Supramolecular Host‐Inhibited Excited‐State Proton Transfer and Fluorescence Switching of the Anti‐Cancer Drug, Topotecan

Abstract

The effect of cucurbit[7]uril (CB[7]) nano-caging on the photophysical properties, particularly excited-state proton transfer (ESPT) reaction, of an eminent anti-cancer drug, topotecan (TPT), is demonstrated through steady-state and time-resolved fluorescence measurements. TPT in water (pH 6) exists exclusively as the cationic form (C) in the ground state. However, the drug emission mainly comes from the excited-state zwitterionic form (Z*) of TPT, and is attributed to water-assisted ESPT between the 10-hydroxyl group and water, which leads to the transformation of C* to Z* of TPT. In the presence of CB[7], it is found that selective encapsulation of the C form of TPT results in the formation of a 1:1 inclusion complex (CB[7]:TPT), and the ESPT process is inhibited by this encapsulation process. As a result, C* becomes the dominant emitting species in the presence of CB[7] rather than Z*, and fluorescence switching takes place from green to blue. Time-resolved studies also support the existence of CB[7]-encapsulated cationic species as the major emitting species in the presence of the macrocyclic host. Semi-empirical quantum chemical calculations are employed to gain insight into the molecular picture of orientation of TPT in the inclusion complex. It is clearly seen from the optimised structure of 1:1 CB[7]:TPT inclusion complex that both 10-hydroxyl and 9-dimethylaminomethylene groups of TPT lie partly inside the cavity, and thereby inhibit the excited-state transformation of C* to Z* by the ESPT process. Finally, controlled release of the drug is achieved by means of fluorescence switching by introducing NaCl, which is rich in cells, as an external stimulus.