Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53706, USA.
Nanoscale. 2012 Nov 21;4(22):7185-93. doi: 10.1039/c2nr31853a.
A multifunctional gold (Au) nanorod (NR)-based nanocarrier capable of co-delivering small interfering RNA (siRNA) against achaete-scute complex-like 1 (ASCL1) and an anticancer drug (doxorubicin (DOX)) specifically to neuroendocrine (NE) cancer cells was developed and characterized for combined chemotherapy and siRNA-mediated gene silencing. The Au NR was conjugated with (1) DOX, an anticancer drug, via a pH-labile hydrazone linkage to enable pH-controlled drug release, (2) polyarginine, a cationic polymer for complexing siRNA, and (3) octreotide (OCT), a tumor-targeting ligand, to specifically target NE cancer cells with overexpressed somatostatin receptors. The Au NR-based nanocarriers exhibited a uniform size distribution as well as pH-sensitive drug release. The OCT-conjugated Au NR-based nanocarriers (Au-DOX-OCT, targeted) exhibited a much higher cellular uptake in a human carcinoid cell line (BON cells) than non-targeted Au NR-based nanocarriers (Au-DOX) as measured by both flow cytometry and confocal laser scanning microscopy (CLSM). Moreover, Au-DOX-OCT-ASCL1 siRNA (Au-DOX-OCT complexed with ASCL1 siRNA) resulted in significantly higher gene silencing in NE cancer cells than Au-DOX-ASCL1 siRNA (non-targeted Au-DOX complexed with ASCL1 siRNA) as measured by an immunoblot analysis. Additionally, Au-DOX-OCT-ASCL1 siRNA was the most efficient nanocarrier at altering the NE phenotype of NE cancer cells and showed the strongest anti-proliferative effect. Thus, combined chemotherapy and RNA silencing using NE tumor-targeting Au NR-based nanocarriers could potentially enhance the therapeutic outcomes in treating NE cancers.
一种多功能金（Au）纳米棒（NR）基纳米载体，能够特异性地共递送针对achaete-scute 复合物样 1（ASCL1）的小干扰 RNA（siRNA）和抗癌药物（阿霉素（DOX）），用于联合化疗和 siRNA 介导的基因沉默。Au NR 通过 pH 不稳定腙键与（1）抗癌药物 DOX 偶联，以实现 pH 控制的药物释放，（2）聚精氨酸，一种用于结合 siRNA 的阳离子聚合物，和（3）奥曲肽（OCT），一种肿瘤靶向配体，以特异性靶向过表达生长抑素受体的神经内分泌（NE）癌细胞。基于 Au NR 的纳米载体表现出均匀的尺寸分布和 pH 敏感的药物释放。通过流式细胞术和共聚焦激光扫描显微镜（CLSM）测量，与非靶向基于 Au NR 的纳米载体（Au-DOX）相比，OCT 偶联的基于 Au NR 的纳米载体（Au-DOX-OCT，靶向）在人类类癌细胞系（BON 细胞）中表现出更高的细胞摄取。此外，通过免疫印迹分析测量，与 Au-DOX-ASCL1 siRNA（非靶向 Au-DOX 与 ASCL1 siRNA 复合）相比，Au-DOX-OCT-ASCL1 siRNA（与 ASCL1 siRNA 复合的靶向 Au-DOX-OCT）在 NE 癌细胞中导致更高的基因沉默。此外，Au-DOX-OCT-ASCL1 siRNA 是改变 NE 癌细胞的 NE 表型的最有效的纳米载体，并显示出最强的抗增殖作用。因此，使用 NE 肿瘤靶向 Au NR 基纳米载体进行联合化疗和 RNA 沉默可能会增强治疗 NE 癌症的治疗效果。
