Tiancheng Fu, Fushun Fan, Yingying Lin, Zhenxian Mo, Minhua Zhou, Xiaolan Ye, Xiong Cai, Zaijun Zhang, Changgeng Qian, Xinjian Liu
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引用次数: 0
摘要
转铁蛋白受体1 (TfR1)是一种普遍表达的受体,具有快速的内化动力学和高效的受体循环,使其成为一个有吸引力的药物递送靶点。在此,我们研究了tfr1结合肽- sirna偶联物在中枢神经系统(CNS)特异性基因沉默中的潜力。我们合成了一组tfr1结合肽和偶联连接体,使siRNA能够附着并评估它们的基因沉默作用。与hTfR No. 894肽结合,在体外和体内均实现了siRNA的有效递送。与核糖2'- o -十六进基(C16)-siRNA偶联物相比,hTfR No. 894-siRNA偶联物(POC2)在局部给药后引起了良好的药代动力学特性和靶基因在中枢神经系统区域的稳定和持久沉默,对外周组织的影响最小。这些发现支持tfr1结合肽偶联作为一种有希望的cns靶向siRNA递送策略。
TfR1-Binding Peptide Conjugation Facilitates Robust and Specific siRNA Delivery to the Central Nervous System.
Transferrin receptor 1 (TfR1) is a ubiquitously expressed receptor characterized by rapid internalization kinetics and efficient receptor recycling, making it an attractive target for drug delivery. Herein, we investigated the potential of TfR1-binding peptide-siRNA conjugates for central nervous system (CNS)-specific gene silencing. A panel of TfR1-binding peptides and conjugation linkers were synthesized to enable siRNA attachment and evaluate their gene-silencing effects. Conjugation with the hTfR No. 894 peptide achieved effective siRNA delivery both in vitro and in vivo. Compared to ribose 2'-O-hexadecyl (C16)-siRNA conjugates, the hTfR No. 894-siRNA conjugation (POC2) elicited favorable pharmacokinetic characteristics and robust and durable silencing of the target gene across CNS regions following local administration, with minimal impact on peripheral tissues. These findings support TfR1-binding peptide conjugation as a promising strategy for CNS-targeted siRNA delivery.
期刊介绍:
Bioconjugate Chemistry invites original contributions on all research at the interface between man-made and biological materials. The mission of the journal is to communicate to advances in fields including therapeutic delivery, imaging, bionanotechnology, and synthetic biology. Bioconjugate Chemistry is intended to provide a forum for presentation of research relevant to all aspects of bioconjugates, including the preparation, properties and applications of biomolecular conjugates.