Improving HyperCEST performance by favorable xenon exchange conditions in liposomal nanocarriers

MRI reporters that combine signal enhancement from saturation transfer with hyperpolarized ¹²⁹ Xe show nanomolar detection sensitivity for in vitro studies. However, they need further improvement for accelerated CEST build-up that sufficiently dominates the intrinsic loss of hyperpolarization under in vivo conditions. This study introduces liposomes with a HyperCEST-active lipopeptide to enhance the efficiency of a well known Xe host, CrA-ma, with medium Xe exchange kinetics in aqueous environment, by two orders of magnitude. The depolarization time for constant saturation power but increasing saturation time is used as a comparative measure to rank different nanocarrier formulations. A variable cage load illustrates that the available CEST sites should be well distributed throughout the nanocarriers to avoid inefficiency from back exchange. For a liposome loading with only 2 mol% CrA-lipopeptide, the higher exchange kinetics allowed us to work even with 17-fold lower saturation power than for CrA-ma itself to achieve significant image contrast with ¹²⁹ Xe. Overall, this study illustrates the wide parameter space that is now available when incorporating CrA-labelled lipopeptides into liposomal carriers.