Strategies to Maximize Anthracycline Drug Loading in Albumin Microbubbles

Human serum albumin (HSA) microbubbles (MBs) are attracting increasing attention as image-guided and stimuli-responsive drug delivery systems. To better understand and maximize drug encapsulation in HSA MBs, we investigated the impact of the loading strategy and the drugs' physicochemical properties on their entrapment in the MB shell. Regarding loading strategy, we explored preloading, i.e., incubating drugs with HSA prior to MB formation, as well as postloading, i.e., incubating drugs with preformed MB. Both strategies were utilized to encapsulate six anthracyclines with different physicochemical properties. We demonstrate that drug loading in the HSA MB shell profits from preloading as well as from employing drugs with high intrinsic HSA binding affinity. These findings exemplify the potential of exploiting the natural bioconjugation interactions between drugs and HSA to formulate optimally loaded MBs, and they promote the development of HSA MBs for ultrasound-triggered drug delivery.