Understanding The Mechanism Behind Ultrasound Responsive PEGylated Liposomes - SANS Before, During, and After Ultrasound Insonation

A major challenge in cancer therapy is the inefficient delivery of chemotherapeutics to tumors due to poor drug accumulation in the tumor area. Ultrasound (US)-triggerable liposomes offer a safe, non-invasive means to enable spatiotemporal drug release, minimizing systemic exposure. However, the mechanism behind US-triggered release from liposomes remains unclear, limiting rational formulation design. Proposed models include cavitation-induced disruption, transient pore formation, and lipid reorganization, but no consensus exists.

Our studies combine molecular dynamics simulations with differential scanning calorimetry (DSC), fluorescence polarization (FP), and atomic force microscopy force spectroscopy (AFM-FS). US-triggered release was tenfold higher in polyethylene glycol-coated liposomes versus polycarboxybetaine and polysarcosine coatings, indicating that stealth layers alone don t enhance release. DSC and FP ruled out thermal and fluidity effects, while AFM-FS showed mechanical differences without direct correlation to release efficiency. Yet, these techniques lack the resolution to capture nanoscale membrane rearrangements. To address this, we will incorporate small-angle neutron scattering to monitor nanoscale membrane changes before, during, and after insonation, providing critical insight into US-triggered release mechanisms, thus establishing a framework for rational design of efficient, clinically translatable US-responsive liposomes.