Mannose-6-phosphate receptor: a target for theranostics of prostate cancer.

The development of personalized and non-invasive cancer therapies based on new targets combined with nanodevices is a major challenge in nanomedicine. In this work, the over-expression of a membrane lectin, the cation-independent mannose 6-phosphate receptor (M6PR), was specifically demonstrated in prostate cancer cell lines and tissues. To efficiently target this lectin a mannose-6-phosphate analogue was synthesized in six steps and grafted onto the surface of functionalized mesoporous silica nanoparticles (MSNs). These MSNs were used for in vitro and ex vivo photodynamic therapy to treat prostate cancer cell lines and primary cell cultures prepared from patient biopsies. The results demonstrated the efficiency of M6PR targeting for prostate cancer theranostic.

Improved gene transfer with histidine-functionalized mesoporous silica nanoparticles.

Mesoporous silica nanoparticles (MSN) were functionalized with aminopropyltriethoxysilane (MSN-NH2) then L-histidine (MSN-His) for pDNA delivery in cells and in vivo. The complexation of pDNA with MSN-NH2 and MSN-His was first studied with gel shift assay. pDNA complexed with MSN-His was better protected from DNase degradation than with MSN-NH2. An improvement of the transfection efficiency in cells was observed with MSN-His/pDNA compared to MSN-NH2/pDNA, which could be explained by a better internalization of MSN-His. The improvement of the transfection efficiency with MSN-His was also observed for gene transfer in Achilles tendons in vivo.

Surfactant behavior of ionic liquids involving a drug: from molecular interactions to self-assembly.

Aggregates formed in an aqueous medium by three ionic liquids CnMImIbu made up of 1-alkyl-3-methyl-imidazolium cation (n = 4, 6, 8) and ibuprofenate anion are investigated. Dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), (1)H nuclear magnetic resonance measurements, and atom-scale molecular dynamics simulations are used to shed light on the main interactions governing the formation of the aggregates and their composition. At high concentration, mixed micelles are formed with a composition that depends on the imidazolium alkyl chain length. For the shortest alkyl chain, micelles are mainly composed of ibuprofenate anions with some imidazolium cations intercalated between the anions. Upon increasing the alkyl chain length, the composition of the aggregates gets enriched in imidazolium cations and aggregates of stoichiometric composition are obtained. Attractive interactions between these aggregates led to the formation of larger aggregates. As suggested by molecular simulations, these larger aggregates might constitute the early stage of phase separation. Transitions from micelles to vesicles or ribbons are observed due to dilution effects and changes in the chemical composition of the aggregates. We also show that aggregation can be probed using simple microscopic quantities such as radial distribution functions and average solvation numbers.

Hyaluronic acid-functionalized mesoporous silica nanoparticles for efficient photodynamic therapy of cancer cells.

Mesoporous silica nanoparticles (MSN) for photodynamic therapy (PDT) were coated with poly-(L-lysine) and hyaluronic acid (HA) by using the layer-by-layer method. HA is able to target cancer cells over-expressing the corresponding CD44 receptor. MSN functionalized with HA (MSN-HA) were more efficient than MSN without the targeting moiety when PDT was performed at low fluence (14 Jcm(-2)) and low dosage of MSN (20 µgmL(-1)) on HCT 116 colorectal cancer cells, known to over-express the CD44 receptor. Incubation of HCT-116 cancer cells with an excess of HA impaired the PDT effect with MSN-HA thus demonstrating that an active endocytosis mechanism was involved in the uptake of MSN-HA by these cells.

Multifunctionalized mesoporous silica nanoparticles for the in vitro treatment of retinoblastoma: Drug delivery, one and two-photon photodynamic therapy.

In this work, we focused on mesoporous silica nanoparticles (MSN) for one photon excitated photodynamic therapy (OPE-PDT) combined with drug delivery and carbohydrate targeting applied on retinoblastoma, a rare disease of childhood. We demonstrate that bitherapy (camptothecin delivery and photodynamic therapy) performed with MSN on retinoblastoma cancer cells was efficient in inducing cancer cell death. Alternatively MSN designed for two-photon excited photodynamic therapy (TPE-PDT) were also studied and irradiation at low fluence efficiently killed retinoblastoma cancer cells.

Cancer therapy improvement with mesoporous silica nanoparticles combining targeting, drug delivery and PDT.

The synthesis of mesoporous silica nanoparticles (MSN) covalently encapsulating fluoresceine or a photosensitizer, functionalized with galactose on the surface is described. Confocal microscopy experiments demonstrated that the uptake of galactose-functionalized MSN by colorectal cancer cells was mediated by galactose receptors leading to the accumulation of the nanoparticles in the endosomal and lysosomal compartments. The MSN functionalized with a photosensitizer and galactose were loaded with the anti-cancer drug camptothecin. Those MSN combining drug delivery and photodynamic therapy were tested on three cancer cell lines and showed a dramatic enhancement of cancer cell death compared to separate treatments.

Silicalites and Mesoporous Silica Nanoparticles for photodynamic therapy.

The synthesis of silicalites and Mesoporous Silica Nanoparticles (MSN), which covalently incorporate original water-soluble photosensitizers for PDT applications is described. PDT was performed on MDA-MB-231 breast cancer cells. All the nanoparticles showed significant cell death after irradiation, which was not correlated with (1)O(2) quantum yield of the nanoparticles. Other parameters are involved and in particular the surface and shape of the nanoparticles which influence the pathway of endocytosis. Functionalization with mannose was necessary to obtain the best results with PDT due to an active endocytosis of mannose-functionalized nanoparticles. The quantity of mannose on the surface should be carefully adjusted as a too high amount of mannose impairs the phototoxicity of the nanoparticles. Fluorescein was also encapsulated in MCM-41 type MSN in order to localize the nanoparticles in the organelles of the cells by confocal microscopy. The MSN were localized in lysosomes after active endocytosis by mannose receptors.

Mannose-targeted mesoporous silica nanoparticles for photodynamic therapy.

Functionalisation of MSN with mannose for PDT applications dramatically improved the efficiency of PDT on breast cancer cells.

Thermal and electrochemically assisted Pd-Cl bond cleavage in the d9-d9 Pd2dppm2Cl2 complex by Pd3 dppm3COn+ clusters (n = 2, 1, 0).

A new aspect of reactivity of the cluster [Pd3(dppm)3(micro3-CO)]n+, ([Pd3]n+, n = 2, 1, 0) with the low-valent metal-metal-bonded Pd2(dppm)2Cl2 dimer (Pd2Cl2) was observed using electrochemical techniques. The direct reaction between [Pd3]2+ and Pd2Cl2 in THF at room temperature leads to the known [Pd3(dppm)3(micro3-CO)(Cl)]+ ([Pd3(Cl)]+) adduct and the monocationic species Pd2(dppm)2Cl+ (very likely as Pd2(dppm)2(Cl)(THF)+, [Pd2Cl]+) as unambiguously demonstrated by UV-vis and 31P NMR spectroscopy. In this case, [Pd3]2+ acts as a strong Lewis acid toward the labile Cl- ion, which weakly dissociates from Pd2Cl2 (i.e., dissociative mechanism). Host-guest interactions between [Pd3]2+ and Pd2Cl2 seem unlikely on the basis of computer modeling because of the strong screening of the Pd-Cl fragment by the Ph-dppm groups in Pd2Cl2. The electrogenerated clusters [Pd3]+ and [Pd3]0 also react with Pd2Cl2 to unexpectedly form the same oxidized adduct, [Pd3(Cl)]+, despite the known very low affinity of [Pd3]+ and [Pd3]0 toward Cl- ions. The reduced biproduct in this case is the highly reactive zerovalent species "Pd2(dppm)2" or "Pd(dppm)" as demonstrated by quenching with CDCl3 (forming the well-known complex Pd(dppm)Cl2) or in presence of dppm (forming the known Pd2(dppm)3 d10-d10 dimer). To bring these halide-electron exchange reactions to completion for [Pd3]+ and [Pd3]0, 0.5 and 1.0 equiv of Pd2Cl2 are necessary, respectively, accounting perfectly for the number of exchanged electrons. The presence of a partial dissociation of Pd2Cl2 into the Cl- ion and the monocation [Pd2Cl]+, which is easier to reduce than Pd2Cl2, is suggested to explain the overall electrochemical results. It is possible to regulate the nature of the species formed from Pd2Cl2 by changing the state of charge of the title cluster.

Stoichiometric and catalytic activation of the alpha- and beta-2,3,4-tri-O-acetyl-5-thioxylopyranosyl bromide inside the cavity of the Pd3(dppm)3(CO)2+ cluster.

The title cluster (Pd(3)(2+)) exhibits a pronounced affinity for Br(-) ions to form the very stable Pd(3)(Br)(+) adduct. Upon a 2-electron reduction, a dissociative process occurs generating Pd(3)(0) and eliminating Br(-) according to an ECE mechanism (electrochemical, chemical, electrochemical). At a lower temperature (i.e. -20 degrees C), both ECE and EEC processes operate. This cluster also activates the C-Br bond, and this work deals with the reactivity of Pd(3)(2+) with 2,3,4-tri-O-acetyl-5-thioxylopyranosyl bromide (Xyl-Br), both alpha- and beta-isomers. The observed inorganic product is Pd(3)(Br)(+) again, and it is formed according to an associative mechanism involving Pd(3)(2+).Xyl-Br host-guest assemblies. In an attempt to render the C-Br bond activation catalytic, these species are investigated under reduction conditions at two potentials (-0.9 and -1.25 V vs SCE). In the former case, the major product is Xyl-H, issued from a radical intermediate Xyl(*) abstracting an H atom from the solvent. Evidence for Xyl(*) is provided by the trapping with TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) and DMPO (5,5'-dimethylpyrroline-N-oxyde). In the second case, only one product is observed, 3,4-di-O-acetyl-5-thioxylal, which is issued from the Xyl(-)() intermediate anion.

New efficient electrochemical synthesis of 1,5-dithioxylopyranosides in the presence of a sacrificial anode.

Electroreduction of the disulfide derivative RSSR (5, R= [bond]C(6)H(4)[bond]CO[bond]C(6)H(4)[bond]CN) on a mercury pool or a carbon gauze electrode in the presence of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide (1), using a sacrificial zinc anode gave an alpha,beta anomeric mixture of [4-(4-cyanobenzoylphenyl)] 2,3,4-tri-O-acetyl-1,5-dithio-D-xylopyranoside (6) in 40-70% yield, according to the experimental conditions used (nature of solvent, electrolyte salt, and temperature). High selectivity favouring the alpha anomer of 6 is observed starting from the alpha anomer of 1. Mechanistic aspects are discussed.

Thermodynamic and kinetic control over the reduction mechanism of the Pd(3)(dppm)(3)(CO)(I)(+) cluster.

The reduction mechanism of the title cluster has been investigated by means of cyclic voltammetry (CV), rotating disk electrode (RDE) voltammetry, and coulometry. The 2-electron reduction proceeds via two routes simultaneously. The first one involves two 1-electron reduction steps, followed by an iodide elimination to form the neutral Pd(3)(dppm)(3)(CO)(0) cluster (EEC mechanism). The second one is a 1-electron reduction process, followed by an iodide elimination, then by a second 1-electron step (ECE mechanism) to generate the same final product. Control over these two competitive mechanisms can be achieved by changing temperature, solvent polarity, iodide concentration, or sweep rate. The reoxidation of the Pd(3)(dppm)(3)(CO)(0) cluster in the presence of iodide proceeds via a pure ECE pathway. The overall results were interpreted with a six-member square scheme, and the cyclic and RDE voltammograms were simulated, in order to extract the reaction rate and equilibrium constants for iodide exchange for all three Pd(3)(dppm)(3)(CO)(I)(n)() (n = +1, 0, -1) adducts.