Drug targeting to hypoxic tissue using self-inactivating bioreductive delivery systems

Hypoxia is a characteristic feature of a number of diseases including some cancers, rheumatoid arthritis and diabetes. Hypoxic tissue facilitates the use of bioreductive drug targeting systems as oxygen suppresses the release of the active drug. This review focuses on bioreductive delivery where accompanying intramolecular cyclisation negates adduct formation between the bioreductive and macromolecules such as DNA. To date, three systems have been reported. In the quinone lactonization system, reduction of the quinone facilitates through bond cyclisation and concomitant release of the drug. In the self-alkylating system, a nucleophile is built into the bioreductive structure to favour intramolecular cyclisation over nucleophilic attack from DNA moieties. The final system is based on vitamin E which undergoes redox mediated cyclisation between its oxidised (tocopherol quionone) and reduced (tocopherol) forms. Self-inactivating bioreductive delivery systems represent a powerful tool for extending bioreductive-based drug delivery to non-cancerous hypoxic tissues.