Small-molecule drugs are utilized in a wide variety of clinical applications, however, many of these drugs suffer from one or more suboptimal properties that can hinder its delivery or cellular action in vivo, or even shelf an otherwise biologically tolerable drug. While high-throughput screening provides a method to discover drugs with altered chemical properties, directly engineering small-molecule bioconjugates provides an opportunity to specifically modulate drug properties rather than sifting through large drug libraries with seemingly ‘random’ drug properties. Herein, we propose that selectively “tethering” a drug molecule to an additional group with favorable properties will improve the drug conjugate's overall properties, such as solubility. Specifically, we outlined the site-specific chemical conjugation of rapamycin (RAP) to an additional “high-affinity” group to increase the overall affinity the drug has for cyclodextrin-based polymers (pCD). By doing so, we found that RAP's affinity for pCD and RAP's window of delivery from pCD microparticles was tripled without sacrificing RAP's cellular action. This synthesis method was applied to the concept of “affinity” for pCD, but other prosthetic groups can be used similarly. This study displays potential for increasing drug delivery windows of small-molecule drugs in pCD systems for chronic drug therapies and introduces the idea of altering drug properties to tune polymer-drug interactions.

小分子药物被广泛用于各种临床应用中，但是，这些药物中有许多具有一种或多种次优特性，这些特性可能会阻碍其在体内的递送或细胞作用，甚至搁置其他生物学可耐受的药物。高通量筛选提供了一种发现化学性质发生改变的药物的方法，而直接工程化小分子生物结合物则提供了一种专门调节药物性质的机会，而不是筛选具有看似“随机”药物性质的大型药物库。本文中，我们建议将药物分子选择性地“束缚”到具有有利特性的其他基团上将改善药物缀合物的整体特性，例如溶解度。特别，我们概述了雷帕霉素（RAP）与其他“高亲和力”基团的位点特异性化学结合，以增加该药物对基于环糊精的聚合物（pCD）的总体亲和力。通过这样做，我们发现RAP对pCD的亲和力和RAP从pCD微粒递送的窗口增加了三倍，而没有牺牲RAP的细胞作用。该合成方法应用于pCD的“亲和力”概念，但其他修复基团也可以类似地使用。这项研究显示了增加用于慢性药物治疗的pCD系统中小分子药物的给药窗口的潜力，并介绍了改变药物性质以调节聚合物-药物相互作用的想法。对pCD的亲和力和RAP从pCD微粒传递的窗口增加了三倍，而没有牺牲RAP的细胞作用。该合成方法应用于pCD的“亲和力”概念，但其他修复基团也可以类似地使用。这项研究显示了增加用于慢性药物治疗的pCD系统中小分子药物的给药窗口的潜力，并介绍了改变药物性质以调节聚合物-药物相互作用的想法。对pCD的亲和力和RAP从pCD微粒传递的窗口增加了三倍，而没有牺牲RAP的细胞作用。该合成方法应用于pCD的“亲和力”概念，但其他修复基团也可以类似地使用。这项研究显示了增加用于慢性药物治疗的pCD系统中小分子药物的给药窗口的潜力，并介绍了改变药物性质以调节聚合物-药物相互作用的想法。