a Department of Biosciences and Nutrition , Karolinska Institutet , Stockholm , Sweden.
Expert Opin Drug Deliv. 2019 Jun;16(6):621-637. doi: 10.1080/17425247.2019.1617693. Epub 2019 May 20.
Oligonucleotide therapeutics such as antisense oligonucleotides and siRNA requires chemical modifications and nano-sized carriers to circumvent stability problems , to reach target tissues, and to overcome tissue and cellular barriers. Hyaluronic acid (HA), already utilized in drug delivery and tissue engineering, possess properties that are useful to solve these problems and achieve full potential of oligonucleotide therapeutics.
Complexes of oligonucleotide therapeutics with HA are discussed in terms of interactions providing the complexes formation and genes targeted by the therapeutics to cure diseases such as cancer, atherosclerosis, liver cirrhosis, and inflammation. The achieved therapeutic effects are rationalized as consequences of biodistribution, cell internalization and endosomal escape provided by HA.
Design of electrostatic, coordination, and hydrophobic interactions as well as covalent conjugation between oligonucleotide drugs, HA macromolecules and intermediate ligands are crucial for carrier-cargo association and dissociation under different conditions to impart oligonucleotides stability , their accumulation in diseased organs, cellular uptake, and dissociation in cytoplasm intact. These are the delivery factors that provides eventual complex formation of oligonucleotide therapeutics with their mRNA, microRNA, or protein targets. Elucidation of the impact of structural parameters of oligonucleotide/HA complexes on their therapeutic effect is important for the future rational design of the delivery agents.
寡核苷酸疗法，如反义寡核苷酸和 siRNA，需要化学修饰和纳米载体来规避稳定性问题，以到达靶组织，并克服组织和细胞屏障。透明质酸（HA）已用于药物输送和组织工程，具有解决这些问题并充分发挥寡核苷酸疗法潜力的有用特性。
讨论了寡核苷酸疗法与 HA 的复合物，根据提供复合物形成的相互作用以及治疗癌症、动脉粥样硬化、肝硬化和炎症等疾病的靶向基因进行讨论。通过 HA 提供的生物分布、细胞内化和内涵体逃逸实现的治疗效果被合理化。
设计静电、配位和疏水相互作用以及寡核苷酸药物、HA 大分子和中间配体之间的共价键合对于在不同条件下载体-货物的缔合和解离至关重要，以赋予寡核苷酸稳定性、在疾病器官中的积累、细胞摄取以及细胞质中完整的解离。这些是提供寡核苷酸治疗与其 mRNA、microRNA 或蛋白质靶标最终复合物形成的输送因素。阐明寡核苷酸/HA 复合物的结构参数对其治疗效果的影响对于未来输送剂的合理设计很重要。
