HPβCDs complexing resveratrol: a novel approach for chemoprevention of squamous cell carcinoma

In the last decade, one of the most investigated vehicles for drugs have been cyclodextrins (CDs), torus-like cyclic oligosaccharides which offer a hydrophobic matrix to form inclusion complexes with a wide variety of lipophilic molecules. Many semisynthetic derivatives have been synthetized from the three natural CDs (α, β and γ) and the choise of the most suitable principally depends on guest chemical-physical properties. In particular a hydrophilic β-CD derivative (2-hydroxypropyl- β-cyclodextrin, HPβCD) is one of the most commonly utilized due to its optimum safety profile, higher water-solubility and complexation potential expecially towards heterocycles and aromatics. A lot of natural compounds share this chemical structure, including a family of stilbene-derivative molecules, such as Resveratrol (RV). It is a fitoalexin that shows a paramount of pharmacological actions on mammalians, including chemoprevention; unfortunately unfavorable clinical results were obtained due to its low water-solubility and unsatisfactory pharmacokinetic properties (it is metabolized quickly and extensively in the body). The aim of our preclinical work has been to investigate if HPβCD complexing RV was able to improve RV antineoplastic activity in vivo, in particular if it was a valid tool to prevent squamous cell carcinoma of oral cavity (OSCC) and correlate with pre-neoplastic lesions (OPLs), often represented by red or white patches named eritroplakia and leukoplakia respectively. From the above, multi-step OSCC development supports the rationale for a chemopreventive strategy that will inhibit, delay or reverse carcinogenesis before it becomes an invasive disease. The sperimentation was performed both in vitro on hamster chemically-induced OSCC cell line (HCPC-1) and in vivo on the corrispondent animal model (DMBA-induced OSCC in Syrian Hamsters buccal pouches). We tested differences between two HPβCD-based preparations, one dispersed in oil/water emulsion (to obtain a cream disposable only in well defined area, CR) and one dissolved in phisiological solution (to mimic mouthwash administration, MR), compared with RV simply dissolved in ethanol (ER). Both vehicles alone and containing RV shown no toxicity in vitro and in vivo. About in vitro efficacy, HPβCD-formulations generally improved growth inhibition early and at a lower concentration if compared to ER. Concerning in vivo results, RV-HPβCD treated animal samples have shown significant differences regarding all considerated parameters: in particular a retard in lesions appearance and a three fold minor number of lesions for animal. Between HPβCDs complexes, MR demonstrated the longest duration and the best effect: particularly, at the end of the experiment, this formulation was able to prevent diameters development of almost 10 fold compared to DMBA only treated group, generating impressive results. Also histological analysis confirmed RV antineoplastic activity for considerated end-points and for its capability to mitigate histological levels of malignancy in buccal pouches lesions. In conclusion, our study demonstrated that HPβCDs may be an ideal vehicle for RV delivery on oral mucosa because provided high levels of drug permeation, improving RV-action significantly: if this will be confirmed by future clinical trials, a safety, easly (that does not require medical supervision) and low cost new chemopreventive tool will be available for OPLs/OSCC suffering patients.