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通过化学改性碳水化合物合物有效和选择性向脏.

Vikas Kumar1, Aniket Wahane1, Ming Shen Tham2

  • 1Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.

Molecular therapy : the journal of the American Society of Gene Therapy
|November 12, 2024
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概括

一种新的管向碳水化合物 (RENTAC) 选择性地将治疗药物输送到脏附近管道. 这种RENTAC连接体在治疗脏疾病方面具有广泛的临床应用潜力.

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科学领域:

  • 生物材料科学 生物材料科学
  • 脏生理学 脏生理学
  • 药物输送系统 药物输送系统

背景情况:

  • 向脏药物输送仍然是一个挑战.
  • 靠近的状管道是功能和疾病的关键位置.
  • 开发选择性管向剂对于有效治疗病至关重要.

研究的目的:

  • 开发和评估管向碳水化合物 (RENTAC),用于选择性地输送到脏附近的状管道.
  • 在纤维化模型中评估RENTAC结合物的疗效,例如反感性核酸 (PNA) 的治疗有效载荷.
  • 为了确认RENTAC连接体的安全性和准特异性.

主要方法:

  • 合成和评估与抗miR-21和光有效载荷的RENTAC合物.
  • 在一个永生细胞系中对RENTAC合物吸收的评估,证实了依赖美加林和库比林的内细胞分裂.
  • 在小鼠体内生物分布研究以确定RENTAC合物保留和分布.
  • 免疫光染色以确认选择性定位在近端卷曲管道中.
  • 在叶酸诱导纤维化小鼠模型中评估PNA 33-RENTAC结合剂的疗效.

主要成果:

  • 在细胞中,RENTAC结合物显示出依赖于大素和素的内细胞吸收.
  • 活体研究显示,RENTAC合物在脏中的保留时间长 (几天),选择性分布在近端卷状管道中.
  • 在纤维化病模型中,针对PNA 33-RENTAC结合物的向输送导致纤维化进展减缓和降低原沉积.
  • 该RENTAC连接体没有引起不良反应,表明了有利的安全性.

结论:

  • 该RENTAC连接体使选择性向和输送到脏近位卷曲管道.
  • RENTAC结合物在提供治疗性核酸类型中是有效的,通过减少纤维化进展来证明这一点.
  • 在向脏疗法中,RENTAC联体对广泛的临床应用具有显著的前景.