FI125400B - Composite particles and process for their preparation - Google Patents

Description

COMPOSITE PARTICLES AND METHOD OF PRODUCING THE SAME

Background of the Invention

Field of the Invention

The present invention relates to composite particles. In particular, the invention concerns shell-core-structures formed by an inorganic core having a mesoporous shell covering at least a part of the core. Described herein is also a method of producing shell-core-structures as well as uses of the particles.

Description of Related Art

Composite materials are designed to synergistically combine the beneficiary properties of two or more material classes. For example, by integrating mesoporous silica with nanocrystals of other inorganic materials uniform core-shell composite nanostructures can be obtained with great potential in various biotechnological and biomedical fields. Additional advantages can be added by creating composites with further inorganic dimensions or properties, for instance mesoporous silica nanocomposite materials with magnetic properties. Such materials are useful in the production of, for example, novel nanodevices for cellular and diagnostic MR-imaging in vivo, magnetofection, hyperthermia, bioseparation, molecular diagnostics, magnetic-controlled drug release systems and combinations thereof.

The mesoporous silica-coated composite material subject to most extensive research is beyond doubt magnetic, typically ferro- or superparamagnetic iron oxide (SPIO). The magnetic nanoparticles can be incorporated or encapsulated into the mesoporous silica via many fabrication strategies.

Five general synthesis pathways to fabricate magnetic iron oxide/ordered mesoporous silica nanocomposites were recently outlined by Wang et al. (Y. Wang, J. Ren, X. Liu, Y. Wang, Y.Guo, Y. Guo, and G. Lu, J. Coll. Interface Sci., 2008, 326, 158). The third one mentioned by the authors, viz. coating a silica shell around the magnetic iron oxide nanocrystals to form a magnetic-core/silica-shell structure (SPIOAwSiCT), most often yields materials with nanoscale morphology. If the starting mesoporous silica materials/of the synthesis are nanoparticulate, other approaches can be feasible.

The mesoporous layer can be deposited either directly onto the magnetic cores or then the magnetic crystals can be pre-coated with a dense silica layer. The thus formed solid silica layer both may protect the underlying iron oxide from acidic environments (in which it would dissolve) as well as facilitate the self-assembly of the cationic surfactant templates on the negatively charged silica surface. Thus, a typical synthesis route to mesoporous coatings, the cores being pre-coated or not, is to apply an MCM-41 type alkaline synthesis in a diluted form using the cationic structure-directing agent CTAB to facilitate these interactions. A few recent studies have also attempted to use neutral surfactants, such as those used as templates for the synthesis of large-pore SBA-15 and related materials, but generally with aggregated morphologies as a result, thus hampering their cellular or in vivo applications.

Currently, much focus is placed on attempts to increase the pore sizes of all-silica mesoporous nanoparticles (MSNPs). Generally, if the pore size is too small, the biomolecule will be adsorbed only on the outside particle surface, yielding significantly low loadings, and will hence not benefit from the shelter of the mesopores, as recently reviewed by S. Hudson, J. Cooney and E. Magner (Proteins in Mesoporous Silicates. Angew. Chem. Int. Ed. 2008, 47, 8582-8594. A particular driver for this development is the fact that the typical pore size of MCM-41-type materials, also valid for SPT0@mSi02 coatings, is around 3 nm. Pores having this pore size are capable of hosting small-molecular drugs, but they are not large enough to efficiently encapsulate most macromolecular substances, such as proteins (for example enzymes, antibodies/FAb, polypeptides and biotech drugs) or nucleic acids. This is because even very small proteins such as lysozymes possess a hydrodynamic diameter of about 3.6 nm. For these types of molecules, the protection provided by the ceramic carrier matrix would still be of utmost importance in delivery, and efficient accommodation throughout the whole accessible pore system would ensure high loadings both in delivery and separation.

Pore expansion is therefore of central interest for many MSNP systems including coatings. Whereas pore expansion is fairly straightforward for regular mesoporous material syntheses, both of the acidic and the basic kind, and it can be achieved by adding auxiliary organic compounds, such as trimethylbenzene (TMB), as pore swelling agent during synthesis, the situation in nanoparticulate syntheses and especially in coating procedures is often made more complicated by the dilute conditions observed, frequently involving co-solvents such as alcohol. The swelling agent is often preferentially dissolved in the co-solvent rather than solubilized in the CTAB micelles.

Alternative approaches have also been suggested, such as “pit corrosion” - deposition of a non-porous amorphous silica layer onto the core with subsequent corrosion using alkalis. This process is not particularly easy to control and does not result in regular mesopores. Also no ordered structures can be produced.

Summary of the Invention

It is an aim of the present invention to provide novel composite particles comprising a shell-core-structure formed by an inorganic core surrounded and covered by a mesoporous shell having an average pore size in the range of about 5 to 10 nm. Such particles are suitable for accommodating molecules having hydrodynamic diameters roughly within that range.

The present composite particles can be produced by a method which comprises the initial steps of - providing inorganic particles having an average diameter of 100 to 1500 nm; - contacting the inorganic particles, in an aqueous alcoholic medium, with a silica source, for example a derivative, e.g. an ester, of orthosilic acid, or a silicate or mixtures thereof, said aqueous medium further containing at least a surfactant and a salt; and - hydrolyzing said silica source with subsequent condensation (silica polymerization) in order to deposit silica together with said surfactant upon the inorganic particles to form a shell-like coating on the particles.

Subsequently, the silica coating is then contacted with a solvent in order to leach at least a part of the surfactant from the coating to provide a mesoporous silica shell on the particles.

The particles such obtained have a coating with average pore sizes in the range of about 5 to 10 nm and they can be used in bio molecule separation and as carriers for drug delivery and gene delivery.

More specifically, the present particles are characterized by what is stated in the characterizing part of claim 1.

The method according to the invention is characterized by what is stated in the characterizing part of claim 5.

The present invention provides considerable advantages. The combination of suitable surfactants (which in the following also are called “structure-directing agents” or “poredirecting agents”) with a leaching/extraction step using a suitable solvent efficiently gives rise to a porous coating on the surfaces of the particles, the coating having pores with sizes in the range of 5 to 10 nm. This cannot be achieved in a similar straight-forward way by alternative approaches. For example, mesoporous nanoparticle-syntheses aiming at swelling “regular” mesopores (3-4 nm size) based on the alkylammonium surfactant system, are disclosed in literature, but cannot be directly applied to a core-shell system due to different mechanisms of formation.

For commercially available products the effective surface area for adsorbing of molecules to be separated is normally determined solely by the particle size. By decreasing the size surface area can be expanded. However, by adding a porous layer of the present kind the effective surface area is drastically increased provided the pore size is not so small that it restricts the adsorption of desired molecules. Particles of the present kind with a porous layer with average pore sizes in the range of about 5 to 10 nm provide for much more efficient surface functionalization than can be achieved on a non-porous surface. In principle, for only achieving enhanced surface functionalization, the porous layer need not be of large-pore size; but if the porous layer is also to be loaded with cargo after functionalization, “regular” sized mesopores are known to be easily blocked by surface functions. Thus the present particles having larger-than-conventional pore sizes provide higher accessibility for guest molecules also after functionalization.

The present inorganic nanoparticles are suitable for bioseparation, drug delivery and gene delivery. Conventionally, with present particle systems, nucleic acids can be adsorbed to the outside of the particle (i.e. on the particle surface). This way the macromolecules may detach during delivery as well as are not well protected from degradative factors in the environment (such as enzymes and pH). The present porous coating provides efficient protection of proteins, nucleic acid and similar biopolymers and biomolecules for use in targeted therapy.

Particles with a magnetic core give additional advantages. First, any drug delivery system (DDS) can be magnetically targeted; second, it can be visualized via MRI; third, the cellular uptake can be enhanced by applying a magnetic field (especially relevant for in vitro studies) aka “magnetofection”.

Further features and advantages of the invention will become evident from the following detailed description.

Brief Description of the Drawings

Figures la to Id are TEM images demonstrating successful deposition of large-pore silica coatings on magnetite beads; and

Figure 2a shows the molecular structure of Rapamycin and Figure 2b shows an adsorption isotherm of Rapamycin to large-pore SPI0@mSi02 as compared to regular SPI0@mSi02 from cyclohexane @RT (b). The line is a guide for the eye.

Description of Presently Preferred Embodiments

As preliminarily discussed above, the present invention provides composite particles comprising a shell-core-structure formed by an inorganic core surrounded by a mesoporous shell which covers at least a part, preferably all of, the surface of the core. The shell has typically an average pore size in the range of 5 to 10 nm, preferably about 7 nm ± 20 %.

The shell comprises an inorganic oxide material, in particular a silicon dioxide or silica material. The pore size of the mesoporous shell is such that the shell is capable of accommodating macromolecules selected from the group of pharmaceuticals, proteins and nucleic acids.

The core has an average diameter of 100 to 1500 nm, in particular about 150 to 1200 nm, preferably about 200 to 1000 nm. The shell has a thickness of about 10 to 250 nm, in particular about 15 to 150 nm. The ratio between the total diameter of the composite particles and the diameter of the core is typically greater than 1.05, in particular greater than 1.1 or 1.15 and up to a maximum ratio of about 5:1, preferably less than 3:1.

The inorganic core is formed by a metal or by a metal oxide, preferably an iron oxide, such as a natural or synthetic magnetite material. Preferably the iron oxide material is a ferro- or superpara-magnetic iron oxide (SPIO). Metallic cores, especially those susceptible to formation of an oxide layer, can also be used.

Typically the composite particles are present in the form of a composition or mixture of a plurality of separate particles of the above indicated kind. The particulate composition can contain other materials and other particles as well. However, it is preferred to have a primarily homogeneous composition which is made up to at least 50 % (by weight), in particular at least 75 %, preferably at least 95 % of the present particles. This is also shown in the TEM images relating to the example below.

In particular, it is preferred that the particles are present in the composition in non-aggregated. This means that the particles are discrete and that individual particles can be identified.

For producing particles of the above kind, a novel method is provided. In the method, inorganic iron oxide particles are coated with silica coating, comprising contacting the silica coating with a suitable solvent for leaching at least a part of the surfactant from the coating.

In particular, composite particles having a shell-core-structure formed by an inorganic core surrounded by a mesoporous shell, are formed by the steps of: - providing inorganic particles having an average diameter of 100 to 1500 nm; - contacting the inorganic particles, in an aqueous alcoholic medium, with a silica source, said aqueous medium further containing at least a surfactant and a salt; and - hydrolyzing said silica source with subsequent condensation (silica polymerization) in order to deposit silica together with said surfactant upon the inorganic particles to form a shell-like coating on the particles.

In the last step of the process the surfactant (structure-directing agent) is removed from the coating. In principle, this can be performed by non-solvent based procedures, for example by calcinations or use of supercritical fluid extraction. In a preferred embodiment of the present invention, the silica coating is however leached using a suitable agent. In particular, the silica coating is contacted with a solvent in order to leach at least a part of the surfactant from the coating to provide a mesoporous silica shell on the particles.

The inorganic particles are slurried in an aqueous alcoholic solution of said surfactant and said salt for a first period of time, and then the silica source is admixed and the mixture thus obtained is stirred for a second period of time. The length of the first period of time is typically about 1 s to 600 min, in particular about 10 s to 300 min, whereas the second period of time (mixing of particles with silica source in alcoholic medium) is generally somewhat longer, extending to about 30 s to 1800 h, in particular about 1 min to 1200 h. The temperature of the process is typically in the range of about 15 to 60 °C, for example about 25 to 50 °C.

After the predetermined time, the reaction mixture can be subjected to aging (hydrothermal treatment) of 1 to about 72 h at elevated temperature of about 60 to 150 °C for example about 65 to 95 °C.

The coating procedure was adapted from a regular mesoporous silica synthesis reported by A.-Y. Chen and S. Cheng, based on an acid-free synthesis route where NaCl salt instead of HC1 serves as the ionic mediator in the formation of the mesophase (A.-Y. Chen and S. Cheng, Acid-free synthesis of mesoporous silica using triblock copolymer as template with the aid of salt and alcohol. Chem. Mater. 19, 2007, 3041-3051).

In a preferred embodiment, surfactants having a micellar diameter in the range of the predetermined pore size are used. Particularly preferably, surfactants of the block-co-polymer type are used.

In one embodiment, the surfactant is nonionic. It can be selected from polyols. Preferably it is selected from the group of amphiphilic triblock copolymers. In particular, the surfactant is selected from nonionic, surfactant polyols having a molecular weight of approximately 5,000 to 25,000 D, in particular about, 10,000 to 15,000 D, for example about 12,500 D.

In one embodiment, any of the above surfactants will work as a pore-directing agent.

In a preferred embodiment, the surfactant or structure-directing agent is a poloxamer selected from triblock copolymers based on poly(alkylene glycol)-poly(alkylene glycol)-poly(alkylene glycol), wherein each alkylene residue is independently the same or different. Suitable polymers of the present kind include poloxamers which are non-ionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Generally, the poloxamer is selected from triblock copolymers based on units ofpoly(ethylene glycol-poly (propylene glycol)-poly(ethylene glycol). Suitable polymers are supplied by BASF and Aldrich.

Thus, for example, Poloxamer P123 can be used. Having a micellar diameter of about 7 nm, it is capable of intrinsically yielding pore sizes of about 7 nm.

Previous attempts to grow mesoporous shells via the Pluronic® templated approach in literature has not lead to discrete particles, but rather regular large-pore mesoporous silica with the cores scattered throughout the matrix.

In an embodiment, the synthesis is performed under neutral or at least essentially neutral conditions; typically pH of 6 to 8, in particular 6.5 to 7.5. This is beneficial from an environmental point of view since no mineral acids or strong bases are used. Another advantage is that core materials of non-precious metals or metal oxides sensitive to corrosion (for example magnetite core material) will be less propone to corrosion or oxidation or degradation of a similar kind due to aging of the material. By contrast, using alternative approaches wherein acids or alkalis are used, magnetite cores are typically subjected to oxidation and corrosion which will impair the magnetic properties of the particles.

Conventionally Poloxamer, e.g. Pluronic®, templated syntheses are typically carried out under acidic conditions, which may lead to at least partial dissolution of the core materials in case the core is an iron oxide. The present synthesis is performed at neutral conditions using salt as a catalyst instead of the acid (or base, in the case of typical alkylammonium surfactant-templated syntheses).

Also the template removal method is mild for the core material. Generally, various aqueous and organic solvents for the surfactants can be employed depending on the specific core material, for example. Thus, it is preferred to use non-acidic and non-alkaline solvents (or at least solvents which are not highly acidic) for iron oxide. Due to the silica shell, non-(highly)-alkaline solvents are preferably not used either.

For example, an organic solvent suitable for leaching of the silica coating can be selected from the group of aliphatic and aromatic ketones.

The solvents may contain salts and other substances which enhance leaching. For example aqueous and alcoholic solutions containing salts, such as alkali metal and earth alkaline metal salts of mineral acids, can be used.

Several methods can be employed for leaching, but in the example below a particularly mild approach (ultrasonication in acetone) is presented.

Thus, in one particular embodiment, the silica coating is contacted with a solvent, for example an aqueous or organic solvent, under agitation, for example by agitation employing using shear forces, preferably by sonication, for leaching at least a part of the surfactant from the coating.

The molar ratio of alcohol to water, in particular ethanol to water, in the aqueous alcoholic solution ranges from about 0.01 to 0.5 depending on the size of the particles. Generally a molar ratio of about 0.05 to 0.3 can be used; a ratio of about 0.075 to 0.25, or even 0.1 to 0.15, being particularly preferred for particles having an average particle size of about 400 to 1500 nm, in particular about 400 to 700 nm. For particles having smaller particle sizes, e.g. in the range of about 100 to 350 nm, molar ratios of alcohol to water (ethanol to water) are preferably about 0.1 to 0.4.

In addition to ethanol, other alkanols can be used, such as lower alcohols having 1 to 4 carbon atoms and 1 to 2 hydroxyl groups. Preferred alcohols are the simple primary Ci to C4 alcohols.

The silica coating is contacted with a solvent of the above-mentioned kind under agitation, preferably intense agitation, for example using strong shear forces. An example of efficient agitation is sonication.

The salt contains an anion derived from a mineral acid and a cation derived from a metal ion. Typically, the cations are selected from alkali metals or earth alkaline metals, such as sodium, potassium, lithium, calcium and magnesium. The anions can be selected from, for example, chloride, sulphate, nitrate, acetate and oxalate. The salts can be used in both anhydrous form and as hydrates.

The salt is used in concentrations of about 0.01 to 10 wt-%, for example about 0.05 to 7.5 wt-%, in particular about 0.1 to 5 wt-%, preferably about 0.25 to 2.5 wt-%, calculated from the total weight of the dispersion. As the below example shows, sodium chloride can be employed for example in amounts of about 0.5 to 1.5 wt-%.

The silica source is selected from derivatives of orthosilic acid. Such derivatives are exemplified by esters, in particular lower alkyl esters of orthosilic acid. A particular example is tetra-alkyl orthosilicate. The alkyl group is preferably a Ci to CV, linear or branched alkyl group. Thus, one particularly interesting silica source is formed by tetraethyl orthosilicate. The silica source can also be formed by silicates, such as water-soluble silicates. These typically have the formula IVLOxSiCL, wherein M is Na, K or Li and x is the molar ratio defining the number of moles of silica (S1O2) per mole of alkali metal oxide (M2O). Preferred alkaline silicates are sodium and potassium silicates, in particular sodium silicate (water glass) having a value of x of typically 2.0 or 3.3. Further soluble silicates are exemplified by sodium metasilicate pentahydrate.

As explained above, the silica is foimed from the source material by a hydrolysis and subsequent or at least partially parallel condensation reaction. The condensation reaction forms the polymeric material, and it is at least partially preceded by a hydrolysis of the source material.

The weight ratio of the silica source material to the structure-directing agent (e.g. the poloxamer) can be selected to be in the range of about 1:10,000 to 10,000:1, for example 1:1000 to 1000:1, preferably the silica source material is used in molar excess to the structuredirecting agent. A convenient amount is a molar excess of 1.5 to 150 times, in particular about 10 to 100 times, for example about 50 to 75 times.

The silica-coated particles can be subjected to a hydrothermal treatment as discussed above for increasing hydrolytic stability of the silica shell.

The composite particles disclosed herein have a number of interesting uses. Thus, one application comprises employing them for molecular and cellular separation, in particular in vitro molecular and cell separation. By virtue of the fact that the particles have a coating which has a clearly defined pore size range, which is rather narrow, typically ranging from an average pore size of about 5 nm up to about 10 nm, the particles are capable preferentially of accommodating molecules having a dynamic radius which falls within that range, whereas larger molecules will not adhere or be absorbed to the same extent to the present materials. Separation ratios (molar ratios) of greater than 10:1, typically at least 50:1 and up to 1000:1 and even 10,000:1 are attainable. Separation can be carried out both in liquid and in gas phase, although liquid phase is preferred.

The porous structure of the coating allows for the use of the present materials also as carriers of pharmaceutically active compounds as well as for diagnostically active reagent molecules.

The following non-limiting example illustrates the invention:

Example

Synthesis of magnetite cores

Silica-coated core/shell magnetic microspheres were provided by Shanghai Allrun Nano Science & Technology Co., Ltd as a kind gift.

Synthesis of large-pore mesoporons silica shells

The coating of the above magnetite cores was adapted from a regular mesoporous silica synthesis reported by A.-Y. Chen and S. Cheng, based on an acid-free synthesis route where NaCl salt instead ofHCl serves as the ionic mediator in the formation of the mesophase.

Thus, the salt concentration was initially kept the same as in the original synthesis with respect to the synthesis solvent, but was later also reduced. The dilution of the total synthesis was increased to ten-fold in order to preserve the integrity of single particles.

In a typical synthesis, 0.1 g of magnetic cores was added to a solution containing 0.05 g P123, 0.58 g NaCl, 40 g TLO and 12.7 g ethanol. After stirring at 35 °C for 30 min, 0.209 g of TEOS was added to the reaction mixture and was stirred 24 h at 35 °C, whereafter the particles were either magnetically separated from the solution (no HT) or transferred to a Teflon-lined autoclave for hydrothermal treatment (aging) continued for 24 h 70 °C.

After room-temperature synthesis (no HT) or aging (HT at 70°C), the particles were separated magnetically and then the surfactant was removed by sonication three times (30 min) in acetone. Thermogravimetric measurements were conducted to ensure the surfactant was removed. Template-extracted materials were either vacuum dried at 35 °C or stored as an acetone suspension prior to further use.

Following the above instruction, samples were prepared using various sodium chloride concentrations. Some of the samples were also analyzed before any hydrothermal treatment.

Materials characterization

Transmission electron microscopy (TEM) images were recorded on a JEM 2010 (JEOL,

Japan) instrument with 200 KV accelerated voltage. Thermogravimetric analyses were performed on a Netzsch TGA 209 by heating from room temperature to 1000 °C with a heating ramp of 10 K/min. Light scattering measurements were performed using a Malvern HPPS Instrument. Nitrogen sorption at 77 K was performed on a Micromeritcs ASAP2010 analyzer. The magnetization curves were obtained by using a Quantum Design PPMS-9 magnetometer at 300 K. HPLC analysis was performed with a Shimadzu LC-20 AD system combined with a SPD-20AUV-vis detector operated at 277 nm (Shimadzu Corp., Japan). Analytical column (5 pm, 250 mnv4.6 mm, ODS Cl8, SinoChrom, eliteHPLC, China) operating at 40 °C was used for separation of rapamycin. The mobile phase was 60 % methanol, 16 % acetonitrile and 24 % water with a flow rate of 1 mL min-1. The internal standard method was used to determine the concentration of rapamycin by comparing the peak area of the sample with that of a standard solution.

Figures lato Id are TEM images demonstrating successful deposition of large-pore silica coatings on magnetite beads. For (a) & (b), a NaCl concentration of 0.65wt% was used, whereas for (c) & (d) a concentration of l.lwt% was employed. As for post-synthetic treatment, (a) & (c) have not been hydrothermally treated, while (b) & (d) have been aged at 70 °C for 24 h.

Drug adsorption

Loading of Rapamycin (RAPA) was performed from cyclohexane by suspending 10 mg of either large-pore or “standard” pore (3 nm) mesoporous silica coated magnetite particles into 5 ml of cyclohexane by sonication and adding a 0.1 mg/ml RAPA solution in desired amounts (0, 0.5, 1, 2.5, 5 or 10 wt-% with respect to the particles) to the suspension. The suspensions were shaken overnight and separated magnetically whereby the supernatant was discarded and the RAPA-loaded particles were dried overnight in vacuum.

The amount of adsorbed RAPA was determined for dried, drug-loaded particles thermogravimetrically. For confirmation, the elution of RAPA for the drug-loaded particles was dispersed in 2 ml methanol in a glass tube and sonicated for 10 min, separated magnetically, the supernatant then being was measured with HPLC.

Rapamycin is an immunosuppressant drug (see Figure 2a) of molecular weight 914.172 g/mol. The molecular size should not inherently be too large to fit into the pores of regular mesoporous silica, but the adsorption may still become restricted if the molecule is too bulky. Also, the molecule is hydrophobic (water solubility about 1.7 pg/ml) so it might be sensitive to residual water in the pore structure, an effect which would be more pronounced for smaller pores. The amount Rapamycin adsorbed on both particle types as a function of concentration was determined by thermogravimetry (Figure 5b) and, as small amounts can be hard to detect reliably by TGA, also confirmed by HPLC for the highest loaded samples (last points in the isotherms). The thus obtained loading degrees (after 10 min elution in methanol, which is a good solvent for Rapamycin) was 3.16 and 0.27 wt% for the large-pore and regular SPI0@mSi02, respectively, confirming that the TGA results are in the correct range. Based on the TGA results, a clear adsorption isotherm can be drawn for the large-pore core-shell material whereas for the regular SPI0@mSi02 such low amounts were detected that no proper isotherm could be determined.

The presented results thus indicate that the large-pore mesoporous coating procedure may provide a feasible host matrix for active molecules from small-molecular to larger molecular size, such as drugs, as well as biomacromolecular species such as peptides, proteins and nucleic acids. Other active agents are possible also (such as natural or synthetic toxins or toxicants).

Claims (10)

A composition of composite particles comprising a shell-core structure formed by an inorganic core surrounded by a mesoporous shell having an average pore size of 5 to 10 nm, the core having an average diameter of 100 to 1500 nm and wherein the inorganic core is metallic or formed of metal oxide and the shell comprises a silica material, the particles being in non-aggregated form. Composition according to claim 1, characterized in that the core of the particles has an average diameter of about 150 to 1200 nm, preferably about 200 to 1000 nm. Composition according to claim 1 or 2, characterized in that the mesoporous shell of the particles is capable of accommodating molecular substances, preferably macromolecules selected from pharmaceutical substances, peptides, proteins, nucleic acids and other active substances. Composition according to any one of claims 1 to 3, characterized in that the inorganic core of the particles is formed by an iron oxide, such as a natural or synthetic magnetic material, in particular a ferrous or superparamagnetic iron oxide (SPIO). Process for producing composite particles having a shell-core structure formed by an inorganic core surrounded by a mesoporous shell, characterized by the combination of - providing inorganic particles selected from metal and metal oxide particles, having an average diameter of 100 to 1500 nm, - the inorganic particles are contacted, in an aqueous and alcoholic medium under substantially neutral conditions, with a source of silica, said aqueous medium additionally containing at least one surfactant and a salt, - the silica source being subjected to hydrolysis and condensation polymerization for precipitation of silica together with the surfactant on the inorganic particles to form a shell-like coating on the particles and - the silica coating is contacted with a solvent for leaching at least a portion of the surfactant from the coating to form a mesoporous silica coating. al of the particles, which has a shell with an average pore size of 5 to 10 µm. Process according to claim 5, characterized in that the inorganic particles are slurried in an aqueous and alcoholic solution of the surfactant and salt for a first period of time and then the silica source is obtained and the mixture thus obtained is stirred for a second period of time. Process according to claim 5 or 6, characterized in that the molar ratio of alcohol to water, especially between a lower alkanol, such as methanol or ethanol, and water, in the aqueous and alcoholic solution amounts to about 0.05 to 0.3. Process according to any one of claims 5 to 7, characterized in that the silica oxide coating is contacted with a solvent, for example an aqueous or organic solvent, during stirring, for example during stirring using shear forces, preferably under the influence of ultrasound. leaching of at least a portion of the surfactant from the coating. Process according to any one of claims 5 to 8, characterized in that the surfactant is non-ionic, selected from polyols, in particular the surfactant is selected from amphiphilic copolymers formed from three blocks, having a molecular weight of about 5,000 to 25,000 D, in particular about 10,000 to 15,000 D, for example about 12,500 D The use of a composition according to any one of claims 1 to 4 or of particles prepared according to a process according to any of claims 5 to 9 for molecular separation, as carriers of pharmaceutically active compounds, as diagnostically active substances or as carriers of diagnostically active reagent molecules or upon cell separation.