Lectin-gated and glycan functionalized mesoporous silica nanocontainers for targeting cancer cells overexpressing Lewis X antigen.

Gated mesoporous silica nanoparticles can deliver payload upon the application of a predefined stimulus, and therefore are promising drug delivery systems. Despite their important role, relatively low emphasis has been placed on the design of gating systems that actively target carbohydrate tumor cell membrane receptors. We describe herein a new Lewis X (Lex) antigen-targeted delivery system comprising mesoporous silica nanoparticles (MSNs) loaded with ATTO 430LS dye, functionalized with a Lex derivative (1) and capped with a fucose-specific carbohydrate-binding protein (Aleuria aurantia lectin (AAL)). This design takes advantage of the affinity of AAL for Lex overexpressed receptors in certain cancer cells. In the proximity of the cells, AAL is detached from MSNs to bind Lex, and selectins in the cells bind Lex in the gated MSNs, thereby inducing cargo delivery. Gated MSNs are nontoxic to colon cancer DLD-1 cells, and ATTO 430LS dye delivered correlated with the amount of Lex antigen overexpressed at the DLD-1 cell surface. This is one of the few examples of MSNs using biologically relevant glycans for both capping (via interaction with AAL) and targeting (via interaction with overexpressed Lex at the cell membrane).

Gold glyconanoparticles coupled to listeriolysin O 91-99 peptide serve as adjuvant therapy against melanoma.

Dendritic cell-based (DC-based) vaccines are promising immunotherapies for cancer. However, several factors, such as the lack of efficient targeted delivery and the sources and types of DCs, have limited the efficacy of DCs and their clinical potential. We propose an alternative nanotechnology-based vaccine platform with antibacterial prophylactic abilities that uses gold glyconanoparticles coupled to listeriolysin O 91-99 peptide (GNP-LLO91-99), which acts as a novel adjuvant for cancer therapy. GNP-LLO91-99, when used to vaccinate mice, exhibited dual antitumour activities, namely, the inhibition of tumour migration and growth and adjuvant activity for recruiting and activating DCs, including those from melanoma patients. GNP-LLO91-99 nanoparticles caused tumour apoptosis and induced antigen- and melanoma-specific cytotoxic Th1 responses (P ≤ 0.5). We propose this adjuvant nanotherapy for preventing the progression of the first stages of melanoma.

Kinetic approach for the study of noncovalent interaction between [Ru(NH3)5pz]2+ and gold nanoparticles.

Gold nanoparticles (AuNPs) capped with N-(2-mercaptopropionyl)glycine have been used to study the strength and character of the binding of a cationic metal complex, [Ru(NH3)5pz]2+ (pz = pyrazine), at pH = 8, to these nanoparticles. The strength of the binding has been studied using a kinetic approach consisting of the study of the kinetics of the oxidation of this ruthenium complex by S2O82- at different NaCl concentrations. When the ionic strength increases, the strength of the binding decreases, as a consequence of the partial neutralization of the charge on the AuNPs which, at pH = 8, has the tiopronin residue negatively charged. The increase of the ionic strength also produces a change in the character of the binding, which changes from anticooperative to noncooperative when the ionic strength increases. The nonelectrostatic and electrostatic components of the free energy of binding are determined. From the latter, we have obtained the values of the electrostatic potential differences at the AuNPs/solutions interface.

Fe impurities weaken the ferromagnetic behavior in Au nanoparticles.

In this Letter, we report on a crucial experiment showing that magnetic impurities reduce the ferromagnetic order temperature in thiol-capped Au glyconanoparticles (GNPs). The spontaneous magnetization of AuFe GNPs exhibits a fast decrease with temperature that contrasts with the almost constant value of the magnetization observed in Au NPs. Moreover, hysteresis disappears below 300 K. Both features indicate that Fe impurities reduce the high local anisotropy field responsible for the ferromagnetic behavior in Au GNPs. As a consequence, the amazing ferromagnetism in Au NPs should not be associated with the presence of magnetic impurities.

Gold nanoparticles with different capping systems: an electronic and structural XAS analysis.

Gold nanoparticles (NPs) have been prepared with three different capping systems: a tetralkylammonium salt, an alkanethiol, and a thiol-derivatized neoglycoconjugate. Also gold NPs supported on a porous TiO(2) substrate have been investigated. X-ray absorption spectroscopy (XAS) has been used to determine the electronic behavior of the different capped/supported systems regarding the electron/hole density of d states. Surface and size effects, as well as the role of the microstructure, have been also studied through an exhaustive analysis of the EXAFS (extended X-ray absorption fine structure) data. Very small gold NPs functionalized with thiol-derivatized molecules show an increase in d-hole density at the gold site due to Au-S charge transfer. This effect is overcoming size effects (which lead to a slightly increase of the d-electron density) for high S:Au atomic ratios and core-shell microstructures where an atomically abrupt Au-S interface likely does not exist. It has been also shown that thiol functionalization of very small gold NPs is introducing a strong distortion as compared to fcc order. To the contrary, electron transfer from reduced support oxides to gold NPs can produce a higher increase in d-electron density at the gold site, as compared to naked gold clusters.

Permanent magnetism, magnetic anisotropy, and hysteresis of thiol-capped gold nanoparticles.

We report on the experimental observation of magnetic hysteresis up to room temperature in thiol-capped Au nanoparticles with 1.4 nm size. The coercive field ranges from 860 Oe at 5 K to 250 Oe at 300 K. It is estimated that the Au atoms exhibit a magnetic moment of mu=0.036mu(B). However, Au nanoparticles with similar size but stabilized by means of a surfactant, i.e., weak interaction between protective molecules and Au surface atoms, are diamagnetic, as bulk Au samples are. The apparent ferromagnetism is consequently associated with 5d localized holes generated through Au-S bonds. These holes give rise to localized magnetic moments that are frozen in due to the combination of the high spin-orbit coupling (1.5 eV) of gold and the symmetry reduction associated with two types of bonding: Au-Au and Au-S.

Adhesion Forces between Lewis(X) Determinant Antigens as Measured by Atomic Force Microscopy.

The adhesion forces between individual molecules of Lewis(X) trisaccharide antigen (Le(X) ) have been measured in water and in calcium solution by using atomic force microscopy (AFM, see graph). These results demonstrate the self-recognition capability of this antigen, and reinforce the hypothesis that carbohydrate-carbohydrate interaction could be considered as the first step in the cell-adhesion process in nature.

Synthesis and investigation of the possible insulin-like activity of 1D-4-O- and 1D-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-myo-inositol 1-phosphate and 1D-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-myo-inositol 1,2-(cyclic phosphate).

The synthesis of the glycosyl-myo-inositol 1-phosphates 1 and 2 and of the glycosyl-myo-inositol 1,2-(cyclic phosphate) 3, starting from previously synthesized intermediates, is reported. Compound 3 was found to display proliferative effects on the early developing inner ear of chick embryo.

The preparation of intermediates for the synthesis of 1D-myo-inositol 1,4,5-trisphosphate, a second messenger for signal transduction in cells.

Racemic 1,2,4-tri-O-benzyl-5,6-O-isopropylidene-myo-inositol was prepared by a new route involving crotyl (but-2-enyl) ethers and converted into the (-)-omega-camphanates to give the pure crystalline 1L-diastereoisomer and the chirally impure, syrupy 1D-diastereoisomer. The latter was converted via the 1-O-allyl or 1-O-p-methoxybenzyl ethers into chirally pure 1D-2,3,6-tri-O-benzyl-myo-inositol [required as an intermediate for the synthesis of 1D-myo-inositol 1,4,5-trisphosphate (1,4,5-IP3)], which was also prepared by de-p-methoxybenzylation of 1D-2,3,6-tri-O-benzyl-1,5-di-O-p-methoxybenzyl-myo-inositol. Racemic 2,4-di-O-benzyl-5,6-O-isopropylidene-1-O-p-methoxybenzyl-myo-inositol was prepared in a similar way to the analogous tribenzyl ether (using crotyl ethers) and the omega-camphanate esters behaved similarly, allowing efficient resolution by crystallisation of the (-)- and (+)-omega-camphanates. Racemic 1,2,4-tri-O-allyl-3-O-(but-2-enyl)-myo-inositol was resolved via the (-)-omega-camphanates and was also converted into 1,2,4-tri-O-(cis-prop-1-enyl)-myo-inositol, an alternative intermediate for the synthesis of 1,4,5-IP3.