Self-assembly of PEG-fluoroalkyl chains into new generation nanodroplets as histotripsy agent with determinable perfluorocarbon content

The development of nanodroplets (NDs) as first-generation agents for nanoparticle-mediated histotripsy (NMH) aimed to overcome the limitations of histotripsy by significantly reducing the cavitation threshold. While effective, conventional NDs present several drawbacks, including complex multistep synthesis, poor long-term stability, and the inability to quantify the perfluorocarbon (PFC) concentration in treatment doses, which limit their clinical utility. To address these issues, a novel advancement has emerged in the form of PEGfluoroalkyl NDs as new histotripsy agents. These NDs are formed through the self-assembly of PEG-fluoroalkyl chains encapsulating perfluorohexane (PFH), a highly efficient PFC derivative for histotripsy. The resulting NDs possess desirable size, detectable PFH content, and enhanced nanoparticle stability. We hypothesize that the presence and increasing number of fluorine (F) groups enhance PFH encapsulation within the ND core, resulting in a more stable structure. To test this, a library of eight NDs was prepared using two poly(ethylene glycol) chain lengths (PEG550 and PEG2000) and four distinct fluoroalkyl chains, in the presence of PFH. The findings highlight facile production, biocompatibility, and a size smaller than 200 nm, with PEG550-based NDs showing quantifiable PFH encapsulation. Moreover, increasing the fluoroalkyl chain length improved the PFH encapsulation for PEG550 derivatives. All PEG-fluoroalkyl NDs reduced cavitation thresholds, ranging from 11.2 to 17.6 MPa, which could be tuned by varying ND concentration. These results suggest PEG-fluoroalkyl NDs represent a promising next-generation agent for NMH applications.