Very Large Pore Mesoporous Bioactive Silicate Glasses: Comparison of Behavior toward Classical Mesoporous Bioactive Glasses in Terms of Drug Loading/Release and Bioactivity.

Considering the increase in patients who suffer from osteoporosis and the bone defects that occur in these patients, bone tissue regeneration is a promising option to solve this problem. To achieve a synergistic effect between the synthesis of a proper structure and bioactive/pharmaceutical activity, ions with a physiological effect can be added to silica structures, such as Ca2+, thanks to its bioactive behavior, and Ga3+ for its antibacterial and anticancer action. In this work, the synthesis of large pore mesoporous silica (LPMS), potential bioactive glasses containing Ca2+ and Ga3+, has been studied. Corresponding structures, in terms of composition, have been synthesized following the Sol-Gel EISA (Evaporation Induced Self-Assembly) process (obtaining Classical Mesoporous Silica, MS). Pore structure characterization of LPMSs and MSs has been performed using N2 adsorption/desorption and Hg-porosimetry, showing the presence of pores for LPMSs in the range of 20-60 and 200-600 nm. Nisin, a polycyclic antibacterial peptide, has been used for load tests. The load and release tests performed highlight a higher loading and releasing, doubled for LPMSs if compared to MSs. To confirm the maintenance of the structure of LPMSs and their mechanical strength and resistance, scanning electron microscopy images were acquired before and after release tests. Ca and Ga release in SBF has been studied through inductively coupled plasma-optical emission spectroscopy (ICP-OES), showing a particularly high release of these ions performed with LPMSs. The bioactive behavior of Ca-containing structures has been confirmed using FT-IR (Fourier-transform infrared spectroscopy), SEM-EDS (Scanning Electron Microscope-Energy Dispersive Spectroscopy), and X-ray powder diffraction (XRDP). In conclusion, LPMSs showed better loading and releasing properties compared with classical MS and better release in terms of active ions. In addition, it has also been demonstrated that LPMSs have bioactive behavior (a well-known characteristic of MSs).

Alginate Beads Containing Cerium-Doped Mesoporous Glass and Curcumin: Delivery and Stabilization of Therapeutics.

Cancer is a leading cause of death worldwide, its genesis and progression are caused by homeostatic errors, and reactive oxygen species play a major role in promoting aberrant cancer homeostasis. In this scenario, curcumin could be an interesting candidate due to its versatile antioxidant, anti-inflammatory, anti-tumor, anti-HIV, and anti-infection properties. Nonetheless, the major problem related to its use is its poor oral bioavailability, which can be overcome by encapsulating it into small particles, such as hydrogel beads containing mesoporous silica. In this work, various systems have been synthesized: starting from mesoporous silica glasses (MGs), cerium-containing MGs have been produced; then, these systems have been loaded with 4 to 6% of curcumin. Finally, various MGs at different compositions have been included in alginate beads. In vitro studies showed that these hybrid materials enable the stabilization and effective delivery of curcumin and that a synergic effect can be achieved if Ce3+/Ce4+ and curcumin are both part of the beads. From swelling tests, it is possible to confirm a controlled curcumin release compartmentalized into the gastrointestinal tract. For all beads obtained, a curcumin release sufficient to achieve the antioxidant threshold has been reached, and a synergic effect of cerium and curcumin is observed. Moreover, from catalase mimetic activity tests, we confirm the well-known catalytic activity of the couple Ce3+/Ce4+. In addition, an extremely good radical scavenging effect of curcumin has been demonstrated. In conclusion, these systems, able to promote an enzymatic-like activity, can be used as drug delivery systems for curcumin-targeted dosing.

Curcumin-Based ß-Diketo Ligands for Ga3+: Thermodynamic Investigation of Potential Metal-Based Drugs.

Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the ß-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the ß-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the ß-keto-enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 ß-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto-enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga3+ anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto-enol form. A complete 1H/13C NMR and UV-Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer.

Applications of Radiolabelled Curcumin and Its Derivatives in Medicinal Chemistry.

Curcumin is a natural occurring molecule that has aroused much interest among researchers over the years due to its pleiotropic set of biological properties. In the nuclear medicine field, radiolabelled curcumin and curcumin derivatives have been studied as potential radiotracers for the early diagnosis of Alzheimer's disease and cancer. In the present review, the synthetic pathways, labelling methods and the preclinical investigations involving these radioactive compounds are treated. The studies entailed chemical modifications for enhancing curcumin stability, as well as its functionalisation for the labelling with several radiohalogens or metal radionuclides (fluorine-18, technetium-99m, gallium-68, etc.). Although some drawbacks have yet to be addressed, and none of the radiolabelled curcuminoids have so far achieved clinical application, the studies performed hitherto provide useful insights and lay the foundation for further developments.