The inclusion complex of 4-hydroxyonenal with a polymeric derivative of beta-cyclodextrin enhances the anti-tumoral efficacy of the aldehyde in several tumor cell lines and in a three-dimensional human melanoma model

4-Hydroxynonenal (HNE) is the most studied end product of the lipoperoxidation process, by virtue of its relevant biological activity. The anti-proliferative and pro-apoptotic effects of HNE have been widely demonstrated in a great variety of tumour cells types in vitro. Thus, it might represent a promising new molecule on strategies in anticancer therapy. However, the extreme reactivity of this aldehyde, as well as its insolubility in water, a limiting factor for drug bioavailability, and its rapid degradation by specific enzymes represent the major obstacles for its possible in vivo application. Different strategies can used to overcome these problems. One of the most attractive strategies is the use of nanovehicles, since drug loading into nanosized structures enhances their stability and solubility, thus improving their bioavailability and their anti-tumoral effectiveness. Several natural or synthetic polymers have been used to synthesize nanosized structures and, among them, beta- cyclodextrin ( beta-CD) polymers are playing a very important role in drug formulation by virtue of the ability of beta-CD ability to form inclusion compounds with a wide range of solid and liquid molecules by molecular complexation. Moreover, several beta-CD derivatives have been designed in order to improve their physicochemical properties and inclusion capacities. Here we report that the inclusion complex of HNE with a derivative of beta-CD, the beta -CD-poly(4-acryloylmorpholine) conjugate (PACM- CD), enhances the aldehyde stability. Moreover, the inclusion of HNE in PACM- CD potentiates its antitumor effects in several tumor cell lines, and in a more complex system, like a human econstructed skin carrying melanoma tumor cells.