Effect of microbubble-assisted gemcitabine delivery with repeated ultrasound exposure in a pancreatic cancer organ-on-a-chip model.

The fibrotic stroma of solid tumours poses a physical barrier to drug delivery and effective treatment. Interaction between cancerous epithelial cells and their surrounding stromal partners results in the development of a rigid, collagenous matrix environment with reduced interstitial flow, crucial for drug delivery to cancer cells, particularly in pancreatic ductal adenocarcinoma (PDAC), an aggressive pancreatic cancer with poor prognosis. Therefore, evaluating novel drug delivery mechanisms using appropriate stroma-mimicking 3D culture models is essential. We previously demonstrated, using a 21-day cultured microfluidic PDAC model that mimics the rigid, collagenous stroma, reduced interstitial flow through the tumour model. In this study, we evaluated the use of microbubbles and ultrasound as an alternative method for disrupting our model's fibrotic stroma to restore interstitial flow and improve gemcitabine delivery and efficacy. Literature shows microbubbles in 2D and 3D static cultures enhance drug delivery and effects by increasing cell membrane permeability through oscillation and bursting under ultrasound (sonoporation). Here, we observed continuous microbubble oscillation and bursting under repeated ultrasound exposure, leading to continuous matrix-microbubble and PDAC cell-microbubble interactions, which improved the gemcitabine effect. This study emphasises the need for disease-specific in vitro models to assess novel drug delivery mechanisms and improve therapeutic outcomes.