Tenifatecan

Vitamin E TPGS is a tocopherol (α-T) based nonionic surfactant that was used in the formulation of the Tocosol™ paclitaxel nanoemulsion, which was withdrawn from phase III clinical trials. Unlike tocopherols, however, the tocotrienol (T₃) isomers of vitamin E were found to have innate anticancer activity and were shown to potentiate the antitumor activity of paclitaxel. The primary objective of the present study was therefore to develop a paclitaxel nanoemulsions by substituting α-T oil core of Tocosol™ with γ-T₃ in, and vitamin E TPGS with PEGylated γ-T₃ as the shell, and test the nanoemulsions against Bx-PC-3 and PANC-1 pancreatic tumor cells. A secondary objective was to test the activity of paclitaxel when directly conjugated with the γ-T₃ isomer of vitamin E. The synthesis of the conjugates was confirmed by NMR and mass spectroscopy. Developed nanoemulsions were loaded with free or lipid conjugated paclitaxel. Nanoemulsions droplets were <300 nm with fastest release observed with formulations loaded with free paclitaxel when γ-T₃ was used as the core. Substituting α-T with γ-T₃ was also found to potentiate the anticancer activity of the nanoemulsions. Although marginal increase in activity was observed when nanoemulsions were loaded with free paclitaxel, a significant increase in activity was observed when lipid conjugates were used. The results from this study suggest that the developed paclitaxel nanoemulsions with either γ-T₃, PEGylated γ-T₃, or paclitaxel lipid conjugates may represent a more promising option for paclitaxel delivery in cancer chemotherapy.

SN2310 is an injectable emulsion composed of vitamin E, a succinate derivative, as well as 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Single intravenous doses of 15, 20, 25, and 30 mg/m(2) of SN2310 emulsion were administered in a total of 26 patients with advanced solid malignancies. Serial blood samples were collected and concentrations of SN2310, SN-38, and SN-38 glucuronide were assayed. Mean systemic clearance of SN2310 ranged between 1.91 and 2.02 L/h/m(2) . Peak concentrations of SN-38 were observed at the end of infusion, suggesting a fast metabolic conversion of SN2310 to its active form, SN-38. Mean t1/2 values of SN-38 across the 20-30 mg/m(2) dose levels (131-199 h) were 33-55-fold longer than those observed for SN2310. The systemic exposure of SN-38 increased in a proportional manner over the dose range studied. SN2310 emulsion displayed an improved safety profile as compared with irinotecan. The most significant safety risk was neutropenia. Considering the rapid formation of SN-38, the proportional increase in exposure levels, and its longer elimination half-life, less frequent dosing of SN2310 emulsion may be considered for the treatment of patients with advanced solid malignancies.