Enhancing fluorescein distribution from in situ forming PLGA implants using therapeutic ultrasound

In situ forming implants (ISFIs) can provide continuous, high dose release of chemotherapeutic drug directly at the tumor site. However, poor drug distribution through the tumor volume has limited the effectiveness and subsequent translation of ISFIs into clinical practice. In this study, mice were subcutaneously injected with phase-inverting ISFIs loaded with fluorescein and exposed to therapeutic ultrasound (TUS) at varying parameters to evaluate fluorescein distribution and release. An increased spatial penetration of fluorescein away from the ISFIs in vivo was linked to increased temperature from the TUS application. Without the increased temperature, ISFIs exposed to a similar amount of total TUS energy saw no significant increase in fluorescein distribution compared to untreated ISFIs. Surprisingly, the total amount of fluorescein released from the ISFIs was consistent among all groups. The observed increase in fluorescein distribution may thus be due to a hyperthermia-induced increase in cell membrane permeability that allows nearby cells to more readily uptake fluorescein. The US-enhanced distribution could improve the clinical efficacy of intratumoral chemotherapy by increasing drug distribution through the tumor volume without increasing drug release from the implant.