Ultrasound-Enhanced Distribution and Treatment Efficacy of Dox-Loaded Intratumoral In Situ Forming Implants in Murine HCT-15 Tumors

Local drug delivery systems, such as in situ forming implants (ISFIs), allow for sustained elevated drug concentration directly at the tumor site. However, these systems have been challenging to translate into clinical practice due to poor drug penetration through the implant/tumor boundary. Ultrasound (US) has emerged as a popular approach to enhance drug release and cellular drug uptake from nanoparticles, but little work has been done with its use in combination with ISFIs. In this study, ISFIs were intratumorally injected and treated with therapeutic ultrasound (TUS). A significant (p <;0.05) increase was seen in Doxorubicin (Dox) distribution with ISFIs treated with TUS as compared to ISFIs not treated with TUS. Additionally, the combination of Dox ISFIs with TUS showed a significant (p <;0.01) reduction in tumor growth at 20 days, compared to all other treatment groups. While the mechanism of increased drug distribution and enhanced therapeutic efficacy is not yet clear, hyperthermia was seen with all groups that involved application of TUS for these US exposure parameters. This could be attributed to elevated drug penetration and synergy with the chemotherapy, but additional experiments need to confirm this hypothesis. This study demonstrates, for the first time, US-enhanced drug distribution from ISFIs. The combination of US with local chemotherapy could eventually facilitate translation of local drug delivery systems into clinical practice.