NUC013 (5-aza-2′,2′-difluroro-deoxycytidine) is preclinically safer and more effective than decitabine (Pharmaceuticals 2017, 10, 65).  5-Azacytidines are hydrolyzed at the cytosine’s 6-position, but in vivo, the short half-life is governed by deamination.  For decitabine, attempts have been made to address these issues with continuous infusion, but use of such a regimen is limited by inconvenience and toxicity.

A hydrophobic prodrug was developed for packaging in a hydrophobic matrix to protect NUC013 from hydrolysis and deamination.  In an aqueous environment, the hydrophobic moieties are readily hydrolyzed with release of NUC013 .  This was achieved by conjugating NUC013 with trimethylsilyl (TMS) at the 3’ and 5’ position (NUC041). 

The half-life of NUC013 administered IV in mice is 20.1 minutes.  Below, PK following administration of a dose of 3mg of NUC041 IM in a PEG-phospholipid-depot to mice:

Analyte       C_max (ng/mL)        T_max (hr)        t½ (hr)         AUC_INF (hr·ng/mL)          MRT_INF (hr)

NUC041             4210                       0.5                1.7                          6261                               2.6

NUC013             1333                       1.0                3.4                          5813                               5.1

In an ongoing study, NUC041 was administered at a dose of 3mg qwk to nude mice with a NSCLC H-460 xenograft.  After 3 days of treatment (n=8), tumor starting volume had decreased by 4%.  However, toxicity, likely from vehicle, was also observed at this dose.

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