Tumor Microenvironment-Responsive Multistaged Nanoplatform for Systemic RNAi and Cancer Therapy.
Tumor Microenvironment-Responsive Multistaged Nanoplatform for Systemic RNAi and Cancer Therapy.
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DOI：
10.1021/acs.nanolett.7b01571
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发表时间：
2017-07-12
期刊：
影响因子：
10.8
通讯作者：
Shi J
中科院分区：
文献类型：
--
作者：
Xu X;Saw PE;Tao W;Li Y;Ji X;Yu M;Mahmoudi M;Rasmussen J;Ayyash D;Zhou Y;Farokhzad OC;Shi J
虽然RNA干扰(RNAi)治疗已显示出巨大的癌症治疗潜力，但在体内有效和安全地将RNAi制剂如小干扰RNA(SiRNA)输送到肿瘤细胞中仍具有挑战性。我们在这里报道了一种独特的多阶段siRNA纳米颗粒(NP)传递平台，它由(I)聚乙二醇(PEG)表面外壳，(Ii)形成NP核心的尖锐的肿瘤微环境(TME)pH响应聚合物，以及(Iii)包裹在NP核心中的siRNA和肿瘤细胞靶向和穿透性多肽两亲性(TCPA)的电荷介导的络合物组成。当设计合理的长循环聚合物纳米粒静脉给药后聚集在肿瘤组织中时，靶向的siRNA-TCPA复合体可以通过TME pH介导的NP解体快速释放，用于随后的肿瘤细胞特异性靶向和胞浆转运，从而实现有效的基因沉默。体内实验结果进一步表明，针对新近发现的调节前列腺癌(Pca)发生发展的靶蛋白--溴域4(BRD4)的siRNA的多阶段NP递送可以显著抑制PCa的生长。
While RNA interference (RNAi) therapy has demonstrated significant potential for cancer treatment, effective and safe systemic delivery of RNAi agents such as small interfering RNA (siRNA) into tumor cells in vivo remains challenging. We herein reported a unique multistaged siRNA delivery nanoparticle (NP) platform, which is comprised of (i) a polyethylene glycol (PEG) surface shell, (ii) a sharp tumor microenvironment (TME) pH-responsive polymer that forms the NP core, and (iii) charge-mediated complexes of siRNA and tumor cell-targeting- and penetrating-peptide-amphiphile (TCPA) that are encapsulated in the NP core. When the rationally designed, long circulating polymeric NPs accumulate in tumor tissues after intravenous administration, the targeted siRNA-TCPA complexes can be rapidly released via TME pH-mediated NP disassembly for subsequent specific targeting of tumor cells and cytosolic transport, thus achieving efficient gene silencing. In vivo results further demonstrate that the multistaged NP delivery of siRNA against bromodomain 4 (BRD4), a recently discovered target protein that regulates the development and progression of prostate cancer (PCa), can significantly inhibit PCa tumor growth.
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影响因子：
82.9
作者：
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通讯作者：
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