Cellular environment-responsive nanomaterials for use in gene and siRNA delivery: molecular design for biomembrane destabilization and intracellular collapse
Cellular environment-responsive nanomaterials for use in gene and siRNA delivery: molecular design for biomembrane destabilization and intracellular collapse
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DOI：
10.1517/17425247.2016.1154531
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发表时间：
2016-03
影响因子：
6.6
通讯作者：
Hiroki Tanaka;Yusuke Sato;H. Harashima;H. Akita
中科院分区：
文献类型：
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作者：
Hiroki Tanaka;Yusuke Sato;H. Harashima;H. Akita
摘要导读：发展基因与核酸为基础的药物治疗是个体化医疗研究领域的终极策略之一。为了实现基因或siRNA的预期功能，这些分子需要被递送到适当的细胞器（即分别是细胞核和细胞质）。所涵盖的领域：本文所涵盖的主题是合理设计，以控制药物动力学，细胞内运输和预期物质的释放（去密实或脱胶囊）。由于核内体和细胞质分别是酸性环境（核内体）和还原性环境（细胞质），因此已经开发了各种各样的材料，通过核内体的质子化诱导核内体的不稳定，或者在细胞质中自发坍塌。最后，我们提出了安装这些传感基序的材料（ss -可切割和ph活化的脂质样材料：ssPalm），即响应酸性环境的正电荷单元（叔胺）和响应还原环境的裂解单元（二硫键）。专家意见：目前，纳米载体介导的siRNA递送系统的主要靶点是肝脏。下一个挑战是靶向非肝组织。在这种情况下，需要设计具有良好组织的细胞内运输的中性粒子，以及鉴定有希望的配体。
ABSTRACT Introduction: The development of gene and nucleic acid-based medication is one of the ultimate strategies in the research field of personalized medicine. For the desired function of a gene or siRNA, these molecules need to be delivered to the appropriate organelle (i.e. nucleus and cytoplasm, respectively). Areas covered: The topics covered herein are rational design in order to control the pharmacokinetics, intracellular trafficking and release (decondensation or decapsulation) of the intended material. Since the endosome and cytoplasm are acidic (endosome) and reducing (cytoplasm) environments, respectively, a large variety of the materials have been developed that induce destabilization of endosome via its protonation, or are spontaneously collapsed in the cytoplasm. Finally, we propose materials (SS-cleavable and pH-activated lipid-like materials: ssPalm) that mount these sensing motifs, i.e., a positive charging unit in response to the acid environment (tertiary amines) and a cleavage unit (disulfide bonding) that is responsive to an reducing environment, respectively. Expert opinion: Currently, the main target of the nanocarrier-mediated siRNA delivery systems is liver. The targeting of non-hepatic tissue is the next challenge. In this case, the design of neutral particle with well-organized intracellular trafficking, as well as an identification of the promising ligand is needed.