Copper-CX-5461: A novel liposomal formulation for a small molecule rRNA synthesis inhibitor

Journal of Controlled Release : Official Journal of the Controlled Release Society
Ada W Y LeungMarcel B Bally

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...Continue Reading

Citations

Jun 5, 2019·International Journal of Molecular Sciences·Yu-Hsuan LeeRong-Jane Chen
Mar 20, 2019·Pharmaceutics·Ada W Y LeungMarcel B Bally
Sep 19, 2019·Expert Opinion on Drug Delivery·Ludger M Ickenstein, Patrick Garidel
Mar 19, 2019·Journal of Pediatric Surgery·Jordan S TaylorBill Chiu
Mar 13, 2021·International Journal of Pharmaceutics·Jacinta O PinhoM Manuela Gaspar

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