New formulations with anti-neoplastic activity: resveratrol-cyclodextrins

Oral Squamous Cell Carcinoma (OSCC) and correlated Oral Preneoplastic Lesion (OPL) currently lack any effective therapeutic approach. In the last decade, many plant-based agents are recognized to exert their anticarcinogenic effects with promising results, but most of them were not able to confirm their antineoplastic activity in vivo for unfavorable phamacokinetic properties. Among these, one of the most studied is resveratrol (3,4’,5-trihydroxy-trans-stilbene) (RV), a molecule produced by plants and found in appreciable amount in a variety of edible fruits including grape skin. RV has shown strong antineoplastic activities in many neoplastic cell lines interfering with more then one hundred pathways but, although serious adverse events are not observed after its systemic administration, it is metabolized very quickly and extensively in the body leading to an irrelevant in vivo effect compared to its remarkable in vitro efficacy. The aim of our work was to test the efficacy of RV-based formulation on OLP and OSCC: to circumvent its degradation and to obtain locally sufficient therapeutic concentration with an improve of half-life, we perform our sperimentation by (i) RV topical administration on oral mucosa (an attractive alternative way for the easy accessibility of the anatomical site) (ii) inclusion of RV in a water-soluble cyclodextrin derivative (hydroxypropyl-β-cyclodextrin) able to form complexes with a wide variety of guest molecules. The experiment was carried out checking 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). The preclinical sperimentation was performed both in vitro on hamster chemically-induced OSCC cell line (HCPC-I) and in vivo on the related animal model (DMBA induced OSCC in Syrian Hamsters buccal pouches, that reflects many aspects of human oral cancer progression) to test our formulations’ efficacy. Obtained results in vitro and in vivo have shown lack of toxicity of both vehicles alone and formulations containing RV. Regarding in vitro efficacy, when RV was complexed in HPβCD, requested time and concentration were earlier and lower if compared with ethanol data. Also the significative growth inhibition was generally improved in HPβCD-formulations. About in vivo experiments, RV-HPβCD treated animal samples have shown significant differences regarding all considerate parameters: in particular a retard in the appearance of lesions, a three fold minor number of lesions for animal (prevalence) and diameter. The strongest action was found in MR group, whereas ER treatment was less effective and durable. CR group demonstrated an intermediate behaviour. Histological analysis confirmed the antineoplastic activity of RV not only for considerate end-points but also for its capability to mitigate histological signs of malignancy in animals buccal pouches lesions. This study indicates that topical chemoprevention with RV included in HPβCD is a promising and realistic approach to perform translational clinical study. If our data will be confirmed by human sperimentation, the unfavorable prognosis of OSCC affected patients could be improved; in addition to fewer systemic side effects, the advantages include easy application that does not require medical supervision and a relatively low cost treatment.