Vitamin E Phosphate Nucleoside Prodrugs: A Platform for Intracellular Delivery of Monophosphorylated Nucleosides

Abstract

Vitamin E phosphate (VEP) nucleoside prodrugs are designed to bypass two mechanisms of tumor resistance to therapeutic nucleosides: nucleoside transport and kinase downregulation. Certain isoforms of vitamin E (VE) have shown activity against solid and hematologic tumors and result in chemosensitization. Because gemcitabine is one of the most common chemotherapeutics for the treatment of cancer, it was used to demonstrate the constructs utility. Four different VE isoforms were conjugated with gemcitabine at the 5′ position. Two of these were δ-tocopherol-monophosphate (MP) gemcitabine (NUC050) and δ-tocotrienol-MP gemcitabine (NUC052). NUC050 was shown to be able to deliver gemcitabine-MP intracellularly by a nucleoside transport independent mechanism. Its half-life administered IV in mice was 3.9 h. In a mouse xenograft model of non-small cell lung cancer (NSCLC) NCI-H460, NUC050 at a dose of 40 mg/kg IV qwk × 4 resulted in significant inhibition to tumor growth on days 11–31 (p < 0.05) compared to saline control (SC). Median survival was 33 days (NUC050) vs. 25.5 days (SC) ((hazard ratio) HR = 0.24, p = 0.017). Further, NUC050 significantly inhibited tumor growth compared to historic data with gemcitabine at 135 mg/kg IV q5d × 3 on days 14–41 (p < 0.05). NUC052 was administered at a dose of 40 mg/kg IV qwk × 2 followed by 50 mg/kg qwk × 2. NUC052 resulted in inhibition to tumor growth on days 14–27 (p < 0.05) and median survival was 34 days (HR = 0.27, p = 0.033). NUC050 and NUC052 have been shown to be safe and effective in a mouse xenograft of NSCLC.

Chemoresistance in Pancreatic Cancer

“…Compared to gemcitabine, NUC050 is not affected by NTs inhibitors, suggesting that it can bypass NTs. Similarly, NUC050 retained most of the activity in CEM dCK(−) cells, indicating that NUC050 delivered gemcitabine-MP intracellularly [112].…”

NUC041, a Prodrug of the DNA Methytransferase Inhibitor 5-aza-2′,2′-Difluorodeoxycytidine (NUC013), Leads to Tumor Regression in a Model of Non-Small Cell Lung Cancer

“…The mouse xenograft model with human NCI-H460 subcutaneous implants has been shown to be robust and reproducible [ 23 ]. In this model, NUC013 administered for three consecutive days a week from study days 4 through 27 demonstrated a significant improvement in animal survival.…”

“…As per methods previously presented [ 23 ], the lipid nano-emulsion (Latitude Pharmaceuticals, San Diego, CA, USA) contained an oil phase consisting of an injectable oil and lecithin and an aqueous phase comprising a tonicity adjuster, a stabilizer, and water. The emulsions were of oil-in-water type with the mean diameter of oil droplets <100 nm.…”

Recent Advances in the Chemical Synthesis and Evaluation of Anticancer Nucleoside Analogues

“…As such, vitamin E phosphate nucleoside analogue prodrugs were envisaged to combat two mechanisms of resistance: i) downregulation of metabolic kinases (deoxycytidine kinase, dCK, in the case of 1) and ii) nucleoside transport [82,83]. Accordingly, Daifuku and co-workers synthesised and evaluated four isoforms of vitamin E conjugated to 1 (Figure 11, compounds 121-124) [84]. The in vitro GI50 of 1, vitamin E phosphate (VEP) isoforms and compounds 121-124 showed these VEP-gemcitabine prodrugs to exhibit anticancer activity, consistent with their catabolism to vitamin E and gemcitabine monophosphate.…”

“…25, x 19 of 24Daifuku and co-workers synthesised and evaluated four isoforms of vitamin E conjugated to 1 (Figure11, compounds 121-124)[84].…”