Department of Chemistry and Biochemistry, The University of Kitakyushu, 1-1 Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka, Japan.
J Control Release. 2011 Apr 30;151(2):155-61. doi: 10.1016/j.jconrel.2011.01.026. Epub 2011 Jan 31.
Antisense therapy, the first concept of oligonucleotide therapeutics, was proposed more than two decades ago. However, the lack of suitable delivering carriers continues to be a major obstacle to practical therapy. In this study, we present a novel complex consisting of β-1,3-glucan and antisense oligonucleotide (AS-ODN) as a new candidate of the carriers. We used schizophyllan (SPG) as a β-1,3-glucan and an AS-ODN sequence to suppress tumor necrosis factor alpha (TNF-α), where the AS-ODN has a (dA)(60) tail to induce complex with SPG. When the complexes were applied to peritoneal macrophages, they were incorporated into the cells via dectin-1 (a β-1,3-glucan receptor expressed on antigen presenting cells) and suppressed lipopolysaccharide (LPS)-induced TNF-α secretion. In-vivo, AS-ODN/SPG decreased the secretion of TNF-α in serum and drastically reduced the inflammation of LPS-induced hepatitis. This new complex could overcome the long outstanding problem for antisense therapy because of its complexation ability, non-toxicity and high target specificity.
反义疗法是寡核苷酸疗法的第一个概念，早在二十多年前就被提出。然而，缺乏合适的输送载体仍然是实际治疗的主要障碍。在本研究中，我们提出了一种由β-1,3-葡聚糖和反义寡核苷酸（AS-ODN）组成的新型复合物，作为载体的新候选物。我们使用裂褶多糖（SPG）作为β-1,3-葡聚糖和抑制肿瘤坏死因子-α（TNF-α）的 AS-ODN 序列，其中 AS-ODN 带有（dA）（60）尾，以诱导与 SPG 形成复合物。当复合物应用于腹腔巨噬细胞时，它们通过树突状细胞（一种在抗原呈递细胞上表达的β-1,3-葡聚糖受体）被细胞摄取，并抑制脂多糖（LPS）诱导的 TNF-α分泌。在体内，AS-ODN/SPG 减少了血清中 TNF-α的分泌，并大大减轻了 LPS 诱导的肝炎的炎症。由于其具有的络合能力、低毒性和高靶向特异性，这种新型复合物可以克服反义疗法长期存在的问题。
