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

JOURNAL OF CONTROLLED RELEASE

卷:286

Article

Leung, Ada W. Y.^1,2,3,5,6  Anantha, Malathi¹  Dragowska, Wieslawa H.¹  Wehbe, Mohamed^1,4  Bally, Marcel B.^1,3,4,5,6 

[1] BC Canc Res Ctr, Expt Therapeut, 675 West 10th Ave, Vancouver, BC V5Z 1L3, Canada

[2] Univ British Columbia, Dept Chem, Vancouver, BC, Canada

[3] Cuprous Pharmaceut Inc, Vancouver, BC, Canada

[4] Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada

[5] Ctr Drug Res & Dev, Vancouver, BC, Canada

[6] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC, Canada

关键词: CX-5461;    Liposomes;    Ribosomal biogenesis;    RNA polymerase I;    Leukemia;    BRCA-deficient cancers;   

DOI  :  10.1016/j.jconrel.2018.07.025

来源: Elsevier

【 摘 要 】

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 degrees 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.

【 授权许可】

Free