Ultrasound-stimulated drug delivery of reconstituted high-density lipoprotein nanoparticles: Effects of drug concentration on tumor uptake

In cancer treatment, there is a need to improve chemotherapeutic drug uptake at the local tumor site to both enhance dose efficacy and minimize any toxic side effects. It is well known now that stably cavitating microbubbles (MBs) in an ultrasound (US) field can increase the permeability of tumor blood vessel walls. This consequently can enhance the extravasation and accumulation of a circulating anticancer drug. Reconstituted high-density lipoprotein (rHDL) nanoparticles (NPs) allow selective delivery of anticancer agents to tumor cells via the overexpressed scavenger receptor class B type 1 (SR-B1). The goal of this study was to evaluate the potential of US-stimulated drug delivery for improving tumor uptake of rHDL NPs that were preloaded with IR-780 dye (i.e., drug surrogate). Mice implanted with human breast cancer cells were divided into five groups: control, and low- or high-dose rHDL NPs ± US therapy. In vivo fluorescence optical imaging was used to quantify intratumoral NP accumulation at baseline and again at 1, 30, 60 min, 24 and 48 h after dosing. At 48 hours after treatment, tumors were resected and subjected to a fluorescent dye extraction study. Results of in vivo optical imaging revealed that the US therapy group animals exhibited stronger rHDL dye localization in the tumor area comparing to non-US groups. Moreover, in the dye extraction study, higher dye levels were detected in the US therapy groups compared to the non-US exposed animals given the same rHDL doses. Meanwhile, administration of a higher dose of rHDL NPs promoted dye accumulation in tumor sites. Overall, US-stimulated drug delivery can noninvasively promote the improved local tumor uptake of rHDL NP vectors.