Pirollo Kathleen F, Rait Antonina, Zhou Qi, Hwang Sung Hee, Dagata John A, Zon Gerald, Hogrefe Richard I, Palchik Guillermo, Chang Esther H
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA.
Cancer Res. 2007 Apr 1;67(7):2938-43. doi: 10.1158/0008-5472.CAN-06-4535.
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 nanoimmunoliposome 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.
作为高效转录序列选择性抑制剂的小干扰RNA（siRNA）领域正在迅速发展。然而，到目前为止，体内给药的siRNA转染效率低、组织穿透力差以及非特异性免疫刺激阻碍了它们的治疗应用。它们作为抗癌治疗药物的潜力取决于一种载体的可用性，该载体能够全身给药，安全且可重复使用，并能将siRNA特异性且高效地递送至肿瘤，包括原发性肿瘤和转移瘤。我们开发了一种基于纳米免疫脂质体的递送复合物（scL），当全身给药时，它将优先靶向并将基因治疗中有用的分子，包括质粒DNA和反义寡核苷酸，递送至体内任何部位的肿瘤细胞。这种肿瘤靶向纳米颗粒递送载体也可以将siRNA递送至原发性和转移性疾病。我们还通过在复合物中加入pH敏感的组氨酸-赖氨酸肽（scL-HoKC）以及递送一种修饰的杂交（DNA-RNA）抗HER-2 siRNA分子来提高该复合物的效率。扫描探针显微镜证实这种修饰后的复合物保持其纳米级尺寸。更重要的是，我们表明这种纳米免疫脂质体抗HER-2 siRNA复合物可以使人类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途径成分，并在胰腺癌模型中显著抑制肿瘤生长。因此，这种复合物有潜力将siRNA的强大作用转化为临床上可行的抗癌治疗方法。
