Department of Pharmacy , Zhengzhou Railway Vocational & Technical College , Zhengzhou 450018 , China.
Université Paris Descartes, PRES Sorbonne Paris Cité, CNRS UMR 860 , Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologique , 45, rue des Saints Peres , 75006 Paris , France.
Bioconjug Chem. 2019 Jul 17;30(7):1938-1950. doi: 10.1021/acs.bioconjchem.9b00385. Epub 2019 Jun 27.
Antisense oligonucleotide (AON)-based therapies concern the treatment for genetic disorders or infections such as a range of neurodegenerative and neuromuscular diseases and have shown benefits in animal models and patients. Nevertheless, successes in the clinic are still strongly limited by unfavorable biodistribution and poor cellular uptake of AONs. Dendrimer macromolecules are synthetically accessible and consist of a core with repeated iterations (named branches) surrounding this core, and on the periphery functional groups which can be modified for ligand attachment. The generations of these branched nanoparticles are based on the number of branches emanating from the core with layered architectures. Dendrimers show promise in several biomedical applications based on their tunable surface modifications allowing the adjustment of their in vivo behavior related to biocompatibility and pharmacokinetic parameters. Dendrimers can be used as nanocarriers of various types of drugs including AONs or nanodrugs. As nanocarriers, polycationic dendrimers can complex multiple negatively charged DNA oligonucleotides on their surface and form stable complexes to promote internalization into the cells based on a good cell membrane affinity. These nanocarriers complexing antisense oligonucleotides must be stable enough to reach the cellular target, but with adequate in vivo global clearance, and have good pharmacokinetic (PK) and pharmacodynamic (PD) profiles. This Review was designed to analyze the development of AONs carried by polycationic and polyanionic (few example) dendrimers. This Review strongly supports the idea that dendrimers, with adequate modulation of their terminal groups, could be used to carry AONs in cells.
反义寡核苷酸（AON）为基础的治疗方法是针对遗传疾病或感染的治疗方法，如一系列神经退行性和神经肌肉疾病，并在动物模型和患者中显示出益处。然而，在临床上的成功仍然受到 AONs 不利的生物分布和较差的细胞摄取的强烈限制。树状大分子是可合成的，由核心和重复迭代（称为分支）组成，这些分支围绕着核心，在核心的外围是可以修饰的功能基团，用于配体的附着。这些分支纳米粒子的代次是基于从核心发射的分支的数量，具有分层结构。树状大分子在几个基于其可调节的表面修饰的生物医学应用中显示出前景，这些修饰允许调整它们与生物相容性和药代动力学参数相关的体内行为。树状大分子可以用作各种类型的药物的纳米载体，包括 AON 或纳米药物。作为纳米载体，阳离子树状大分子可以在其表面上结合多个带负电荷的 DNA 寡核苷酸，并形成稳定的复合物，基于良好的细胞膜亲和力，促进进入细胞内。这些与反义寡核苷酸结合的纳米载体必须足够稳定以到达细胞靶标，但具有足够的体内整体清除率，并具有良好的药代动力学（PK）和药效学（PD）特征。本综述旨在分析由阳离子和阴离子（少数例子）树状大分子携带的 AON 的发展。本综述强烈支持这样的观点，即通过适当调节其末端基团，树状大分子可以用于在细胞中携带 AONs。
