a Innovative Technology Laboratories, Research Functions Unit, R&D Division , Kyowa Hakko Kirin Co., Ltd , Tokyo , Japan.
b Research Core Function Laboratories, Research Functions Unit, R&D Division , Kyowa Hakko Kirin Co., Ltd , Tokyo , Japan.
J Biomater Sci Polym Ed. 2018 Mar;29(4):448-459. doi: 10.1080/09205063.2017.1422853. Epub 2018 Jan 11.
Nucleic acid medicine is the next-generation therapeutic modality for refractory diseases with its unique mode of action as an alternative to traditional therapies. A nucleic acid delivery system targeted to liver was validated clinically; however, the delivery system of nucleic acids targeting solid tumors following systemic administration is not efficient enough for clinical use. In this study, we first utilized an antisense oligonucleotide (ASO) and polyethylene glycol (PEG) in one-to-one conjugation (PEG-ASO) at the endo-position of the ASO (endo-PEG-ASO). The effects of ASO modification position, PEG structure and molecular weight, and PEG-ASO tumor accumulation were evaluated in vivo. The endo-PEG-ASO showed prolonged pharmacokinetics and enhanced tumor accumulation compared with the conventional ASO and the PEG-ASO modified at the ASO exo-position (exo-PEG-ASO), indicating that the modification position of PEG is crucial for targeting tumors. We also observed that the endo-PEG-ASO indicated possibility of enhanced permeability inside the tumor. Further research is needed to optimize the linker in the endo-PEG-ASO for clinical application as a novel and promising therapeutic format for targeting solid tumors.
核酸药物是一种针对难治性疾病的下一代治疗方式，具有独特的作用模式，可以作为传统疗法的替代方法。一种针对肝脏的核酸药物递送系统已在临床上得到验证；然而，全身给药后针对实体瘤的核酸药物递送系统还不够高效，无法用于临床应用。在这项研究中，我们首先利用反义寡核苷酸（ASO）和聚乙二醇（PEG）在 ASO 的内位（endo-PEG-ASO）进行一对一缀合。我们在体内评估了 ASO 修饰位置、PEG 结构和分子量以及 PEG-ASO 的肿瘤积累。与常规 ASO 和在 ASO 外位修饰的 PEG-ASO（exo-PEG-ASO）相比，endo-PEG-ASO 表现出延长的药代动力学和增强的肿瘤积累，表明 PEG 的修饰位置对于靶向肿瘤至关重要。我们还观察到，endo-PEG-ASO 显示出增强肿瘤内通透性的可能性。需要进一步研究来优化内-PEG-ASO 中的连接子，使其成为针对实体瘤的新型有前途的治疗方式。
