A mutual induced fit mechanism is responsible for the exceptional complexation performances exhibited by calix[8]arene polycations towards heparin. The recognition process was studied in comparison with two other heparin antagonists: protamine and polylysine. The arrangement of multiple functional groups on the flexible macrocyclic scaffold of calix[8]arene, with respect to the conformationally rigid protamine and low ordered polylysine, allowed a mutual adaptability between calixarene polycations and heparin, significantly enhancing the recognition performances. Fluorescence, NMR titration, and activated partial thromboplastin time (aPTT) experiments confirmed that these calixarene derivatives have a very high specificity and affinity towards heparin neutralization as in aqueous solution as in blood. Analogous results were obtained with low molecular weight heparin (LMWH) whose effect protamine is unable to completely reverse.

Curcumin is an Indian spice with a wide spectrum of biological and pharmacological activities but poor aqueous solubility, rapid degradation, and low bioavailability that affect medical benefits. To overcome these limits in ophthalmic application, curcumin was entrapped in a polycationic calix[4]arene-based nanoaggregate by a simple and reproducible method. The calix[4]arene-curcumin supramolecular assembly (Calix-Cur) appeared as a clear colloidal solution consisting in micellar nanoaggregates with size, polydispersity index, surface potential, and drug loading percentage meeting the requirements for an ocular drug delivery system. The encapsulation in the calix[4]arene nanoassembly markedly enhanced the solubility, reduced the degradation, and improved the anti-inflammatory effects of curcumin compared to free curcumin in both in vitro and in vivo experiments. Calix-Cur did not compromise the viability of J774A.1 macrophages and suppressed pro-inflammatory marker expression in J774A.1 macrophages subjected to LPS-induced oxidative stress. Histological and immunohistochemical analyses showed that Calix-Cur reduced signs of inflammation in a rat model of LPS-induced uveitis when topically administrated in the eyes. Overall, the results supported the calix[4]arene nanoassembly as a promising nanocarrier for delivering curcumin to anterior ocular tissues.

Structure and conformation of spontaneous self-assembled calix[8]arenes derivatives are studied by means of static and dynamic light scattering and electrophoretic mobility. These amphiphilic molecules are in the aggregated form in aqueous solution, in a wide range of pH; they take a vesicle structure in neutral and basic pH environment, but, in relatively strong acidic conditions (below pH=4.5), a transition from vesicle to micelle occurs. The structural change is driven by the surface charge density. At neutral pH calix[8]arenes take a negative surface charge, which prevents coagulation and ensures stability; at acidic pH the surface charge tend to become positive because of the protonation of the hydrophilic head. These pH-responsive aggregates, able to release an encapsulated hydrophilic guest, are promising systems for application as nanocarriers.

Novel calix[4 or 8]arene-based glycoconjugates exposing terminal N-acetyl-D-glucosamine clusters have been synthesized using amino acid-calixarenes as building blocks. The obtained glycosamino acid-calixarenes 9b-14b have lectin-binding ability and amplified inhibitory effects on erythrocyte agglutination induced by wheat germ (Triticum vulgaris) agglutinin (WGA). The inhibitory ability is dependent on the presence of the spacer and on the shape and rigidity of the calixarene skeleton.

No abstract