Acute Effects of Ultrasound-Targeted Microbubble Destruction on Tumor Interstitial Fluid Pressure and Intratumoral Distribution of Doxorubicin and Nab-Paclitaxel in an Orthotopic Breast Cancer Model

Insufficient drug delivery remains a critical challenge in solid tumor therapy. Ultrasound-targeted microbubble destruction (UTMD) can modulate the tumor microenvironment and facilitate intratumoral drug delivery. This study investigated the acute effects of UTMD on tumor interstitial fluid pressure (IFP) and on the intratumoral distribution of the small-molecule chemotherapeutic doxorubicin and the albumin-bound nanoparticle formulation nab-paclitaxel in an MCF7-derived orthotopic breast cancer model. Post-treatment IFP was assessed approximately 2 min after completion of the assigned 10-min treatment procedure. Marked acute IFP reductions were observed in the doxorubicin-USMB and nab-paclitaxel-USMB groups, and the additional USMB-alone group also showed an acute decrease in IFP in the absence of chemotherapy. Fluorescence imaging showed increased doxorubicin-associated signal in both peripheral and central tumor regions after UTMD, whereas the increase in Cy5-labeled nab-paclitaxel was predominantly observed in the tumor periphery, with no significant enhancement in the tumor center. H&E staining showed vascular dilation, erythrocyte extravasation, and microthrombus formation after USMB treatment, including in the absence of chemotherapy. These findings indicate that UTMD itself contributes to the acute IFP response and is associated with altered intratumoral drug distribution. Because doxorubicin and nab-paclitaxel differ in multiple drug and formulation characteristics and direct antitumor efficacy endpoints were not evaluated, the observed distribution differences should not be attributed solely to size and should not be interpreted as evidence of improved antitumor efficacy. Overall, UTMD combined with chemotherapeutics can reduce IFP and enhance drug accumulation and penetration in breast tumors, particularly in the periphery. The findings should be considered specific to the present orthotopic breast cancer model.