Lipid Shell Composition Plays a Critical Role in the Stable Size Reduction of Perfluorocarbon Nanodroplets

Abstract

Perfluorocarbon nanodroplets (PFCnDs) are phase-change contrast agents that have the potential to enable extravascular contrast-enhanced ultrasound and photoacoustic (US/PA) imaging. Producing consistently small, monodisperse PFCnDs remains a challenge without resorting to technically challenging methods. We investigated the impact of variable shell composition on PFCnD size and US/PA image properties. Our results suggest that increasing the molar percentage of PEGylated lipid reduces the size and size variance of PFCnDs. Furthermore, our imaging studies demonstrate that nanodroplets with more PEGylated lipids produce increased US/PA signal compared to those with the standard formulation. Finally, we highlight the ability of this approach to facilitate US/PA imaging in a murine model of breast cancer. These data indicate that, through a facile synthesis process, it is possible to produce monodisperse, small-sized PFCnDs. Novel in their simplicity, these methods may promote the use of PFCnDs among a broader user base to study a variety of extravascular phenomena.

Phase-shift nanodroplets as an emerging sonoresponsive nanomaterial for imaging and drug delivery applications

“…Although numerous studies used lipid formulated nanodroplets, only a few studies have investigated the effect of the lipid shell composition on nanodroplets' size distribution and acoustic property. 51,54 Mountford et al used a series of lipids with acyl chain lengths ranging from C14 to C20 to form nanodroplets. The results showed The polymer could facilitate the loading of drugs with high loading efficiency in the shell Upon vaporisation, bubbles formed are highly unstable due to the presence of gas molecules within the polymer shell Polymer nanodroplets possess a high surface to volume ratio so the rate of adsorption (on what?)…”

“…Increasing the molar percentage of PEGylated lipid reduces the average size and size variation of nanodroplets, and facilitates ultrasound imaging contrast in a murine model of breast cancer. 54 The influence of the PEG chain length was also addressed by Melich et al They prepared 90% DPPC nanodroplets with 10% DSPE-PEG5000 or DSPE-PEG2000 using the microfluidics method. They concluded that there was no significant impact on the nanodroplet formulation quality under their operating parameters.…”

Mechanistic Insights and Therapeutic Delivery through Micro/Nanobubble-Assisted Ultrasound

“…For example, emulsions made of perfluorocarbon (PFC) express ideal inertness and biocompatibility with increased circulation time and larger loading capability compared to PFC MBs [ 50 ]. Studies have shown that smaller droplets are more stable and require higher negative pressure amplitudes [ 51 , 52 ]. Besides, emulsions are smaller than MBs and can potentially extravasate out of blood vessels.…”

Spatially Localized Sono-Photoacoustic Activation of Phase-Change Contrast Agents

“…Phase-change contrast agents are a new class of medical ultrasound (US) imaging agent emerging as an alternative to conventional gaseous perfluorocarbon (PFC) microbubbles [ [1] , [2] , [3] , [4] , [5] ]. They are liquid droplets with a PFC core stabilized with a lipid, protein, polymer, or particle-based shell [ [6] , [7] , [8] , [9] , [10] ]. Although they can be synthesized using core and shell materials chemically identical to currently FDA approved gaseous microbubble contrast agents, they differ from microbubbles in that they are stored and delivered as liquid droplets [ [10] , [11] , [12] ].…”