Ming Xin, Laing Brian
Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Adv Drug Deliv Rev. 2015 Jun 29;87:81-9. doi: 10.1016/j.addr.2015.02.002. Epub 2015 Feb 15.
Bioconjugates have been used to deliver therapeutic oligonucleotides to their pharmacological targets in diseased cells. Molecular-scale conjugates can be prepared by directly linking targeting ligands with oligonucleotides and the resultant conjugates can selectively bind to cell surface receptors in target cells in diseased tissues. Besides targeted delivery, additional functionality can be incorporated in the conjugates by utilization of carrier molecules, and these larger conjugates are called carrier-associated conjugates. Both molecular and carrier-associated conjugates have achieved initial successes in clinical trials for treating liver diseases; therefore, currently the greater challenge is to deliver oligonucleotides to extrahepatic tissues such as tumors. This review will provide an update on the application of oligonucleotide conjugates for targeted delivery during the last decade. By identifying key elements for successful delivery, it is suggested that oligonucleotide conjugates with intermediate size, cell targeting ability, and endosomal release functionality are superior systems to advance oligonucleotides to achieve their full therapeutic potentials.
生物共轭物已被用于将治疗性寡核苷酸递送至患病细胞中的药理学靶点。分子尺度的共轭物可通过将靶向配体与寡核苷酸直接连接来制备，所得共轭物可选择性地结合患病组织中靶细胞的细胞表面受体。除了靶向递送外，还可通过利用载体分子在共轭物中引入额外功能，这些更大的共轭物被称为载体相关共轭物。分子共轭物和载体相关共轭物在治疗肝脏疾病的临床试验中均已取得初步成功；因此，目前更大的挑战是将寡核苷酸递送至肝外组织，如肿瘤。本综述将提供过去十年中寡核苷酸共轭物用于靶向递送的应用更新情况。通过确定成功递送的关键要素，表明具有中等大小、细胞靶向能力和内体释放功能的寡核苷酸共轭物是推进寡核苷酸以充分发挥其治疗潜力的更优系统。
