Focused Ultrasound-mediated Disruption of Plasma Protein Binding Enhances Chemotherapeutic Effects of Paclitaxel on Xenografted Ovarian Cancer in Mice.

BACKGROUND/AIM: Paclitaxel (PTX), a widely-used chemotherapeutic agent, exhibits a high rate of plasma protein binding, which severely limits its bioavailability and reduces therapeutic efficacy. This study explored a novel strategy using low-intensity, non-thermal focused ultrasound (FUS) to locally disrupt PTX-albumin binding, thereby enhancing drug delivery and tumoricidal efficacy at tumor sites without increasing systemic toxicity.

MATERIALS AND

METHODS

We applied sonication (600 kHz) with varying pulse durations and duty cycles to OVCAR3 cell constructs in vitro and identified the parameters that maximally enhanced PTX uptake and induced tumor cell death. Intracellular PTX concentrations and cell viability were quantified across the conditions. The optimized FUS parameters were then applied to a mouse xenograft model of ovarian cancer using athymic nu/nu mice. Luciferase-expressing OVCAR3 tumor growth was longitudinally monitored using bioluminescence imaging.

RESULTS

The sonication parameters (70% duty cycle and 100 ms pulse duration), applied using 3 W/cm2 spatial peak temporal average intensity, optimally enhanced intracellular PTX uptake and increased cell death, independent of thermal or flow-related effects. In vivo, a single FUS treatment nearly doubled intratumoral PTX levels, without altering serum concentration. Repeated FUS sessions combined with PTX treatments over two weeks significantly suppressed tumor growth, compared to no treatment, PTX alone, or FUS alone. Histological analysis in PTX-treated groups showed that FUS did not cause additional damage to the liver, kidney, or surrounding tissues, nor did it affect peripheral blood markers of liver and kidney function.

CONCLUSION

FUS can reversibly unbind PTX from albumin, increasing its bioavailability specifically at tumor sites. This targeted approach enhances chemotherapeutic effectiveness without elevating systemic toxicity or causing off-target damage, highlighting FUS as a promising adjuvant strategy for improving anticancer drug delivery in solid tumors.