Nanoplex delivery of siRNA and prodrug enzyme for multimodality image-guided molecular pathway targeted cancer therapy.
Nanoplex delivery of siRNA and prodrug enzyme for multimodality image-guided molecular pathway targeted cancer therapy.
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DOI：
10.1021/nn102187v
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发表时间：
2010-11-23
期刊：
影响因子：
17.1
通讯作者：
Bhujwalla ZM
中科院分区：
文献类型：
--
作者：
Li C;Penet MF;Wildes F;Takagi T;Chen Z;Winnard PT;Artemov D;Bhujwalla ZM
在癌症治疗中，破坏癌细胞同时保留正常组织的能力是非常受欢迎的。小干扰RNA（siRNA）介导的癌细胞特异性靶点沉默，或使用递送至肿瘤的前药酶将无毒前药转化为活性药物是实现这一目标的两种有前途的方法。将这两种方法结合到一种治疗策略中可以增强对癌细胞的选择性靶向，同时保留正常组织。非侵入性成像可以通过确定siRNA和前药酶的有效肿瘤递送以确定前药施用的时间，并检测siRNA的靶下调和酶的前药转化来帮助优化这种策略。在原理验证研究中，我们合成了携带用于体内检测的磁共振成像（MRI）报告分子和用于显微镜的光学报告分子的纳米复合物，以成像siRNA和功能性前药酶在乳腺肿瘤中的递送，并实现图像引导的分子靶向癌症治疗。将靶向胆碱激酶-α（Chk-α）（一种在侵袭性乳腺癌细胞中显著上调的酶）的siRNA与前药酶细菌胞嘧啶脱氨酶（bCD）组合，该酶将无毒前药5-氟胞嘧啶（5-FC）转化为细胞毒性5-氟尿嘧啶（5-FU）。体内MRI和光学成像显示有效的肿瘤内纳米复合物递送。用1H MR波谱成像和19 F MR波谱无创检测siRNA介导的Chk-α下调和bCD将5-FC转化为5-FU。组合siRNA和前药酶活化处理比单独处理实现更高的生长延迟。该策略可以扩展到用siRNA靶向多个通路。
The ability to destroy cancer cells while sparing normal tissue is highly sought after in cancer therapy. Small interfering RNA (siRNA)-mediated silencing of cancer-cell specific targets, or the use of a prodrug enzyme delivered to the tumor to convert a non-toxic prodrug to an active drug are two promising approaches in achieving this goal. Combining both approaches into a single treatment strategy can amplify selective targeting of cancer cells while sparing normal tissue. Noninvasive imaging can assist in optimizing such a strategy, by determining effective tumor delivery of the siRNA and prodrug enzyme to time prodrug administration, and detecting target downregulation by siRNA, and prodrug conversion by the enzyme. In proof-of-principle studies, we synthesized a nanoplex carrying magnetic resonance imaging (MRI) reporters for in vivo detection, and optical reporters for microscopy, to image the delivery of siRNA and a functional prodrug enzyme in breast tumors, and achieve image-guided molecular targeted cancer therapy. siRNA targeting of choline kinase-α (Chk-α), an enzyme significantly up regulated in aggressive breast cancer cells, was combined with the prodrug enzyme bacterial cytosine deaminase (bCD) that converts the non-toxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU). In vivo MRI and optical imaging showed efficient intratumoral nanoplex delivery. siRNA-mediated downregulation of Chk-α and the conversion of 5-FC to 5-FU by bCD were detected noninvasively with 1H MR spectroscopic imaging and 19F MR spectroscopy. Combined siRNA and prodrug enzyme activated treatment achieved higher growth delay than either treatment alone. The strategy can be expanded to target multiple pathways with siRNA.
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影响因子：
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作者：
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