Effect of temperature on the structure and drug-release behaviour of inclusion complex of β-cyclodextrin with cyclophosphamide: a molecular dynamics study

Cyclodextrins (CDs) are suitable drug carriers because of their doughnut-shaped cavities with hydrophilic outer and hydrophobic inner surfaces. Temperature-responsive CD-based drug carriers are expected to be one of the most promising candidates for drug delivery systems. In this study, we performed molecular dynamics simulations of the inclusion complex of β-CD with cyclophosphamide (CP) at temperatures from 300 K to 400 K to investigate the temperature dependency of the release behaviour of CP and structural changes of β-CD in an aqueous solution. We analysed the distance between the centres of mass of β-CD and CP and the radius of gyration of β-CD. The CP molecule was released from the β-CD cavity at 400 K, whereas two different inclusion complexes, partially and completely, were observed at T < 400 K. β-CD encapsulating a CP molecule had a more spherical shape and rigidity than β-CD without a CP, and the rigidity of their inclusion complex decreased with increasing temperature. Our findings provide fundamental insights into the behaviours of the β-CD/CP complex and drug release at the molecular level and can facilitate the development of new temperature-responsive drug delivery systems with CD nanocarriers triggered by localised temperature increases using focused ultrasound.