LAUSR

ABSTRACT CX‐5461 is currently in Phase I/II clinical trials for advanced hematologic malignancies and triple negative or BRCA‐deficient breast cancer. The compound is currently administered to patients intravenously (i.v.) at low pH (3.5) due to solubility challenges. Reliance of low pH to enhance solubility of CX‐5461 can adversely impact pharmacokinetics, biodistribution and therapeutic potential. We have addressed this solubility issue through a formulation method that relies on the interactions between CX‐5461 and copper. Copper binds CX‐5461 through the nitrogens of the pyrazine ring. Here, we describe synthesizing this copper‐complexed CX‐5461 (Cu(CX‐5461)) within liposomes. CX‐5461 was added to copper‐containing liposomes and incubated at 60 °C for 30 min. The pharmacokinetics of CX‐5461 was assessed in mice following a single i.v. injection at 30 mg/kg. Efficacy studies were completed in multiple subcutaneous mouse xenografts as well as in a bone marrow engraftment model of acute myeloid leukemia (AML). The novel Cu(CX‐5461) formulation was stable at pH 7.4 and exhibited increased plasma circulation longevity, increasing the total exposure to CX5461 by an order of magnitude. Cu(CX‐5461) was more active than CX‐5461 in AML models in vivo. In HCT116‐B46 and Capan‐1 solid tumour models that are BRCA‐deficient, the Cu(CX‐5461) formulation engendered activity that was comparable to that of the low pH CX‐5461 formulation. We have generated the first Cu(CX‐5461) formulation suitable for i.v. administration that is more efficacious than the existing low‐pH formulation in pre‐clinical models of AML. The Cu(CX‐5461) formulation may serve as an alternative formulation for CX‐5461 in BRCA‐deficient cancers. Graphical abstract Figure. No caption available. HighlightsThe phase I/II targeted agent CX‐5461 is poorly soluble at physiological pH.Metal‐binding property of CX‐5461 can be exploited for formulation strategies.The first Cu(CX‐5461) nanoformulation extends CX‐5461 circulation lifetime.Cu(CX‐5461) is equally or more efficacious than the low pH CX‐5461 formulation.