Ultrasound-activated poly(butyl cyanoacrylate) microbubbles enhance the therapeutic effect of Doxil.

Microbubble-assisted ultrasound can improve the delivery of drugs to tumors by temporarily opening biological barriers, a process commonly referred to as sonopermeation. The type of microbubbles plays a key role in this context, with size distribution and the associated degree of polydispersity being important determinants of treatment efficiency, as a broad size distribution makes it difficult to control the induced effects. Poly(butyl cyanoacrylate) (PBCA) microbubbles have been shown to be suitable for sonopermeation applications due to their narrow, tunable size distribution and unique acoustic response profile. In this study, we investigated their potential to improve the anti-tumor efficacy of liposomal nanomedicines. First, we demonstrated that PBCA microbubble-assisted sonopermeation enhances the penetration of cell layers and the cellular uptake of 70 kDa dextran in vitro. The extravasation of dextran was also promoted in orthotopic murine breast tumors due to increased vascular and stromal permeability. Importantly, combining our sonopermeation protocol using PBCA microbubbles with low-dose Doxil therapy resulted in improved tumor responses, reflected by an inhibition of tumor growth, enhanced apoptosis and reduced cancer cell proliferation. Thus, this study underlines the therapeutic potential of PBCA microbubble-assisted sonopermeation and paves the way for further translational research.