Temperature-sensitive paramagnetic liposomes for image-guided drug delivery: Mn(2+) versus [Gd(HPDO3A)(H2O)]

Temperature-sensitive liposomes (TSLs) loaded with doxorubicin (Dox), and Magnetic Resonance Imaging contrast agents (CAs), either manganese (Mn(2+)) or [Gd(HPDO3A)(H2O)], provide the advantage of drug delivery under MR image guidance. Encapsulated MRI CAs have low longitudinal relaxivity (r1) due to limited transmembrane water exchange. Upon triggered release at hyperthermic temperature, the r1 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 r1 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 r1 increase, from 5.1±1.3mM(-1)s(-1) before heating to 32.2±3mM(-1)s(-1) after heating at 60MHz and 37°C as compared to TSL(Gd,Dox) where the longitudinal relaxivities before and after heating were 1.2±0.3mM(-1)s(-1) and 4.4±0.3mM(-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, r1 of [Gd(HPDO3A)(H2O)] gradually increased due to increase transmembrane water exchange, while no Dox release was observed. From 38°C, the release of [Gd(HPDO3A)(H2O)] 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.