Pro-apoptotic liposomes-nanobubble conjugate synergistic with paclitaxel: a platform for ultrasound responsive image-guided drug delivery

Recently, liposomes-microbubble conjugates have emerged as a promising ultrasound (US)-responsive platform for cancer therapeutics. However, these are limited by their size in terms of tumor penetration. Additionally, there have been no attempts to enhance the smartness of such conjugates which have been used only as passive carriers. The present study explores submicron sized (756 +/- 180.0 nm), US-responsive, phosphatidylserine (PS)-based paclitaxel-liposomes-nanobubble conjugates (PSPLBC) with an additional pro-apoptotic effect towards enhanced anti-cancer efficacy and image-guidance. The developed PSPLBC underwent cavitation in response to US-trigger, exhibiting in vitro pulsatile release with a 10-fold increase in cellular internalization as compared to control. The PS-containing formulations were found to be pro-apoptotic and exhibited strong synergism between PS and paclitaxel (Combination Index, CI < 0.1). This resulted in significantly high anti-tumor efficacy both in vitro and in vivo conditions (98.3 +/- 0.8% tumor growth inhibition, TGI). Significant reduction in tumor proliferation index and MVD, as well as significant increase in apoptosis, were observed for the treated tumor sections. Further, the intravenous (i.v.) administration of PSPLBC enhanced the tumor US-contrast by 2-fold as compared to SonoVue. These results, show the potential of PSPLBC as a promising non-invasive, pro-apoptotic, smart DDS for US-responsive, image-guided cancer therapeutics.