Abstract
Resveratrol is naturally occurring phytochemical with diverse biological activities such as chemoprevention, anti-inflammatory, anti-cancer, anti-oxidant. But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as α-methoxy-ω-carboxylic acid poly(ethylene glycol) succinylamide resveratrol (MeO-PEGN-Succ-RSV) (2 and 20 kDa); MeO-PEG succinyl ester resveratrol (MeO-PEGO-Succ-RSV) (2 kDa); α-methoxy poly(ethylene glycol)-co-polylactide succinyl ester resveratrol (MeO-PEG-PLAO-Succ-RSV) (2 and 6.6kDa) were prepared by carbodiimide coupling reactions. Resveratrol-PEG ethers (2 and 5 kDa) were synthesized by alkali-mediated etherification. All polymer conjugates were fully characterized in vitro and the pharmacokinetic profile of selected conjugates was characterized in rats. Buffer and plasma stability of conjugates was dependent on polymer hydrophobicity, aggregation behavior and PEG corona, with MeO-PEG-PLAO-Succ-RSV (2 kDa) showing a 3h half-life in rat plasma in vitro. Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro. MeO-PEG-PLAO-Succ-RSV (2 kDa), Resveratrol-PEG ether (2 and 5 kDa) displayed improved pharmacokinetic profiles with significantly higher plasma area under curve (AUC), slower clearance and smaller volume of distribution, compared to resveratrol.
Highlights
Resveratrol is a naturally occurring polyphenolic phytochemical with beneficial biological activities such as anti-inflammatory, anticancer, antioxidant, and cardio protection [1,2,3]
Resveratrol has been confirmed to be an allosteric activator of SIRT1 [4], an enzyme that belongs to the sirtuin family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases
Resveratrol delivery approaches based on polymeric conjugation should not permanently block hydroxyl groups and, even if permanent conjugation is considered, only selected hydroxyl groups should be modified with appropriate polymers and with minimum impact on the biological activity of resveratrol
Summary
Resveratrol is a naturally occurring polyphenolic phytochemical with beneficial biological activities such as anti-inflammatory, anticancer, antioxidant, and cardio protection [1,2,3]. The pharmacokinetic profile of resveratrol after oral administration in humans was described as high absorption but very low bioavailability due to extensive first-pass metabolism and short elimination half-life [8]. This rapid metabolism pattern has been seen in other species including mouse, rat, pig and dog [9,10,11,12]. The objective of our investigation was to evaluate various polymer conjugation technologies for stabilizing resveratrol against metabolism and consequent impact on resveratrol’s pharmacokinetics profile and in turn its biological effects in vivo. The selected polymer conjugates were evaluated for in vitro antioxidant activity, metabolism and pharmacokinetic profile in Wistar rats
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