Role of thermal and mechanical effects on drug release from thermosensitive nanocarriers

The combination of focused ultrasound (FUS) with thermosensitive liposomes (TSL) is a promising method for drug delivery since it allows a localized release upon moderate heating with ultrasound. Besides thermal effects, FUS also induces mechanical stresses on drug nanocarriers. We propose in this study to examine the influence of both effects (thermal and mechanical) on drug release. For this, an in-vitro setup allowing liposomal drug delivery using FUS was first evaluated. Calcein was used as a model drug. FUS experiments were performed in water at 37°C using a 1 MHz transducer focused at 48 mm, at 1 kHz PRF and 40% duty cycle. The driving pressure and the insonation duration were varied from 1 to 2 MPa and from 0 to 30 min, respectively. Thermal heating using a water-bath was also performed with temperatures from 37 to 49°C. For TSL, the release reaches a plateau above 42°C (45%) after 10 min heating while no release is observed for non-thermosensitive liposomes (NTSL). Using FUS, a rapid calcein release is observed for pressures from 1 to 1.5 MPa (from 0% to 49%) for TSL. Above 1.5 MPa, the release increases slightly (59% at 2 MPa). For NTSL, a weak calcein release is measured for acoustic pressures higher than 1.5 MPa. This release is attributed to the mechanical stress generated by FUS which is sufficient to destabilize the liposomal membrane. Mechanical stress alone can enhance the calcein release by up to 17% for pressures higher than 1.75 MPa.