Effects of Linker Length and Flexibility on Multivalent Targeting
Effects of Linker Length and Flexibility on Multivalent Targeting
复制标题
DOI：
10.1021/bm800529b
复制
发表时间：
2008-11-01
影响因子：
6.2
通讯作者：
Caplan, Michael R.
中科院分区：
文献类型：
--
作者：
Shewmake, Thomas A.;Solis, Francisco J.;Caplan, Michael R.
增加化合价可以增强分子靶向构建体特异性结合靶向细胞用于药物递送的能力。在这里，我们数学模型的长度和灵活性的连接器用于连接两个肽配体的二价靶向构建体，并调查结合亲和力和特异性的影响。使用四种不同的模型来近似不同程度的接头柔性（无规卷曲、刚性杆、接合杆和组合杆-无规卷曲），并且对于每个修补器，导出结合增强因子（V-R），其量化每个构建体的第二结合事件超过第一结合事件的增加速率。结果表明，适度灵活的模型可以最好地再现实验测量的亲合力。此外，V的大小，结合受体密度和配体浓度，显著影响可达到的特异性。因此，该模型阐明了在设计用于递送靶向治疗或成像的多价靶向构建体中的重要考虑。
Increasing valence can enhance the ability of molecular targeting constructs to bind specifically to targeted cells for drug delivery. Here, we mathematically model the length and flexibility of a linker used to conjoin two peptide ligands of a divalent targeting construct and investigate the influence both on binding avidity and specificity. Four different models are used to approximate varying degrees of linker flexibility (random coil, rigid rod, jointed rods, and combined rod-random coil) and for each tinker a binding enhancement factor (V-R) is derived that quantifies the increased rate of each construct's second binding event over the first. Results indicate that the moderately flexible models can best reproduce experimentally measured avidities. Also, the magnitude of V., in conjunction with receptor density and ligand concentration, significantly influences the achievable specificity. Thus, the model elucidates important considerations in designing multivalent targeting constructs for use in delivery of targeted therapy or imaging.