Noncovalent Host-Guest Complexes of Artemisinin with α-, ß-, and γ- Cyclodextrin Examined by Structural Mass Spectrometry Strategies.

ABSTRACT

Cyclodextrins (CDs) are a family of macrocyclic oligosaccharides with amphiphilic properties, which can improve the stability, solubility, and bioavailability of therapeutic compounds. There has been growing interest in the advancement of efficient and reliable analytical methods that assist with elucidating CD host-guest drug complexation. In this study, we investigate the noncovalent ion complexes formed between naturally occurring dextrins (αCD, ßCD, γCD, and maltohexaose) with the poorly water-soluble antimalarial drug, artemisinin, using a combination of ion mobility-mass spectrometry (IM-MS), tandem MS/MS, and theoretical modeling approaches. This study aims to determine if the drug can complex within the core dextrin cavity forming an inclusion complex or nonspecifically bind to the periphery of the dextrins. We explore the use of group I alkali earth metal additives to promote the formation of various noncovalent gas-phase ion complexes with different drug/dextrin stoichiometries (11, 12, 13, 14, and 21). Broad IM-MS collision cross section (CCS) mapping (n > 300) and power-law regression analysis were used to confirm the stoichiometric assignments. The 11 drugαCD and drugßCD complexes exhibited strong preferences for Li+ and Na+ charge carriers, whereas drugγCD complexes preferred forming adducts with the larger alkali metals, K+, Rb+, and Cs+. Although the ion-measured CCS increased with cation size for the unbound artemisinin and CDs, the 11 drugdextrin complexes exhibit near-identical CCS values regardless of the cation, suggesting these are inclusion complexes. Tandem MS/MS survival yield curves of the [artemisininßCD + X]+ ion (X = H, Li, Na, K) showed a decreased stability of the ion complex with increasing cation size. Empirical CCS measurements of the [artemisininßCD + Li]+ ion correlated with predicted CCS values from the low-energy theoretical structures of the drug incorporated within the ßCD cavity, providing further evidence that gas-phase inclusion complexes are formed in these experiments. Taken together, this work demonstrates the utility of combining analytical information from IM-MS, MS/MS, and computational approaches in interpreting the presence of gas-phase inclusion phenomena.