Multifunctional Envelope-Type siRNA Delivery Nanoparticle Platform for Prostate Cancer Therapy.
Multifunctional Envelope-Type siRNA Delivery Nanoparticle Platform for Prostate Cancer Therapy.
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DOI：
10.1021/acsnano.6b07195
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发表时间：
2017-03-28
期刊：
影响因子：
17.1
通讯作者：
Shi J
中科院分区：
文献类型：
--
作者：
Xu X;Wu J;Liu Y;Saw PE;Tao W;Yu M;Zope H;Si M;Victorious A;Rasmussen J;Ayyash D;Farokhzad OC;Shi J
RNA干扰（RNA interference，RNAi）技术能够特异性沉默靶基因的表达，是一种治疗癌症和其他疾病的有效方法。RNAi的临床应用的一个关键挑战是将RNAi剂如小干扰RNA（siRNA）安全有效地递送至特定的非肝脏病变组织（例如，肿瘤）和具有足够胞质转运的细胞类型。在这项工作中，我们提出了一种多功能的前列腺癌（PCa）特异性siRNA体内递送的纳米颗粒（NP）平台。合成了寡聚精氨酸功能化的和尖锐的pH响应性聚合物的文库，并用于与siRNA自组装成具有长血液循环和pH触发的寡聚精氨酸介导的内体膜渗透的特征的NPs。通过用ACUPA（一种特异性识别前列腺特异性膜抗原（PSMA）受体的小分子配体）进一步修饰，这种具有多功能特性的生物型纳米平台可以有效靶向表达PSMA的PCa细胞并沉默靶基因表达。siRNA NP的全身递送可以有效地沉默在PCa和其他癌症中上调的抑制素1（PHB1）的表达，并显著抑制PCa肿瘤生长。这些结果表明，这种多功能的生物型纳米平台可以成为一种有效的工具，PCA特异性治疗。
With the capability of specific silencing of target gene expression, RNA interference (RNAi) technology is emerging as a promising therapeutic modality for the treatment of cancer and other diseases. One key challenge for the clinical applications of RNAi is the safe and effective delivery of RNAi agents such as small interfering RNA (siRNA) to a particular nonliver diseased tissue (e.g., tumor) and cell type with sufficient cytosolic transport. In this work, we proposed a multifunctional envelope-type nanoparticle (NP) platform for prostate cancer (PCa)-specific in vivo siRNA delivery. A library of oligoarginine-functionalized and sharp pH-responsive polymers was synthesized and used for self-assembly with siRNA into NPs with the features of long blood circulation and pH-triggered oligoarginine-mediated endosomal membrane penetration. By further modification with ACUPA, a small molecular ligand specifically recognizing prostate-specific membrane antigen (PSMA) receptor, this envelope-type nanoplatform with multifunctional properties can efficiently target PSMA-expressing PCa cells and silence target gene expression. Systemic delivery of the siRNA NPs can efficiently silence the expression of prohibitin 1 (PHB1), which is upregulated in PCa and other cancers, and significantly inhibit PCa tumor growth. These results suggest that this multifunctional envelope-type nanoplatform could become an effective tool for PCa-specific therapy.
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