Interazione di nanoparticelle solide lipidiche con l'endotelio vascolare: strumenti colloidali per mirare selettivamente oncocanali nell'angiogenesi tumorale

A vast amount of data shows that angiogenesis (the development of new vasculature from preexisting one) has a pivotal role in tumor growth, progression, invasiveness and metastasis. On the other hand tumor vasculature is often accompanied by changes in the expression and/or activity of ion channels, including the TRP (Transient Receptor Potential) family of channels. Among these channels, the cold receptor TRPM8 has emerged as an important factor in cell migration and tumor progression. Studies from the Molecular and Cellular Angiogenesis Laboratory where I did my research work, show a role for this channels in the inhibition of endothelial cells (ECs) migration and adhesion describing a possible protective role for this channel in both cancer cells as well as ECs. Beside cold, TRPM8 is activated by several cooling agents including menthol (derived from the plant Mentha piperita). Menthol is commercially used for various applications in cosmetics to package perfumes, in pharmaceutical products as an analgesic and decongestant; it is used as an additive in cigarettes to reduce irritation to the throat caused by smoking, in products for oral hygiene such as toothpastes and mouthwashes, and as a food additive/flavour (chewing gum and candy). It is considered to be Generally-Recognized-As-Safe (GRAS) and has been approved for over-the-counter external use in the concentration up to 16%. The aim of my research project was to formulate menthol nanoparticulate systems and test them in vitro on ECs migration and capillary-like structure formations on matrigel. To achieve this goal part of my research work was performed in collaboration with Nanovector s.r.l., who has a long experience in colloidal nanoparticles (NPs) preparation for drug delivery. The use of NPs systems present several advantages in terms of drug delivery, since they allow improving drug bioavailability and alter the pharmacokinetics and biodistribution of the drug in the body as compared with free drugs. In the present study I produced several NPs formulations and performed an accurate screening of many components to arrive at the most promising formulation, Menthol_G NPs, that was then used to study its role on ECs in vitro. They are internalized by ECs and closely colocalize in lysosomic compartments within 4 hours. No cytotoxic effect was observed on ECs within 24 hours of treatment. However, similarly to free menthol application, Menthol_G NPs inhibit ECs migration. Interestigly the effect was observed at two different concentration doses, showing better results with the lower menthol concentration (75 µM). On the other hand the effect of Menthol_G NPs on capillary-like formation in vitro were less evident as compared with free menthol: we show a clear trend in the inhibition of tubules although not statistically significant. These data represent the first promising evidence of a Menthol NPs formulation and represent a first in vitro step to study the potential use of Menthol_G NPs in vivo to block tumor vascularization.