Dual-Function, Cationic, Peptide-Coated Nanodiamond Systems: Facilitating Nuclear-Targeting Delivery for Enhanced Gene Therapy Applications,ACS Sustainable Chemistry & Engineering

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Dual-Function, Cationic, Peptide-Coated Nanodiamond Systems: Facilitating Nuclear-Targeting Delivery for Enhanced Gene Therapy Applications
ACS Sustainable Chemistry & Engineering ( IF 7.1 ) Pub Date : 2018-07-06 00:00:00 , DOI: 10.1021/acssuschemeng.8b00446
Hoi Man Leung , Miu Shan Chan , Ling Sum Liu , Sze Wing Wong , Tsz Wan Lo , Cia-Hin Lau , Chung Tin ₁ , Pik Kwan Lo ₂

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Nuclear-targeting therapy is considered to be a promising strategy of disease treatment. So far, developing biocompatible and nucleus-permeable delivery systems remains a great challenge. Here, we report a nuclear-targeted delivery platform based on 30 nm nanodiamonds (NDs) which were coated with dual-function, cationic peptides consisting of the human immounodeficiency virus TAT protein and a nuclear localization signal (NLS) peptide in aqueous media. As compared to uncoated NDs, cationic peptide-functionalized NDs were confirmed as a small, safe, and efficient carrier which not only facilitates the enhanced cellular uptake and delivery of loaded cargos to the nucleus in a number of cell lines but also shows their advantages of low cytotoxicity and high affinity to antisense oligonucleotides. This peptide-based modification strategy does not contribute greatly to the size of the ND which is important in its use in constructing nuclear targeting vehicles. Compared with traditional gene silencing in cytoplasm, our findings suggest that the nuclear localization effect of ANA4625-TAT-NLS-NDs enhances the therapeutic efficacy of antisense oligonucleotide ANA4625 as evidenced by suppression of the targets bcl-2 and bcl-xL pre-mRNA/protein expressions and the induction of cell apoptosis. The studies have also revealed that NDs can be used to mediate sustained release of antisense agents with preserved therapeutic activity as inhibition of target mRNA expression in a time- and dose-dependent manner. This work not only demonstrates the design of a new nanodiamond-based platform for nuclear targeting but also provides significant insights on nuclear-targeting delivery of cell membrane impermeable therapeutic agents for enhanced disease treatment.

中文翻译：

双重功能，阳离子，肽包被的纳米金刚石系统：促进核靶向递送，增强了基因治疗的应用

核靶向治疗被认为是一种有前途的疾病治疗策略。迄今为止，开发生物相容性和核可渗透的递送系统仍然是一个巨大的挑战。在这里，我们报告基于30纳米纳米金刚石（NDs）的核靶向递送平台，该纳米涂层涂有双功能阳离子肽，该肽由人免疫缺陷病毒TAT蛋白和核定位信号（NLS）肽在水性介质中组成。与未包被的NDs相比，阳离子肽官能化的NDs被证实是一种小型，安全且有效的载体，它不仅促进了细胞在许多细胞系中的细胞摄取和向细胞核的转运，而且还显示出它们的优势。低细胞毒性和对反义寡核苷酸的高亲和力。这种基于肽的修饰策略对ND的大小贡献不大，而ND的大小在构建核靶向载体中很重要。与细胞质中的传统基因沉默相比，我们的发现表明ANA4625-TAT-NLS-NDs的核定位作用增强了反义寡核苷酸ANA4625的治疗效果，这可通过抑制靶标来证明bcl-2和bcl-xL的前mRNA /蛋白表达和细胞凋亡的诱导。研究还表明，NDs可用于以时间和剂量依赖性方式抑制靶mRNA表达，从而保持治疗活性，从而介导反义剂的持续释放。这项工作不仅证明了用于核靶向的新的基于纳米金刚石的平台的设计，而且还提供了对细胞膜不可渗透的治疗剂进行核靶向递送以增强疾病治疗的重要见解。

更新日期：2018-07-06

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