A Designed 5‐Fluorouracil‐Based Bridged Silsesquioxane as an Autonomous Acid‐Triggered Drug‐Delivery System

Abstract

Two new prodrugs, bearing two and three 5-fluorouracil (5-FU) units, respectively, have been synthesized and were shown to efficiently treat human breast cancer cells. In addition to 5-FU, they were intended to form complexes through H-bonds to an organo-bridged silane prior to hydrolysis-condensation through sol-gel processes to construct acid-responsive bridged silsesquioxanes (BS). Whereas 5-FU itself and the prodrug bearing two 5-FU units completely leached out from the corresponding materials, the prodrug bearing three 5-FU units was successfully maintained in the resulting BS. Solid-state NMR ((29) Si and (13) C) spectroscopy show that the organic fragments of the organo-bridged silane are retained in the hybrid through covalent bonding and the (1) H NMR spectroscopic analysis provides evidence for the hydrogen-bonding interactions between the prodrug bearing three 5-FU units and the triazine-based hybrid matrix. The complex in the BS is not affected under neutral medium and operates under acidic conditions even under pH as high as 5 to deliver the drug as demonstrated by HPLC analysis and confirmed by FTIR and (13) C NMR spectroscopic studies. Such functional BS are promising materials as carriers to avoid the side effects of the anticancer drug 5-FU thanks to a controlled and targeted drug delivery.

Sequential delivery of synergistic drugs by silica nanocarriers for enhanced tumour treatment

“…As drug candidates, we chose for the pore-blocker a commonly used anticancer drug, 5-fluorouracil (5-FU), which exhibits complementary molecular recognition properties to Stalk. Previously, 23 we have demonstrated that a derivative such as Cap (Fig. 1) with a three-fold H-bonding pattern favours stable complexation at neutral pH in bulk hybrid silica materials.…”

“…In contrast, the complex begins to dissociate at lower pH after triazine unit protonation, leading to the breakdown of H-bonds initially involved in stabilization of the capping complex, thus promoting removal of Cap at pH 5.5 and below and its associated release. The biological activity of Cap was previously evaluated 23 by cytotoxic assay on MCF-7 human breast cancer cells, showing a relatively high efficiency (43% of breast cancer cell death at 50 mM) for this molecule as an anticancer drug compared with the parent 5-FU (68% of cell death at 50 mM).…”

Chemistry of Mesoporous Organosilica in Nanotechnology: Molecularly Organic–Inorganic Hybridization into Frameworks

“…Therefore, MONs can also act as drug-delivery systems (DDSs). [ 94,205,211,[230][231][232][233][234][235][236][237][238] The organic fragments within the framework can bring tunable hydrophobicity/hydrophilicity as well as specifi c host-guest interactions with guest molecules, showing more advantages and specifi c behaviors regarding encapsulation, delivery, and release of drug molecules compared to MSNs.…”

Synthesis and Kinetic Study of Novel Coumarin- Based Mutual Prodrug of 5-fluorouracil and 5-ethynyluracil

“…As an oral antitumor agent, the use of 5-FU was deserted in the last decades due to its atypical intestinal absorption that results in irregular plasma levels with marked inter-and intra-individual variations [9]. This is primarily attributed to the mutable activity of HDPD located in the gastrointestinal mucosa [10].…”