1-Alkylcarbonyloxymethyl Prodrugs of 5-Fluorouracil (5-FU): Synthesis, Physicochemical Properties, and Topical Delivery of 5-FU

Abstract

1-Alkylcarbonyloxymethyl (1-ACOM) prodrugs of 5-fluorouracil (5-FU) have been synthesized and characterized by their solubilities in isopropyl myristate (SIPM) and pH 4.0 buffer (SH2O), by their partition coefficients between isopropyl myristate (IPM) and pH 4.0 buffer (K) and by their abilities to deliver total 5-FU species into (Cs) and through (Ji) hairless mouse skin from an IPM vehicle. All of the prodrugs were much more lipophilic (SIPM) than 5-FU (> 60 times), and two members of the series (alkyl = C1 and C2, acetyl- and propionyloxymethyl) were also more soluble in water than 5-FU. The two more water-soluble members gave larger Ji values than the other members of the series, with C2 exhibiting the best biphasic solubility and the largest Ji value (16 times that of 5-FU). The ability of the 1-ACOM-5-FU prodrugs to deliver total 5-FU species into skin (Cs) was greater than the delivery of 5-FU by 5-FU, except for the last two members of series (alkyl = C7 and C9, octanoyl- and decanoyl-oxymethyl). However, the ratios of normalized Cs to Ji for the series was less than that exhibited by 5-FU, except for C7 and C9. Also, except for C9, significant amounts of intact prodrug as percentages of total 5-FU species were found in the receptor phases during the course of the diffusion cell experiments, ranging from 55% for C1 to 12% for C7.

Multifunctional Nanoparticles Based on a Single-Molecule Modification for the Treatment of Drug-Resistant Cancer

“…12 PTX and 5-FU–TPGS were dissolved in chloroform and coprecipitated by evaporation of the chloroform with a steady flow of nitrogen gas. A trace amount of chloroform was removed by keeping the precipitates under a vacuum in a desiccator for 2–4 h. After being hydrated and vortexed in water for 30 min, suspensions were sonicated for 15 min in a bath-type sonicator (output of 80 kC, 80 W) to form MFNPs.…”

“…It has been reported that 5-FU was released from its prodrug using CH 2 O as a linker after hydrolysis (two steps). 12 As the 5-FU is conjugated to TPGS using the CH 2 O linker, the release of 5-FU may also occur through the two-step hydrolysis process.…”

Novel 5-Fluorouracil Carbonate-Loaded Liposome: Preparation, In Vitro, and In Vivo Evaluation as an Antitumor Agent

“…However, as a good water-soluble drug, 5-FU is not suitable for being directly encapsulated into excellent liposomes with a high encapsulation efficiency (EE). Besides, the lack of proper functional groups of 5-FU also hampers the possibility of constructing a prodrug. − Given that N 1 -hydroxymethyl-5-FU is easily converted to 5-FU in vivo , we introduced a hydroxymethyl first to the N 1 of the 5-FU and then constructed a lipophilic prodrug of 5-FU via modification of the hydroxyl group. The myristoyl moiety widely existed in the main phospholipids (such as DMPC and DMPG) of the liposome.…”