A gradient-loadable 64Cu-chelator for quantifying tumor deposition kinetics of nanoliposomal therapeutics by positron emission tomography

Effective drug delivery to tumors is a barrier to treatment with nanomedicines. Non-invasively tracking liposome biodistribution and tumor deposition in patients may provide insight into identifying patients that are well-suited for liposomal therapies. We describe a novel gradient-loadable chelator, 4-DEAP-ATSC, for incorporating 64Cu into liposomal therapeutics for positron emission tomographic (PET). 64Cu chelated to 4-DEAP-ATSC (> 94%) was loaded into PEGylated liposomal doxorubicin (PLD) and HER2-targeted PLD (MM-302) with efficiencies > 90%. 64Cu-MM-302 was stable in human plasma for at least 48 h. PET/CT imaging of xenografts injected with 64Cu-MM-302 revealed biodistribution profiles that were quantitatively consistent with tissue-based analysis, and tumor 64Cu positively correlated with liposomal drug deposition. This loading technique transforms liposomal therapeutics into theranostics and is currently being applied in a clinical trial (NCT01304797) to non-invasively quantify MM-302 tumor deposition, and evaluate its potential as a prognostic tool for predicting treatment outcome of nanomedicines.From the Clinical EditorThis study describes a PET-based detection method utilizing in vivo localization of 64Cu-labeled liposomes. In addition to the presented rodent model, a clinical trial is already underway to investigate the clinical utility of this technique.

Graphical AbstractWe have synthesized a novel chelator, 4-DEAP-ATSC, for loading 64Cu into liposomal drugs for positron emission tomography (PET). The 64Cu-loading technique based on the transmembrane ion gradient principle results in > 90% labeling efficiency without post-labeling purification. The 64Cu-liposomes are stable in vitro and in vivo; preclinical PET in tumor xenografts demonstrated that image-based analysis provides an accurate non-invasive quantification of the liposomal drug's in vivo distribution.Figure optionsDownload high-quality image (250 K)Download as PowerPoint slide