Modulation of photophysics and pKa shift of the anti-cancer drug camptothecin in the nanocavities of supramolecular hosts.

Abstract

This article reports the pK(a) shift of an anti-cancer drug, 20(S)-camptothecin (CPT), upon encapsulation into the nanocavity of a cucurbit[7]uril (CB7) macrocycle. Steady-state, time-resolved fluorescence and electrospray ionisation mass spectrometry (ESI-MS) studies provide evidence for the formation of both 1:1 and 2:1 (CB7⋅CPT) stoichiometries. Astonishingly, we have found that protonation of CPT takes place at a higher concentration of macrocycle (≥50 μM) when the 2:1 stoichiometric complex develops. However, we did not find any proof for protonation of CPT when it is encased by a β-cyclodextrin cavity, which has a cavity size almost the same as that of CB7. Hence, we conclude that electron-rich carbonyl portals of CB7 have an important role in protonation of the drug in the 2:1 inclusion complex. Docking and semi-empirical quantum chemical calculations have been employed to gain an insight into the molecular picture of orientation of CPT in the inclusion complexes. It is clearly seen from the optimised structure of the 2:1 (CB7⋅CPT) inclusion complex that the quinoline nitrogen of CPT does not reside within either of the CB7 cavities, rather it is almost sandwiched between two CB7 rings, and therefore, it experiences huge electron density exerted by both carbonyl portals of the macrocycles. As a result, the pK(a) of CPT shifts from 1.2 to 6.2. Finally, controlled release of the drug has been achieved through the introduction of NaCl, which is rich in cells, as an external stimulus. We hope this recognition-mediated binding and release mechanism can be useful for activation of the drug and controlled release of the drug in therapeutic uses.

• Authors: Krishna Gavvala, Abhigyan Sengupta, Partha Hazra
• Journal: Chemphyschem : a European journal of chemical physics and physical chemistry (Chemphyschem) Vol. 14 Issue 3 Pg. 532-42 (Feb 25 2013) ISSN: 1439-7641 [Electronic] Germany
• PMID: 23401373 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Nanocapsules
• Camptothecin

Topics

• Antineoplastic Agents (chemistry)
• Camptothecin (chemistry)
• Drug Carriers (chemistry)
• Drug Stability
• Hydrogen-Ion Concentration
• Models, Molecular
• Molecular Structure
• Nanocapsules (chemistry)
• Photochemistry
• Quantum Theory