. We have developed a nanosized immunoliposome-based delivery complex (scL) that, when systemically administered, will preferentially target and deliver molecules useful in gene medicine, including plasmid DNA and antisense oligonucleotides, to tumor cells wherever they occur in the body. This tumor-targeting nanoparticle delivery vehicle can also deliver siRNA to both primary and metastatic disease. We have also enhanced the efficiency of this complex by the inclusion of a pH-sensitive histidine-lysine peptide in the complex (scL-HoKC) and by delivery of a modified hybrid (DNA-RNA) anti-HER-2 siRNA molecule. Scanning probe microscopy confirms that this modified complex maintains its nanoscale size. More importantly, we show that this nanoinummoliposome anti-HER-2 siRNA complex can sensitize human tumor cells to chemotherapeutics, silence the target gene and affect its downstream pathway components in vivo, and significantly inhibit tumor growth in a pancreatic cancer model. Thus, this complex has the potential to help translate the potent effects of siRNA into a clinically viable anticancer therapeutic.