Synthesis of water-soluble and gastrointestinal transit-resistant FA-FOS conjugate for targeted delivery to the colon: pharmacokinetics, pharmacodynamics, efficacy

Abstract Ferulic acid is known to be a water-insoluble compound present in many fruits and vegetables and is known to possess antioxidant, anti-cancer, and anti-inflammatory properties. They are quickly absorbed in the stomach and metabolized in the liver. Their colonic exposure is found to be low due to their quick absorption and metabolism in the upper gastrointestinal tract, and due to this reason, only a small fraction of FA found in a bound form is associated with the insoluble and soluble fiber of the food matrix reaching the colon. Here we describe the synthesis and characterization of ferulic acid (FA) bound to fructo oligosaccharide (FOS) rendering the resultant FA-FOS conjugate water soluble, resistant to gastrointestinal digestion and absorption, along with the capability to deliver a therapeutically meaningful dose of FA to the large intestine. Free FA is released from FA-FOS conjugate by the digestive action of gut microflora, and the pharmacokinetic profile and pharmacodynamics are evaluated in a rat model. The efficacy of FA-FOS conjugate in the delivery of FA to the large intestine and its accumulation in tumours were evaluated in colitis induced colon cancer model and their efficacy through plasma bioavailability is determined in xenograft mice model carrying tumour from human colon cancer cells. The accumulation of FA derived from FA-FOS conjugate in the tumour was demonstrated by the MALDI imaging technique. The major metabolites of FA-FOS conjugate in plasma were determined through a data-dependent MS/MS experiment of precursor ion scan, utilizing triple quad (QTRAP) equipped LC-MS.