Abstract
The ability of ultrasound contrast agents to enhance the cell membrane permeability in response to an ultrasound pulse has unveiled avenues to facilitate the delivery of a higher intracellular payload at target sites. In light of the above, we report the development of submicron-sized (528.7 ± 31.7 nm) nanobubble-paclitaxel liposome (NB-PTXLp) complexes for ultrasound imaging and ultrasound responsive drug delivery in cancer cells. With a paclitaxel entrapment efficiency of 85.4 ± 4.39%, the 200 nm-sized liposomes tethered efficiently (conjugation efficiency ∼98.7 ± 0.14%) with the nanobubbles to form conjugates. Sonoporation of MiaPaCa-2 cells upon treatment with nanobubbles and ultrasound enhanced cellular permeability, resulting in 2.5-fold higher uptake of liposomes in comparison to only liposome treatment. This manifested into more than 300-fold higher anticancer activity of NB-PTXLps in the presence of ultrasound in MiaPaCa-2, Panc-1, MDA-MB-231, and AW-8507 cell lines, compared to commercial formulation ABRAXANE. Also, the NB-PTXLp conjugates were found to exhibit echogenicity comparable to the commercial ultrasound contrast agent SonoVue. In addition, the developed nanobubbles were found to exhibit more than 1 week echogenic stability as opposed to 6 h stability of the commercially available ultrasound contrast agent SonoVue. Hence, the NB-PTXLps developed herein could prove to be a promising and minimally invasive theranostic platform for cancer treatments in the future.