Ultrasound-induced cell permeabilisation and hyperthermia: Strategies for local delivery of compounds with intracellular mode of action

There is an increasing clinical need for novel, externally triggered, local drug delivery methods since many drugs are characterised by high systemic toxicity and/or suffer from limited bioavailability. Thermosensitive liposomes (TSLs) demonstrate great potential for local delivery and release of the payload. They are particularly effective in combination with ultrasound (US) under magnetic resonance (MR) guidance that is known to induce hyperthermia locally in a precisely controlled manner. Bioeffects of hyperthermia include increased blood flow, blood volume and enhanced vascular permeability thus potentiating anti-tumoural efficacy of TSLs. However, bioeffects of ultrasound are not limited to hyperthermia only, and under certain parameters may include locally enhanced extravasation and permeabilisation of cell membrane for compounds. This opens up opportunities for delivery of cell-impermeable and weakly permeable drugs that can be employed together with thermosensitive liposomes. In the latter case US-mediated cavitation and/or radiation forces local permeabilisation of the cells and US-induced hyperthermia releases the drug. This review focuses on bioeffects of US such as hyperthermia, enhanced extravasation and cell permeabilisation utilised for local drug delivery.