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Titolo: Self-organization of mixtures of fluorocarbon and hydrocarbon amphiphilic thiolates on the surface of gold nanoparticles
Abstract: Self-assembled monolayers composed of mixture of thiolate molecules, featuring hydrocarbon or perfluorocarbon chains (H- and F-chains) terminating with a short poly(oxoethylene) (PEG) moiety is the most extreme example of surfactants immiscibility on gold nanoparticles (NPs) reported so far. The phase-segregation between H-chains and F-chains and the consequent, peculiar folding of PEG chains are responsible for the increased affinity of a selected radical probe for the fluorinated region, which increases as the size of the fluorinated domains decreases, independently of the shape of such domains. This feature has been revealed by ESR measurements and an in silico innovative multiscale molecular simulations approach in explicit water. Our results reveal an underlying mechanism of a transmission of the organization of the monolayer from the inner region close to the gold surface toward the external hydrophilic PEG region. Moreover, this study definitively proves that a mixed monolayer is a complex system with properties markedly different from those characterizing the parent homoligand monolayers.

Titolo: Synthesis and receptor binding studies of some new arylcarboxamide derivatives as sigma-1 ligands
Abstract: We describe here the synthesis and the binding interaction with simga1 and sigma2 receptors of a series of new arylcarboxamide derivatives variously substituted on the aromatic portions. Maintaining a partial scaffold of a series of compounds previously synthesized by us, we evaluate the effect of the substitution on sigma binding. The synthesized compounds have been tested to estimate their affinity and selectivity toward sigma1 and sigma2 receptors. Two out of 16 derivatives showed an interesting sigma1 affinity (21.2 and 13.6 nM - compounds 2m and 2p) and a good selectivity (Ki(sigma2) / Ki(sigma1) >140 and >40 respectively).

Titolo: Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance
Abstract: Drug resistance and toxicity constitute challenging hurdles for cancer therapy. The application of nanotechnology for anticancer drug delivery is expected to address these issues and bring new hope for cancer treatment. In this context, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramolecular micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug-loading capacity (>40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles were able to enhance drug potency and combat doxorubicin resistance in breast cancer models by significantly enhancing cellular uptake while considerably decreasing efflux of the drug. In addition, the AmDM/DOX nanoparticles abolished significantly the toxicity related to the free drug. Collectively, our studies demonstrate that the drug delivery system based on nanomicelles formed with the self-assembling amphiphilic dendrimer constitutes a promising and effective drug carrier in cancer therapy.

Titolo: The role of Multiscale Modeling in Horizon 2020

Titolo: Nano tools for macro problems: multiscale molecular modeling of nanostructured polymer systems

Titolo: Resistance to Hedgehog inhibitor through Smoothened receptor mutation in basal cell carcinoma.
Abstract: The inappropriate activation of Hedgehog (Hh) pathway is involved in the pathogenesis of skin basal cell carcinoma (BCC). Loss of function of the transmembrane receptor Patched (PTCH1), or gain of function of the Smoothened (SMO), Sonic Hh (SHH), and GLI family transcription factors can be ligand-independent oncogenic drivers of this disease. The activity of Vismodegib, a small molecule inhibitor of the Hh pathway that binds and inhibits SMO, is currently being evaluated in clinical trials against advanced BCC. Here, we report two cases of BCC, the first showing primary resistance to Vismodeginb treatment and the second characterized by a dramatic response to Vismodegib treatment (150 mg/day) followed by insurgence of secondary resistance. Formalin-fixed specimens of pre-treatment primary tumors and, for the second case, recurrence arisen during Vismodegib regimen were investigated for the mutational status of the serpentine receptor SMO by sequencing (3500DX Genetic Analyzer). In the case of primary resistance, SMO sequencing revealed the presence of the missense point mutation G497W while in the case of secondary resistance the D473Y mutant isoform of SMO receptor was found in the recurrence specimen. This substitution was not detected in the corresponding primary tumor specimen. In silico simulations of the wild type and mutated SMO receptor proteins in complex with Vismodegib showed that two different mechanisms are at work leading to primary and secondary inhibitor resistance, respectively. In the case of G497W (primary resistance), this residue is in a distal position with respect to the receptor drug binding site; however, the mutant residue reflects in a rearrangement of the corresponding loop ultimately leading in a partial obstruction to inhibitor entry. In the case of D473Y (secondary resistance), this residue is involved with other two residues (R400, H470) in a peculiar hydrogen bonds network, and hence appears to play a crucial role in stabilizing Vismodegib binding to the receptor. The mutation D473Y alters this equilibrium leading to a substantial decrease in receptor affinity for the inhibitor. Accordingly, the G497W and the D473Y mutations in SMO could represent two paradigm of primary and acquired resistance to Vismodegib in BCC, driven by different mechanism of SMO/Vismodegib interactions. Further ongoing elucidation of such mechanisms will help in developing therapeutic strategies able to overcome both type of Hh inhibitors resistance.

Titolo: Nano tols for macro problems: multiscale molecular modeling of polymer nanocomposites.

Titolo: Multiscale molecualr modeling for the design of materials in the nano-bio-based economy.

Titolo: Multiscale molecular modeling of polymer nanocomposites

Titolo: Genes with bottles. Combined experimental/modeling investigations of dendron-based nanovectors for DNA delivery