Regulation of IFP in solid tumors through acoustic pressure to enhance infiltration of nanoparticles of various sizes

Numerous nanomedicines have been developed recently that can accumulate selectively in tumours due to the enhanced permeability and retention (EPR) effect. However, the high interstitial fluid pressure (IFP) in solid tumours limits the targeted delivery of nanomedicines. We were previously able to relieve intra-tumoural IFP by low-frequency non-focused ultrasound (LFNFU) through ultrasonic targeted microbubble destruction (UTMD), improving the targeted delivery of FITC-dextran. However, the accumulation of nanoparticles of different sizes and the optimal acoustic pressure were not evaluated. In this study, we synthesised Cy5.5-conjugated mesoporous silica nanoparticles (Cy5.5-MSNs) of different sizes using a one-pot method. The Cy5.5-MSNs exhibited excellent stability and biosafety regardless of size. MCF7 tumour-bearing mice were subjected to UTMD over a range of acoustic pressures (0.5, 0.8, 1.5 and 2.0 MPa), and injected intravenously with Cy5.5-MSNs. Blood perfusion, tumour IFP and intra-tumoural accumulation of Cy5.5-MSNs were analysed. Blood perfusion and IFP initially rose, and then declined, as acoustic pressure intensified. Furthermore, UTMD significantly enhanced the accumulation of differentially sized Cy5.5-MSNs in tumour tissues compared to that of the control group, and the increase was sevenfold higher at an acoustic pressure of 1.5 MPa. Taken together, UTMD enhanced the infiltration and accumulation of Cy5.5-MSNs of different sizes in solid tumours by reducing intra-tumour IFP.