Medarova Zdravka, Kumar Mohanraja, Ng Shu-wing, Moore Anna
Molecular Imaging Program, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Methods Mol Biol. 2009;555:1-13. doi: 10.1007/978-1-60327-295-7_1.
The vision of using a single therapeutic agent with sufficient generality to allow application to a wide variety of diseases, yet specific enough to permit intervention at single molecular stages of the pathology, is rapidly becoming a reality through the emergence of RNA interference. RNA interference can be used to inhibit the expression of virtually any gene and, at the same time, has single-nucleotide specificity. Major challenges in applying RNA interference in vivo are adequate delivery of the siRNA molecule to the tissue of interest and methods of monitoring this delivery in a noninvasive manner. With this in mind, we have developed an approach not only to deliver siRNA to tumors, but also to track the success of the delivery by noninvasive imaging. To accomplish this, we designed a dual-function probe, MN-NIRF-siRNA, which consists of magnetic nanoparticles (MN) for magnetic resonance imaging (MRI), labeled with Cy5.5 dye for near-infrared in vivo optical imaging (NIRF), conjugated to myristoylated polyarginine peptides (MPAPs) for translocation of the complex into the cytosol, and carrying siRNA targeting tumor-specific genes. Administration of MN-NIRF-siRNA to tumor-bearing mice allowed us to monitor the delivery of the agent to tumors by MRI and NIRF imaging and resulted in efficient silencing of the target genes. This approach can significantly advance the therapeutic potential of RNA interference by providing a way not only to effectively shuttle siRNA to target sites but also to noninvasively assess the bioavailability of the siRNA molecule.
利用一种具有足够通用性的单一治疗剂，使其能够应用于多种疾病，同时又具有足够的特异性，能够在病理过程的单个分子阶段进行干预，随着RNA干扰的出现，这一设想正迅速成为现实。RNA干扰可用于抑制几乎任何基因的表达，同时具有单核苷酸特异性。在体内应用RNA干扰的主要挑战是将小干扰RNA（siRNA）分子充分递送至感兴趣的组织，并以非侵入性方式监测这种递送。考虑到这一点，我们开发了一种方法，不仅能将siRNA递送至肿瘤，还能通过非侵入性成像追踪递送的成功情况。为实现这一目标，我们设计了一种双功能探针MN-NIRF-siRNA，它由用于磁共振成像（MRI）的磁性纳米颗粒（MN）组成，用Cy5.5染料标记用于体内近红外光学成像（NIRF），与肉豆蔻酰化聚精氨酸肽（MPAP）缀合以使复合物易位进入细胞质，并携带靶向肿瘤特异性基因的siRNA。向荷瘤小鼠施用MN-NIRF-siRNA使我们能够通过MRI和NIRF成像监测该药剂向肿瘤的递送，并导致靶基因的有效沉默。这种方法不仅可以通过有效地将siRNA转运到靶位点，还可以通过非侵入性评估siRNA分子的生物利用度，显著提高RNA干扰的治疗潜力。
