Nano-engineered vehicles for pharmacological applications: improvement in the chemopreventive effect and pharmacokinetic properties of resveratrol

The attention of the scientific community about natural molecules has progressively grown because of a number of reports highlighting their benefits, but clinical use has often been frustrated due to chemical structures that unfavorably affect their pharmacokinetic properties. This work has been focused on the study of different approaches to improve the activities of naturally occurring compounds, in particular resveratrol (3,4’,5-trihydroxy-trans-stilbene, RV). RV is the most well-characterized stilbene, small secondary metabolites produced as protective agents by a wide range of medicinal sources. RV is a polyphenolic phytoalexin with pleiotropic effects. Unfortunately, when it has been administered systemically, results have been disappointing owing to its low hydrosolubility and inactivating metabolism, resulting in extremely low bioavailability that haven’t enabled RV to reach the effective concentrations required for its actions. A strategy followed to improve RV properties is the possibility to include it into protective vehicles: we selected as nanovectors hydroxypropyl-β-cyclodextrins (HPβCDs), cyclic oligosaccharides forming stable aqueous complexes with molecules containing the stilbene skeleton [1]. We demonstrated RV efficacy in the chemoprevention of chemical-induced oral carcinogenesis and its significant increase when applied in HPβCDs formulations, if compared with free RV simply dissolved in ethanol, both on cells and in vivo when topically applied on hamster cheek pouches. We evaluated if inclusion in HPβCDs got also better RV systemic bioavailability after oral administration in mice. Results showed that plasma concentrations of HPβCDs-vehiculated RV was significantly higher than those obtained with the non-complexed form [2]. Then, we compared RV delivery in vivo in the principal organs and mammary tumors in BALB–NeuT transgenic mice. Also here data confirmed HPβCDs protection in every organ, in particular in tumors complexed RV showed a kinetic characterized by high concentrations, while RV-ethanol was no detected. Both in plasma and tumors HPβCDs allowed RV to reach concentrations greatly exceeding those required for oral chemoprevention in vitro. The only tissue showing similar temporal profile was the heart: this could be of great importance considering the antioxidant RV action in the cardiovascular system (French Paradox). Another strategy to block RV metabolism improving bioavailability is the development of derivatives, using it as the prototype. RV simple structure offers promise for the design of new agents and the demonstrated pharmacological properties have inspired the synthesis of a lot of analogues. Similar to RV, these phytochemicals possess a multitude of biological activities. We performed a comprehensive analysis of the structure–activity relationships to determine the specific pharmacophores for RV actions. Several structural determinants could be revealed so far, such as the stereoisomery, the number and position of substituent groups and the stilbenic double bond. So we’re evaluating plasma and tissues concentrations of piceatannol (trans-3,4,3’,5’-tetrahydroxystilbene, PC), one of the most studied RV analog, from which structurally differs by possessing an additional hydroxyl group (forming an ortho-dihydroxy structure) that enhances its water solubility and makes it more reactive. Identification of a suitable transporter may be crucial for a drug’s clinical success. We demonstrated that RV concentrations are significantly improved after HPβCDs complexation: they represent ideal vehicles for RV. We also summarized several critical pharmacophores for RV and derivatives. Based on our evidences, we will evaluate the efficacy of the formulations after oral administration and synthesize new complexes with potent analogues. 1) Berta GN, Salamone P et al. PCT/IB2008/003271 2) Berta GN, Salamone P et al. (2010) - Oral Oncol;46(1):42-8.