Liposomes are attractive vehicles for the controlled release of drugs and
cytotoxins and have a long-standing history in medical research and clinical practice. In addition to established therapeutic indications,
liposomes have several favorable properties for molecular imaging, including high stability and the ability to be labeled with
radioisotopes, as well as paramagnetic and fluorescent
contrast agents. However, long circulation times and difficulties in creating targeted
liposomes have proven challenges for imaging. In this study, we have addressed these limitations using a recently developed strategy for bioorthogonal conjugation, the reaction between tetrazines and trans-
cyclooctenes. By coating radiolabeled
liposomes with trans-cyclooctene and pretargeting with a tetrazine coupled to a targeted
peptide, we were able to selectively enhance the retention of
liposomes and bind them to
tumor tissue in live animals. The rapid reaction between tetrazines and trans-
cyclooctenes allowed imaging to be performed with the short-lived PET tracer (18)F, yielding signal-to-background activity ratios of 7:1. The covalent, bioorthogonally driven
tumor-targeting of
liposomes by in vivo click chemistry is promising and should be explored for more selective and rapid delivery of radiodiagnostics and radiotherapeutics, two classes of drugs which particularly benefit from fast clearance, low nonspecific binding, and the associated reduced toxicity to kidneys and bone marrow.