Temperature-sensitive paramagnetic liposomes for image-guided drug delivery: Mn2+ versus [Gd(HPDO3A)(H2O)]

Abstract Temperature-sensitive liposomes (TSLs) loaded with doxorubicin (Dox), and Magnetic Resonance Imaging contrast agents (CAs), either manganese (Mn 2 + ) or [Gd(HPDO3A)(H 2 O)], provide the advantage of drug delivery under MR image guidance. Encapsulated MRI CAs have low longitudinal relaxivity ( r 1 ) due to limited transmembrane water exchange. Upon triggered release at hyperthermic temperature, the r 1 will increase and hence, provides a means to monitor drug distribution in situ. Here, the effects of encapsulated CAs on the phospholipid bilayer and the resulting change in r 1 were investigated using MR titration studies and 1 H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles. Our results show that Mn 2 + interacted with the phospholipid bilayer of TSLs and consequently, reduced doxorubicin retention capability at 37 °C within the interior of the liposomes over time. Despite that, Mn 2 + -phospholipid interaction resulted in higher r 1 increase, from 5.1 ± 1.3 mM − 1  s − 1 before heating to 32.2 ± 3 mM − 1  s − 1 after heating at 60 MHz and 37 °C as compared to TSL(Gd,Dox) where the longitudinal relaxivities before and after heating were 1.2 ± 0.3 mM − 1  s − 1 and 4.4 ± 0.3 mM − 1  s − 1 , respectively. Upon heating, Dox was released from TSL(Mn,Dox) and complexation of Mn 2 + to Dox resulted in a similar Mn 2 + release profile. From 25 to 38 °C, r 1 of [Gd(HPDO3A)(H 2 O)] gradually increased due to increase transmembrane water exchange, while no Dox release was observed. From 38 °C, the release of [Gd(HPDO3A)(H 2 O)] and Dox was irreversible and the release profiles coincided. By understanding the non-covalent interactions between the MRI CAs and phospholipid bilayer, the properties of the paramagnetic TSLs can be tailored for MR guided drug delivery.