Journal
ADVANCED DRUG DELIVERY REVIEWS
Volume 64, Issue 9, Pages 764-783Publisher
ELSEVIER
DOI: 10.1016/j.addr.2012.01.015
Keywords
Drug delivery; Drug stability; Formulation; Activation; Toxicity; Acid-base properties; Cucurbiturils; Cyclodextrins; Calixarenes; Macrocycles; Host-guest complexes
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [NA 686/5, NA 686/6]
- Fonds der Chemischen Industrie
- COST Action [CM1005]
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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. (C) 2012 Elsevier RV. All rights reserved.
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