School of Engineering and Science, Jacobs University Bremen, D-28759 Bremen, Germany.
Adv Drug Deliv Rev. 2012 Jun 15;64(9):764-83. doi: 10.1016/j.addr.2012.01.015. Epub 2012 Feb 2.
Macrocyclic hosts of the cyclodextrin, sulfonatocalixarene, and cucurbituril type can be employed as discrete supramolecular drug delivery systems, thereby complementing existing supramolecular drug formulation strategies based on polymers, hydrogels, liposomes, and related microheterogeneous systems. Cucurbiturils, in particular, stand out in that they do not only provide a hydrophobic cavity to encapsulate the drug in the form of a host-guest complex, but in that they possess cation-receptor properties, which favor the encapsulation of protonated drugs over their unprotonated forms, resulting in pronounced pK(a) shifts up to 5 units. These pK(a) shifts can be rationally exploited to activate prodrug molecules, to stabilize the active form of drug molecules, to enhance their solubility, and to increase their degree of ionization, factors which can jointly serve to enhance the bioavailability of drugs, particularly weakly basic ones. Additionally, macrocycles can serve to increase the chemical stability of drugs by protecting them against reactions with nucleophiles (e.g., thiols) and electrophiles, by increasing their photostability, and by causing a higher thermal stability in the solid state. Detailed examples of the different effects of macrocyclic encapsulation of drugs and the associated pK(a) shifts are provided and discussed. Other important considerations, namely a potential lowering of the bioactivity of drugs by macrocyclic complexation, interferences of the macrocycles with biocatalytic processes, the toxicity of the macrocyclic host molecules, and problems and opportunities related to a targeted release and the rate of release of the drug from the host-guest complexes are critically evaluated.
大环主体如环糊精、磺化杯芳烃和瓜环，可以作为离散的超分子药物传递系统，从而补充现有的基于聚合物、水凝胶、脂质体和相关微相系统的超分子药物制剂策略。瓜环特别突出的一点是，它们不仅提供了一个疏水性空腔，可以将药物包裹在主客体复合物的形式中，而且还具有阳离子受体性质，有利于将质子化药物封装在其中，而不是将其未质子化的形式封装在其中，从而导致明显的 pK(a) 位移高达 5 个单位。这些 pK(a) 位移可以被合理利用来激活前药分子，稳定药物分子的活性形式，提高它们的溶解度，并增加它们的离解度，这些因素可以共同提高药物的生物利用度，特别是弱碱性药物。此外，大环主体可以通过保护药物免受亲核试剂（如巯基）和亲电试剂的反应、提高其光稳定性以及在固态中引起更高的热稳定性，来提高药物的化学稳定性。提供并讨论了大环主体对药物的不同包封作用和相关的 pK(a) 位移的详细实例。其他重要的考虑因素，即大环主体对药物的生物活性的潜在降低、大环主体与生物催化过程的干扰、大环主体分子的毒性，以及与药物从主体-客体复合物的靶向释放和释放速度相关的问题和机遇，都进行了批判性评估。
