Microbubble-free mechanical sonoporation for MR-guided drug delivery in solid tumours: a proof-of-concept study

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Molecular Imaging

Background:

• Ultrasound (US)-mediated drug delivery, often using microbubbles, faces challenges like short half-life, cost, and cytotoxicity.
• Clinical translation of microbubble-assisted sonoporation is hindered by these limitations.

Purpose of the Study:

• To develop and validate a microbubble-free sonoporation technique for efficient intracellular delivery of hydrophilic agents.
• To demonstrate non-invasive monitoring of drug delivery using magnetic resonance imaging (MRI).
• To compare the efficacy and safety of microbubble-free sonoporation with existing permeabilization methods.

Main Methods:

• A low-intensity, non-focused ultrasound protocol (1 MHz, MI 0.25, 25% duty cycle, 1 Hz PRF) was employed.
• Intracellular delivery of Gadoteridol (MRI contrast agent) and propidium iodide (PI) was assessed in vitro.
• Cell viability, membrane resealing, and agent distribution were evaluated.
• In vivo studies in K562 tumor-bearing mice utilized intravenous co-administration followed by local sonoporation.

Main Results:

• Efficient intracellular uptake of Gadoteridol (~7 × 10⁹ Gd ions/cell) was achieved in vitro with >70% cell viability.
• Complete membrane resealing occurred within 30 minutes post-sonoporation.
• Co-delivery with PI confirmed cytosolic distribution via fluorescence microscopy and MRI, with minimal passive uptake in controls.
• Microbubble-free sonoporation showed higher uptake and lower oxidative stress compared to electroporation, pinocytosis, and hypotonic swelling.
• In vivo, sonoporation led to significantly enhanced and prolonged T1 MRI contrast and increased intratumoral accumulation of agents.

Conclusions:

• Microbubble-free sonoporation is an effective and controllable method for intracellular delivery of hydrophilic agents.
• The technique offers non-invasive MRI-based monitoring, addressing key limitations of microbubble-based approaches.
• This strategy shows significant potential for image-guided therapeutic applications, particularly in solid tumors.