Associate Professor University of Texas at Dallas, United States
Introduction:: 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 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”, to enhance vascular retention of nanoparticles in the tumor space to achieve targeted drug delivery and increase therapeutic efficacy.
Materials and Methods:: An existing mathematical model was adapted [1] to simulate the concentration of free and liposome encapsulated doxorubicin in circulation (fig A). The simulations were performed in MATLAB and specifically evaluate doxorubicin uptake in low EPR tumors. To increase drug uptake, sonoporation was employed where efficiency of intratumoral liposomal doxorubicin uptake was increased. An alternative non-permeabilizing strategy, called “tumor painting”, was utilized to improve vascular retention instead of increasing permeability. After retention, the small molecule doxorubicin is allowed to leak into the tumors space via concentration mediated Fickian Diffusion.
Results, Conclusions, and Discussions:: While free drug infusion results in high off-target drug uptake in heart and rapid clearance by the body (fig B), traditional sonoporation improved the on-target drug uptake by approximately 1.5-fold (fig D), compared to liposomal doxorubicin infusions (fig C). Tumor painting provided a much more significant improvement in drug delivery achieving up to 3.5-fold increase in maximum drug concentration (fig E). Importantly, our results show that enhancing EPR exhibits diminishing returns while tumor painting can continuously be improved with better adhesion strategies.
This study demonstrates that ultrasound-based drug delivery can be improved with tumor painting. This method has shown enhanced on-target drug uptake and a significant increase in maximum drug concentration. Tumor painting is a valuable tool to overcome the limitations of traditional sonoporation and has exciting potential for enhancing the therapeutic efficacy of chemotherapy.
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References (Optional): : [1] Gasselhuber A, Dreher MR, Rattay F, Wood BJ, Haemmerich D. Comparison of conventional chemotherapy, stealth liposomes and temperature-sensitive liposomes in a mathematical model. PloS one. 2012;7(10): e47453. pmid:23082168.
