A mathematical model for maximizing drug uptake in low-EPR tumors using ultrasound-mediated drug delivery strategies

Cancer remains a significant health burden and research efforts aim to improve drug delivery options. Focused ultrasound has emerged as a potential mechanism for enhanced targeted drug delivery in tumors with a low enhanced permeability and retention (EPR) effect by sonoporation. Traditional sonoporation, which utilizes microbubble ultrasound contrast agents (UCAs) to create pores in cells, has shown promise, but it can still benefit from improvements in drug uptake. The current study investigates the use of a new non-portative technique, called ultrasonic tumor painting (UTP), to enhance vascular retention of liposome nanoparticles in the tumor space to achieve targeted drug delivery and increase therapeutic efficacy. After retention, the small molecule doxorubicin is allowed to leak from the nanoparticles into the tumor space via concentration mediated Fickian Diffusion. An existing mathematical model was adapted to simulate the concentration of free and liposome-encapsulated doxorubicin in circulation. The simulations were performed in MATLAB and specifically evaluate doxorubicin uptake in low-EPR tumors. Traditional sonoporation was compared to UTP. This study demonstrates that ultrasound-based small molecule delivery can be improved with tumor painting strategies and could be a valuable tool to overcome the limitations of traditional sonoporation.