A Chemical Strategy for the Relaxivity Enhancement of GdIII Chelates Anchored on Mesoporous Silica Nanoparticles

Functionalised MCM‐41 mesoporous silica nanoparticles were used as carriers of Gd^III complexes for the development of nanosized magnetic resonance imaging contrast agents. Three Gd^III complexes based on the 1,4,7,10‐tetraazacyclododecane scaffold (DOTA; monoamide‐, DOTA‐ and DO3A‐like complexes) with distinct structural and magnetic properties were anchored on the silica nanoparticles functionalised with NH₂ groups. The interaction between Gd^III chelates and surface functional groups markedly influenced the relaxometric properties of the hybrid materials, and were deeply modified passing from ionic ? NH₃⁺ to neutral amides. A complete study of the structural, textural and surface properties together with a full ¹H relaxometric characterisation of these hybrid materials before and after surface modification was carried out. Particularly for the anionic complex 2 attached to MCM‐41, an impressive increase in relaxivity (r_1p) was observed (from 20.3 to 37.8 mM ^?1 s^?1, 86.2 % enhancement at 20 MHz and 310 K), mainly due to a threefold faster water exchange rate after acetylation of the surface ? NH₃⁺ ions. This high r_1p value, coupled with the large molar amount of grafted 2 onto the silica nanoparticles gives rise to a value of relaxivity per particle of 29 500 mM ^?1 s^?1, which possibly allows it to be used in molecular imaging procedures. Smaller changes were observed for the hybrid materials based on neutral 1 and 3 complexes. In fact, whereas 1 shows a weak interaction with the surface and acetylation induced only some decrease of the local rotation, complex 3 appears to be involved in a strong interaction with surface silanols. This results in the displacement of a coordinated water molecule and in a decrease of the accessibility of the solvent to the metal centre, which is unaffected by the modification of ammonium ions to neutral amides.     

Amphiphilic Ditopic Bis‐Aqua Gd‐AAZTA‐like Complexes Enhance Relaxivity of Lipidic MRI Nanoprobes

Two amphiphilic mono‐ and dimeric GdAAZTA‐like chelates composed of stable bis‐aquo Gd^III complexes (q=2) linked to one (for the monomer) or two dodecyl aliphatic chains (for the dimer) were synthesized. Both chelates showed high relaxivity when incorporated into the lipid bilayer of liposomes or after interaction with human serum albumin (HSA). The ditopic complex shows a significantly decreased internal motion relative to the monomeric complex, associated with an enhanced relaxivity (r₁≈60 mm ^?1 s^?1, at 30 MHz and 310 K). The presence of two metal‐bound water molecules in fast exchange and the restricted rotational freedom make the relaxivity of this system the highest measured for paramagnetic liposomes.     

Drug Encapsulation and Release by Mesoporous Silica Nanoparticles: The Effect of Surface Functional Groups

Mesoporous silica nanoparticles (MSNPs) have been widely used as drug carriers for stimuli‐responsive drug delivery. Herein, a catalysis screening technique was adopted for analyzing the effects of chain length, terminal group, and density of disulfide‐appended functional ligands on the surface of MSNPs on drug‐loading capacity and glutathione‐triggered drug‐release kinetics. The ligand with an intermediate length (5 carbon atoms) and a bulky terminal group (cyclohexyl) that complexes with theβ‐cyclodextrin ring showed the highest drug loading capacity as well as good release kinetics. In addition, decreasing the surface coverage of the functional ligands led to an enhancement in drug release. In vitro drug‐delivery experiments on a melanoma cell line (B16‐F10) by using the functionalized MSNPs further supported the conclusion. The results obtained may serve as a general guide for developing more effective MSNP systems for drug delivery.     

Modification of Amorphous Mesoporous Zirconia Nanoparticles with Bisphosphonic Acids: A Straightforward Approach for Tailoring the Surface Properties of the Nanoparticles

The use of readily prepared bisphosphonic acids obtained in few steps through a thio-Michael addition of commercially available thiols on tetraethyl vinylidenebisphosphonate enables the straightforward surface modification of amorphous mesoporous zirconia nanoparticles. Simple stirring of the zirconia nanoparticles in a buffered aqueous solution of the proper bisphosphonic acid leads to the surface functionalization of the nanoparticles with different kinds of functional groups, charge and hydrophobic properties. Formation of both chemisorbed and physisorbed layers of the bisphosphonic acid take place, observing after extensive washing a grafting density of 1.1 molecules/nm² with negligible release in neutral or acidic pH conditions, demonstrating stronger loading compared to monophosphonate derivatives. The modified nanoparticles were characterized by IR, XPS, ζ-potential analysis to investigate the loading of the bisphosphonic acid, FE-SEM to investigate the size and morphologies of the nanoparticles and ³¹P and ¹H MAS NMR to investigate the coordination motif of the phosphonate units on the surface. All these analytical techniques demonstrated the strong affinity of the bisphosphonic moiety for the Zr(IV) metal centers. The functionalization with bisphosphonic acids represents a straightforward covalent approach for tailoring the superficial properties of zirconia nanoparticles, much straightforward compared the classic use of trisalkoxysilane or trichlorosilane reagents typically employed for the functionalization of silica and metal oxide nanoparticles. Extension of the use of bisphosphonates to other metal oxide nanoparticles is advisable.     

Bifunctional Cage‐Type Cubic Mesoporous Silica SBA‐1 Nanoparticles for Selective Adsorption of Dyes

Bifunctional SBA‐1 mesoporous silica nanoparticles (MSNs) with carboxylic acid and amino groups (denoted as CNS‐10‐10) have been successfully synthesized, characterized, and employed as adsorbents for dye removal. Adsorbent CNS‐10‐10 shows high affinity towards cationic and anionic dyes in a wide pH range, and exhibits selective dye removal of a two‐dye mixture system of cationic methylene blue and anionic eosin Y. By changing the pH of the medium, the selectivity of the adsorption behavior can be easily modulated. For comparison purposes, the counterparts, that is, pure silica SBA‐1 MSNs (CS‐0) and those with either carboxylic acid or amino functional groups (denoted as CS‐10 and NS‐10, respectively) were also prepared to evaluate their dye‐adsorption behaviors. As revealed by the zeta‐potential measurements, the electrostatic interaction between the adsorbent surface and the dye molecule plays an important role in the adsorption mechanism. Adsorbent CNS‐10‐10 can be easily regenerated and reused, and maintains its adsorption efficiency up to 80 % after four cycles.     

Chemical Design of Nuclear‐Targeting Mesoporous Silica Nanoparticles for Intra‐nuclear Drug Delivery

Targeted drug delivery has been widely explored for efficient tumor therapy with desired efficacy but minimized side effects. It is widely known that large numbers of DNA‐toxins, such as doxorubicin, genes, reactive oxygen species, serving as therapeutic agents, can result in maximized therapeutic effects via the interaction directly with DNA helix. So after cellular uptake, these agents should be further delivered into cell nuclei to play their essential roles in damaging the DNA helix in cancer cells. Here, we demonstrate the first paradigm established in our laboratory in developing nuclear‐targeted drug delivery systems (DDSs) based on MSNs for enhanced therapeutic efficiency in the hope of speeding their translation into the clinics. Firstly, nuclear‐targeting DDSs based on MSNs, capable of intranuclear accumulation and drug release therein, were designed and constructed for the first time, resulting in much enhanced anticancer effects both in vitro and in vivo. Such an MSNs‐based and nuclear‐targeted drug/agent delivery strategy was further applied to overcome multidrug resistance (MDR) of malignant tumors, intra‐nuclearly deliver therapeutic genes, photosensitizers, radio‐enhancement agents and photothermal agents to realize efficient gene therapy, photodynamic therapy, radiation therapy and photothermal therapy, respectively.     

Photochemical Preparation of Nanoparticles of Ag in Aqueous-Alcoholic Solutions and on the Surface of Mesoporous Silica

Stable nanoparticle colloids of silver were obtained by irradiation of aqueous-alcoholic solutions of AgNO₃ in the presence of mesoporous SiO₂ powder and films modified with benzophenone (BP/SiO₂). Colloidal solutions of Ludox silica were used to stabilize the photochemically produced nanoparticles of silver in solution. Formation of nanoparticles of Ag on the surface of mesoporous silica occurred on irradiation of SiO₂ modified with silver ions (Ag⁺/SiO₂) in the presence of benzophenone solution.__________Translated from Teoreticheskaya i Eksperimental’naya Khimiya, Vol. 41, No. 2, pp. 100–104, March–April, 2005.     

Acetylcholinesterase‐capped Mesoporous Silica Nanoparticles Controlled by the Presence of Inhibitors

Two different acetylcholinesterase (AChE)‐capped mesoporous silica nanoparticles (MSNs), S1‐AChE and S2‐AChE , were prepared and characterized. MSNs were loaded with rhodamine B and the external surface was functionalized with either pyridostigmine derivative P1 (to yield solid S1 ) or neostigmine derivative P2 (to obtain S2 ). The final capped materials were obtained by coordinating grafted P1 or P2 with AChE′s active sites (to give S1‐AChE and S2‐AChE , respectively). Both materials were able to release rhodamine B in the presence of diisopropylfluorophosphate (DFP) or neostigmine in a concentration‐dependent manner via the competitive displacement of AChE through DFP and neostigmine coordination with the AChE‘s active sites. The responses of S1‐AChE and S2‐AChE were also tested with other enzyme inhibitors and substrates. These studies suggest that S1‐AChE nanoparticles can be used for the selective detection of nerve agent simulant DFP and paraoxon.     

High Surface Area Mesoporous Silica Nanoparticles with Tunable Size in the Sub-Micrometer Regime: Insights on the Size and Porosity Control Mechanisms

Mesoporous silica nanostructures (MSNs) attract high interest due to their unique and tunable physical chemical features, including high specific surface area and large pore volume, that hold a great potential in a variety of fields, i.e., adsorption, catalysis, and biomedicine. An essential feature for biomedical application of MSNs is limiting MSN size in the sub-micrometer regime to control uptake and cell viability. However, careful size tuning in such a regime remains still challenging. We aim to tackling this issue by developing two synthetic procedures for MSN size modulation, performed in homogenous aqueous/ethanol solution or two-phase aqueous/ethyl acetate system. Both approaches make use of tetraethyl orthosilicate as precursor, in the presence of cetyltrimethylammonium bromide, as structure-directing agent, and NaOH, as base-catalyst. NaOH catalyzed syntheses usually require high temperature (>80 °C) and large reaction medium volume to trigger MSN formation and limit aggregation. Here, a successful modulation of MSNs size from 40 up to 150 nm is demonstrated to be achieved by purposely balancing synthesis conditions, being able, in addition, to keep reaction temperature not higher than 50 °C (30 °C and 50 °C, respectively) and reaction mixture volume low. Through a comprehensive and in-depth systematic morphological and structural investigation, the mechanism and kinetics that sustain the control of MSNs size in such low dimensional regime are defined, highlighting that modulation of size and pores of the structures are mainly mediated by base concentration, reaction time and temperature and ageing, for the homogenous phase approach, and by temperature for the two-phase synthesis. Finally, an in vitro study is performed on bEnd.3 cells to investigate on the cytotoxicity of the MNSs.     

Differential Effects of Polymer‐Surface Decoration on Drug Delivery,Cellular Retention,and Action Mechanisms of Functionalized Mesoporous Silica Nanoparticles

Polymer‐surface decoration has been found to be an effective strategy to enhance the biological activities of nanomedicine. Herein, three different types of polymers with a cancer‐targeting ligand Arg‐Gly‐Asp peptide (RGD) have been used to decorate mesoporous silica nanoparticles (MSNs) and the functionalized nanosystems were used as drug carriers of oxaliplatin (OXA). The results showed that polymer‐surface decoration of the MSNs nanosystem by poly(ethylene glycol) (PEG) and polyethyleneimine (PEI) significantly enhanced the anticancer efficacy of OXA, which was much higher than that of chitosan (CTS). This effect was closely related to the enhancement of the cellular uptake and cellular drug retention. Moreover, PEI@MSNs‐OXA possessed excellent advantages in penetrating ability and inhibitory effects on SW480 spheroids that were used to simulate the in vivo tumor environments. Therefore, this study provides useful information for the rational design of a cancer‐targeted MSNs nanosystem with polymer‐surface decoration.     

Comprehensive Evaluation of the Physicochemical Properties of LnIII Complexes of Aminoethyl‐DO3A as pH‐Responsive T1‐MRI Contrast Agents

N‐Substituted aminoethyl groups were attached to 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acid (DO3A) with the aim to design pH‐responsive Ln^III complexes based on the pH‐dependent on/off ligation of the amine nitrogen to the metal ion. The following ligands were synthesized: AE ‐ DO3A (aminoethyl‐DO3A), MAE ‐ DO3A (N‐methylaminoethyl‐DO3A), DMAE ‐ DO3A (N,N‐dimethylaminoethyl‐DO3A) and MEM ‐ AE ‐ DO3A (N‐methoxyethyl‐N‐methylaminoethyl‐DO3A). The physicochemical properties of the Ln^III complexes were investigated for the evaluation of their potential applicability as magnetic resonance imaging (MRI) contrast agents. In particular, a ¹H and ¹⁷O NMR relaxometric study was carried out for these Gd^III complexes at two different pH values: at basic pH (pendant amino group coordinated to the metal centre) and at acidic pH (protonated amine, not interacting with the metal ion). Eu^III complexes allow one to estimate the number of inner‐sphere water molecules through luminescence lifetime measurements and obtain some structural information through variable‐temperature (VT) high‐resolution ¹H NMR studies. Equilibria between differently hydrated species were found for most of the complexes at both acidic and basic pH. The thermodynamic stability of Ca^II, Zn^II, Cu^II and Ln^III complexes and kinetics of formation and dissociation reactions of Ln^III complexes of AE ‐ DO3A and DMAE ‐ DO3A were investigated showing stabilities comparable to currently approved Gd^III‐based CAs. In detail, higher total basicity (Σlog K_i^H) and higher stability constants of Ln^III complexes were found for AE ‐ DO3A with respect to DMAE ‐ DO3A (i.e., log K_{Gd‐ AE‐DO3A} =22.40 and log K_{Gd‐ DMAE‐DO3A} =20.56). The transmetallation reactions of Gd^III complexes are very slow (Gd‐ AE ‐ DO3A : t_1/2=2.7×10⁴ h; Gd‐ DMAE ‐ DO3A : 1.1×10⁵ h at pH 7.4 and 298 K) and occur through proton‐assisted dissociation.     

A Selective Fluoroionophore Based on BODIPY‐functionalized Magnetic Silica Nanoparticles: Removal of Pb2+ from Human Blood

Get the lead out : The title fluorescence receptor exhibits a high affinity and selectivity for Pb²⁺ over competing metal ions in water (see picture) with an overall emission change of approximately 8‐fold at the emission maximum for Pb²⁺. The fluorescence receptor can remove 96 % of 100 ppb Pb²⁺ from human blood, and can be useful and effective for the selective and rapid removal of Pb²⁺ in vivo.

     

Dual Soft‐Template System Based on Colloidal Chemistry for the Synthesis of Hollow Mesoporous Silica Nanoparticles

A new dual soft‐template system comprising the asymmetric triblock copolymer poly(styrene‐b‐2‐vinyl pyridine‐b‐ethylene oxide) (PS‐b‐P2VP‐b‐PEO) and the cationic surfactant cetyltrimethylammonium bromide (CTAB) is used to synthesize hollow mesoporous silica (HMS) nanoparticles with a center void of around 17 nm. The stable PS‐b‐P2VP‐b‐PEO polymeric micelle serves as a template to form the hollow interior, while the CTAB surfactant serves as a template to form mesopores in the shells. The P2VP blocks on the polymeric micelles can interact with positively charged CTA⁺ ions via negatively charged hydrolyzed silica species. Thus, dual soft‐templates clearly have different roles for the preparation of the HMS nanoparticles. Interestingly, the thicknesses of the mesoporous shell are tunable by varying the amounts of TEOS and CTAB. This study provides new insight on the preparation of mesoporous materials based on colloidal chemistry.     

A Nanocomposite Chitosan Based on Ferrocene‐Modified Silica Nanoparticles and Carbon Nanotubes for Biosensor Application

A novel amperometric biosensor for glucose was developed by entrapping glucose oxidase (GOD) in a chitosan composite doped with ferrocene monocarboxylic acid‐aminated silica nanoparticles conjugate (FMC‐ASNPs) and multiwall carbon nanotubes (MWNTs). The entrapped FMC‐ASNPs conjugate performed excellent redox electrochemistry and the presence of MWNTs improved the conductivity of the composite film. This matrix showed a biocompatible microenvironment for retaining the native activity of the entrapped GOD and was in favor of the accessibility of substrate to the active site of GOD, thus the affinity to substrates is improved greatly. Under optimal conditions this biosensor was able to detect glucose with a detection limit of 10 μM (S/N=3) in the linear range of 0.04 to 6.5 mM. The proximity of these three components FMC‐ASNPs, MWNTs and GOD enhanced the electron transfer between the film and electrode. This composite film can be extended to immobilize other enzymes and biomolecules, which will greatly facilitate the development of biosensors and other bioelectrochemical devices.     

Highly Luminescent Colloidal Eu3+‐Doped KZnF3 Nanoparticles for the Selective and Sensitive Detection of CuII Ions

This article describes a green synthetic approach to prepare water dispersible perovskite‐type Eu³⁺‐doped KZnF₃ nanoparticles, carried out using environmentally friendly microwave irradiation at low temperature (85 °C) with water as a solvent. Incorporation of Eu³⁺ ions into the KZnF₃ matrix is confirmed by strong red emission upon ultraviolet (UV) excitation of the nanoparticles. The nanoparticles are coated with poly(acrylic acid) (PAA), which enhances the dispersibility of the nanoparticles in hydrophilic solvents. The strong red emission from Eu³⁺ ions is selectively quenched upon addition of Cu^II ions, thus making the nanoparticles a potential Cu^II sensing material. This sensing ability is highly reversible by the addition of ethylenediaminetetraacetic acid (EDTA), with recovery of almost 90 % of the luminescence. If the nanoparticles are strongly attached to a positively charged surface, dipping the surface in a Cu^II solution leads to the quenching of Eu³⁺ luminescence, which can be recovered after dipping in an EDTA solution. This process can be repeated for more than five cycles with only a slight decrease in the sensing ability. In addition to sensing, the strong luminescence from Eu³⁺‐doped KZnF₃ nanoparticles could be used as a tool for bioimaging.     

Lanthanide(III) Complexes of 4,10‐Bis(phosphonomethyl)‐1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid (trans‐H6do2a2p) in Solution and in the Solid State: Structural Studies Along the Series

Complexes of 4,10‐bis(phosphonomethyl)‐1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid (trans‐H₆do2a2p, H₆ L ) with transition metal and lanthanide(III) ions were investigated. The stability constant values of the divalent and trivalent metal‐ion complexes are between the corresponding values of H₄dota and H₈dotp complexes, as a consequence of the ligand basicity. The solid‐state structures of the ligand and of nine lanthanide(III) complexes were determined by X‐ray diffraction. All the complexes are present as twisted‐square‐antiprismatic isomers and their structures can be divided into two series. The first one involves nona‐coordinated complexes of the large lanthanide(III) ions (Ce, Nd, Sm) with a coordinated water molecule. In the series of Sm, Eu, Tb, Dy, Er, Yb, the complexes are octa‐coordinated only by the ligand donor atoms and their coordination cages are more irregular. The formation kinetics and the acid‐assisted dissociation of several Ln^III–H₆ L complexes were investigated at different temperatures and compared with analogous data for complexes of other dota‐like ligands. The [Ce( L )(H₂O)]^3? complex is the most kinetically inert among complexes of the investigated lanthanide(III) ions (Ce, Eu, Gd, Yb). Among mixed phosphonate–acetate dota analogues, kinetic inertness of the cerium(III) complexes is increased with a higher number of phosphonate arms in the ligand, whereas the opposite is true for europium(III) complexes. According to the ¹H NMR spectroscopic pseudo‐contact shifts for the Ce–Eu and Tb–Yb series, the solution structures of the complexes reflect the structures of the [Ce(H L )(H₂O)]^2? and [Yb(H L )]^2? anions, respectively, found in the solid state. However, these solution NMR spectroscopic studies showed that there is no unambiguous relation between ³¹P/¹H lanthanide‐induced shift (LIS) values and coordination of water in the complexes; the values rather express a relative position of the central ions between the N₄ and O₄ planes.