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WO2009040843A2 - Préparation de micro- ou nanosystèmes détectables dans des environnements biologiques basés sur des oxydes inorganiques avec une porosité contrôlée pour transporter des substances biologiquement actives ou activables - Google Patents

Préparation de micro- ou nanosystèmes détectables dans des environnements biologiques basés sur des oxydes inorganiques avec une porosité contrôlée pour transporter des substances biologiquement actives ou activables Download PDF

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WO2009040843A2
WO2009040843A2 PCT/IT2008/000533 IT2008000533W WO2009040843A2 WO 2009040843 A2 WO2009040843 A2 WO 2009040843A2 IT 2008000533 W IT2008000533 W IT 2008000533W WO 2009040843 A2 WO2009040843 A2 WO 2009040843A2
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micro
targeting
substance
procedure
preparation
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PCT/IT2008/000533
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WO2009040843A3 (fr
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Rosario Aiello
Flaviano Testa
Luigi Pasqua
Umberto Maione
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Universita' Della Calabria
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L51/00—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C08L51/10—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers grafted on to inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
    • A61K49/0082—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion micelle, e.g. phospholipidic micelle and polymeric micelle
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F292/00—Macromolecular compounds obtained by polymerising monomers on to inorganic materials

Definitions

  • the invention described therein is a procedure for the preparation of a multifunctional system in which an inorganic oxide with controlled porosity that carries on a biologically active species (drug) or activable (prodrug) and, at the same time, supports on the external surface a function able to reveal the presence of the system in biological fluids or in the cells (marker) and a fu ⁇ ction (targeting) able to be recognized from particular biological tissues.
  • a schematic representation of the invention is depicted. Background of the invention
  • MCM-41 is the member of the family M41S characterized by regular hexagonal array of mesopores with uniform diameter. They are synthesized using cationic surfactants as structuring agents (C. T. Kresge, M. E, Leonowicz, WJ. Roth, J. C Vartuli, J. S. Beck, Nature ,359, (1992), 710-712; J.S. Beck, J.C. Vartuli, V.J. Roth, M. E. Leonowicz, CT. Kresge, K.D. Schmitt, C.T.W. Chu, D. H. Olson, E.W.
  • cationic surfactants as structuring agents
  • Mesoporous materials have been obtained using anionic surfactants (Q. Huo, D.I. Margolese, U. Cielsa, P. Feng, T.E. Gier, P. Sieger, R. Leon, P.M. Petroff, F. Sch ⁇ th, G.D. Stucky, Nature, 1994, 368, 317) and neutral such as alchilamine with long chains [P.T. Tanev, T.J. Field of invention
  • the invention described therein is a procedure for the preparation of a multifunctional system in which an inorganic oxide with controlled porosity that carries on a biologically active species (drug) or activable (prodrug) and, at the same time, supports on the external surface a function able to reveal the presence of the system in biological fluids or in the cells (marker) and a function (targeting) able to be recognized from particular biological tissues.
  • a schematic representation of the invention is depicted.
  • MCM-41 is the member of the family M41S characterized by regular hexagonal array of mesopores with uniform diameter. They are synthesized using cationic surfactants as structuring agents (C. T. Kresge, M. E, Leonowicz, W.J. Roth, J. C Vartuli, J. S. Beck, Nature ,359, (1992), 710-712; J.S. Beck, J.C. Vartuli, V.J. Roth, M. E. Leonowicz, CT. Kresge, K.D. Schmitt, C.T.W. Chu, D.H. Olson, E.W.
  • cationic surfactants as structuring agents
  • Mesoporous materials have been obtained using anionic surfactants (Q. Huo, D.I. Margolese, U. Cielsa, P. Feng, T.E. Gier, P. Sieger, R. Leon, P.M. Petroff, F. Sch ⁇ th, G. D. Stucky, Nature, 1994, 368, 317) and neutral such as alchilamine with long chains [PT. Tanev, TJ. Pinnavaia, Science, 1995, 267, 865] and polyethilene oxides [G. Attard, J. C.
  • the aluminosilicate-type MCM-41 have been considered since their discovery as the natural extension of zeolites and immediately fields of applications such as catalysis or separation processes of substrates sterically hindered too large to diffuse in the narrow zeolites micropores have been defined.
  • the discovery of ordered mesoporous silica opened the route for new developments , for example in the "host-guest" synthesis of nanostructured materials. Active sites with high definition has been created by grafting of metallocene complexes on mesoporous silicas.
  • the synthesis strategies offered by the chemistry of sol-gel processes together with the ability of surfactants to self-assembly liquid-crystalline mesophases represents a modular code which allows to develop innovative materials with complex architectures which makes the ideal substrate in the design of a structured nanofunctional material.
  • the hybridization of a inorganic precursor allows, in fact, the design and the development of innovative multifunctional materials with complex structure and with various properties.
  • Hybrid organic- inorganic materials have been obtained by covalently binding chemically active groups to the inorganic structure of the mesoporous materials through post- synthesis grafting or through simultaneous condensation of silossanic and organo- silossanic reactants, the latter being provided with a not hydrolizable Si-C bond.
  • Enzymes and proteins can be adsorbed on the hydroxilated surface of activated inorganic oxides or on the functionalized pore walls of hybrid materials with regular porosity.
  • MCM-41 mesoporous silicas have been studied for the immobilization of non-steroidal anti-inflammatory drugs provided of a carboxilic acid functional group.
  • the confinement in the matrix can be obtained through phisisorption of the molecule or through chemical grafting, for example, on the suitably functionalized silica surface [M. Vallet.Regi, A. Ramila, RP. Del Real, and J. Perez pariente, Chem. Mater, 2001 , (13), 308; G.Cavallaro, P. Pierro F.S. Palumbo, F.
  • ibuprofen drug has been covalently linked to the surface of MCM-41 type mesoporous silica.
  • the esterification has been realized using the ibuprofen carboxilic group in the opening of the epoxidic ring of 3-glycidoxypropylsilane grafted on the silica surface.
  • a similar system based on a pro-drug involves the advantage due to the enzimatic activation through the breakage of the ester bond due to esterasi "in vivo".
  • Pentagastrine peptide an activator of the gastric secretion, has been introduced through soaking from the solution in a mesoporous silica synthesized using a Tween-80 type surfactant [C. Tourne-Peteihl, D.A. Lerner, C. Charnay, L. Nicole, S. Begu, J. M. Devoisselle, ChemPhysChem, 3 (2003) 281].
  • Tween-80 type surfactant C. Tourne-Peteihl, D.A. Lerner, C. Charnay, L. Nicole, S. Begu, J. M. Devoisselle, ChemPhysChem, 3 (2003) 281.
  • a system for the controlled drug release with nanospheres of MCM-41 type mesoporous silica has been optimized.
  • Therasphere® system is a new therapeutic system, commercialized by MDS Nordion, utilized as local radiotherapic agent in the hepatic carcinome. It is made of unsoluble glass microspheres partially constituted by a ⁇ emitter introduced through the hepatic artery.
  • the active targeting of a drug on a characteristic tissue can be based on the recognition of a functional group linked to a preselected molecule (target).
  • Folic acid can be employed in the active targeting of a drug.
  • Receptors of folic acid in fact, constitute a useful target in the active carrying of antitumoral drugs.
  • Targeting of folate receptors can be employed for the intracellular release of macromolecular therapeutical agents [K.Kono, M.Liu, J.M.J. Frechet, Bioconjugate Chem., 1999, 10, 1115] but also drugs that do not need intracellular release can be carried to neoplastic tissues. In this way tumors of difficult therapeutic treatment with classical methods can be specifically reached using conjugated therapeutic agents-folic acid.
  • a nanodevice for drug release which allows an intracellular release and, at the same time, is provided with imaging properties has been obtained by covalently bonding fluorescein, methotrexate and folic acid, to the surface of a ethylendiaminic nucleus of a polyamidoamine-based dendrimer [A. Quintana, E. Raczka, L. Piehler.l. Lee, A. Myc, I. Mayoros, A.K. Patri, T. Thomas, J. Mule, J. R. Baker Jr, Pharm. Res. 19 (2002) 1310]. Recently, a conjugated folate-ciclodestrine has been prepared and characterized [P. Caliceti, S. Salmaso, A.
  • Nanoparticles of mesoporous silica have been synthesized using gold nanoparticles as templating agent. Gold nanoparticles have been successively removed using sodium cyanide. Silica nanoparticles have been studied as drug carriers in the study of fluorescein isothiocanate (FITC) release used as "in vitro" model [Liu Y., Miyoshi H., Nakamura M., Colloids Surf B Biointerfaces. 2007 Mar 12; 17420116].
  • FITC fluorescein isothiocanate
  • a new vector made by mesoporous silica nanoparticles conjugated with FITC has been prepared. It has been studied in the cellular internalization using mesenchymal stem cells of human bone marrow and cells 3T3-L1 with the aim of evaluate the use as detector of the distribution of stem cells which is fundamental for their therapeutic use [The FASEB Journal Express Article doi:10.1096/fj.05- 4288fje Published online October 17, 2005].
  • a silica sol made of nanoparticles with average size between 3 and 50 nm has been treated on its surface by grafting or adsorbing an organic molecule or by doping with a dopant substance. These substances have been monodispersed in a liquid phase and show a concentration higher or equal to 10 %.
  • Nanoparticles core which have an average diameter lower than 1 micron and preferably ranging between 1 and 100 nm or 2 and 10 nm can be magnetic and can include a metal chosen between magnetite, maeghmite and greigite.
  • the core can include a pigment that can be potassium permanganate, potassium dichromate, nickel sulphate, cobalt chloride, iron (III) chloride and cuprum nitrate.
  • it can include a dye as Ru/Bpy, Eu/Bpy and similar or a metal as Ag or Cd.
  • Silica shell which coats nanoparticles can be derivatized with a functional group as a protein (e.g. an antibody), a nucleic acid (e.g.
  • the proposed method in the invention can be used to produce silica-coated nanoparticles derivatized with proteins which contain a metal such as magnetite, maeghmite or greigite.
  • the invention features a method for identifying cells expressing preselected molecule. In this case a cells plurality in which at least a part of them express the particular molecule is mixed with a plurality of silica-coated nanoparticles in conditions allowing the nanoparticles to specifically bind the cells expressing the preselected molecule.
  • the silica-coated nanoparticles are fluorescent.
  • the nanoparticle is solid and preferably without pores but for some applications can be made porous by degrading the nanoparticles coating with a corrosive agent and eventually by reconstructing it with silica.
  • solid particles are preferred when it is desired to isolate them from the outside environment while those porous are preferred when it is desired to increase the surface area of the coating in contact with the outside environment.
  • the core can be formed by any substance compatible with the coating with the goal to satisfy to particular requirements for the application for the use of the particle.
  • the core is made up of a magnetic metal and the particles can be used in applications such as cells separation/purification or diagnostic imaging.
  • the core can be also made of a mixture of different substances.
  • the core in a magnetic and dye-doped particle, can be constituted by a magnetic metal and a inorganic salt useful as pigment.
  • the core can have any size but it must be lower than that of the desired particle.
  • the core must preferably have a diameter ranging between 1 and ca. 200 nm.
  • the core must be small enough so to be contained in a particle with size lower than 100 nm.
  • Coating can be made with a polymer (polystyrene, polyvinylchloride, acrylic polymers), a polysaccharide as destrane, an inorganic oxide as alumina, silica, or a mixture of them.
  • silica is preferred because it is relatively inert in many environments, is biocompatible, prevents agglomeration with others nanoparticles in a dispersion and can be easily derivatized with* many functional groups.
  • Coating can be made by a layer that coats the core and by a second layer that coats the first one. This second layer can be made of a biodegradable material, for example a sugar or a polymer, impregnated with a drug.
  • This biodegradable material when introduced in a animal organism, can be dissolved and the drug can gradually diffuse.
  • Coating can be made by 3, 4, 5 or more separated layers.
  • Functional groups can be derivatized on the coating. They can be any chemical or biological function that can be linked to the nanoparticle through the coating: as an example, one or more proteins such as antibodies (monoclonals, polyclonals), enzymes, biotine, streptavidine, nucleic acids molecules, chemosensors, fluorescent probes and biochemical groups as amines and carboxylate groups.
  • Nucleic acid-nanoparticles complexes are allowed to sediment on to the cells. Release of genetic material on the cells is carried out through standard transfection agents.
  • Essential requirement of the nanoparticles is that they are non toxic and biocompatible, able to associate with nucleic acids or with complexes of nucleic acids and can sediment in an aqueous medium in order to increase the nucleic acid concentration on the cells surface. It is preferable that they do not form aggregates.
  • Document US 2003/203206 describes a preparation methodology of hexagonal mesoporous silica able to produce a controlled release of an incorporated substance. It is provided of a photo-dimerizable organic functional group at the pore opening which lock its entrance. The incorporated active substance can be released where and when desired after a photoinduced splitting of the dimer.
  • Document US 2003/203206 describes a system for the carrying of biologically active substances in a mesoporous silica matrix provided with a system for the diffusion control of the same substances but not able to target characteristic tissues through a recognition mechanism.
  • the method can be, for example, utilized in the preparation of serial analytical probes.
  • the aminic groups present after the loading of the biomolecule (which could generate undesirable interactions in the medium where the loaded support is used) are selectively removed from the surface without affecting the loaded part of the surface.
  • the method of the invention is applicable in all the situations in which free aminic groups must be selectively removed from the surface of the metallic oxide loaded with biomolecules.
  • the pH of the solution where the loaded support can be treated substantially depends on the kind of the molecule linked to the surface and on the bond (covalent or adsorption).
  • Supports prepared through the method of the invention are very useful for diagnostic tools as, for example, in the analytical probes. For example, in this regard are very suitable series or microseries without free aminic groups.
  • the series can include different biomolecules in different points allowing the detection of multiple analytes.
  • an analyte is a substance, normally a biomolecule, which detection is possible because of its ability to specifically interact with a certain reactant.
  • a sample that includes an analyte is put in contact with loaded support prepared through the method described in the invention.
  • the analyte is allowed to react with a biomolecule which is linked to the surface of the support.
  • the interaction can be followed through a detection method.
  • Document WO 01/12846 describes a system based on a surface where biomolecules or different kind of biomolecules in different "spots" able to recognize other species in a mixture are grafted or adsorbed.
  • Italian Patent Application CS2005A00003 describes a device realized starting form inorganic oxides with regular porosity. The control of the porosity is obtained during the synthesis using any surfactant through a molecular imprinting mechanism.
  • Oxides con be provided by one or more functions introduced directly during the synthesis of the material or through a procedure of post-synthesis grafting. The introduced functions are used for the anchoring of molecules or particles of different quality and size on the external surface of the mesoporous material.
  • Such a molecule or particle is devoted to the molecular recognition and with this goal biologically active molecules or involved in recognition mechanisms of cells, peptides or antibodies can be used.
  • the functionalization the contains the targeting function is addressed on the external surface using the as-made material before the surfactant extraction process which made available the reactants to the pore surface.
  • pores are made available through solvent extraction after the anchoring of the targeting function and the obtained porous volume is useful for the drug-loading and the transport of biologically active or activable substances that will be released in the site of interest.
  • molecules, atoms, ions of different type and size such as antitumoral drugs, antiflammatory, hormones, peptides, DNA fragments can be transported.
  • biologically activable we intend any kind of prodrug.
  • the invention has been realized starting from inorganic oxides with regular porosity.
  • the porosity control is carried out during the synthesis through the use of whatever surfactant or through a mechanism of molecular imprinting.
  • Oxides can be provided of a function introduced during the synthesis of the material or through a post-synthesis grafting procedure.
  • the introduced function is useful for the grafting of molecules or particles different for nature and size on the external surface of the mesoporous material. Where not specified such molecules or particles will be generically named as marker function if it allows detection in biological fluids targeting function if it works for molecular recognition .
  • the marker function is a specie grafted to the surface and it allows to detect the system in a biological fluid while as targeting function particularly important seems to be the use of biologically active or involved in cellular recognition molecules, peptides or antibodies.
  • the functionalization is addressed only to the external surface using the as-made material before the extraction processes which make the internal pores accessible to the reactants.
  • the introduction of the targeting function occurs before the surfactant removal and the immobilization of the active substance.
  • the grafting of the marker function and/or targeting function drastically reduces the operative conditions successively needed for the surfactant removal. In fact, they must be compatible with the chemical stability and the biological activity of the introduced groups. Pore volume available after the extraction processes is useful for the drug-loading and the transport of biologically active or activable substances for their release on the target site.
  • Molecules, atoms, ions having very different kind and sizes such as antitumoral drugs, anti-inflammatory, hormones, peptides, DNA fragments, can be carried.
  • biologically activable means any kind of pro-drug. Where not specified the molecule, ion, or material will be generically indicated with the term active substance.
  • Targeting molecule is linked to the chemical function through covalent or ionic bond.
  • the marker molecule is linked to the chemical function through covalent or ionic bond.
  • Release can be diffusive with slow profile or pH-controlled in environments in which pH is different from that of the medium where the system is administered.
  • Extraction procedure of the surfactant from the pore after functionalization must be compatible with the preservation of the biological activity of the targeting and marker functions. It can be carried out in water at room or slightly higher temperature, in a solvent which does not damage the targeting function and/or the marker function or in a soxhlet extractor at moderate temperature. Drug loading is possible even in complete or partial presence of surfactant, being the surfactant itself a dispersing agent and carrier.
  • the choice of the elements constituting a modular system such as matrix, functionalization agent, marker function, targeting function and drug is one of the phases of the design of the system and is based on pharmacological, biological, physical and chemical considerations. In the design phase are also involved the knowledge of the adsorption kinetics of the drug in the solvent selected for drug-loading and of drug release from the system in the administration, crossed and release fluid.
  • the material has been prepared starting from a synthesis mixture with the following molar composition:
  • Procedure B Preparation of a 3-aminopropyl mesoporous silica.
  • Post-synthesis functionalization of mesoporous silica obtained from procedure A 3 g of mesoporous silica obtained according procedure A are activated in oven for 2 hours at 120 0 C and then suspended in anhydrous toluene (25 ml), aminopropyltriethoxysilane (APTES, 5 ml) is successively added and the suspension is kept under reflux for 7 hours. The solid is then filtered and washed with tetrahydrofuran.
  • APTES aminopropyltriethoxysilane
  • Procedure C Preparation of a fluorescent 3-aminopropyl mesoporous silica.
  • APTES (1.42 g; 0.0064 moles) and Fluoresceine isothiocyanate (FITC) (0.004 g; 0.0103 mmoles) were stirred in ethanol (3 ml) at room temperature for 24 hours; then a suspension of mesoporous silica obtained according procedure A in ethanol (700 mg in 2.5 ml) was added to the first solution and the whole mixture stirred for 2 days.
  • FITC Fluoresceine isothiocyanate
  • Procedure D Preparation of a fluorescent 3-aminopropyl mesoporous silica. 0.004 g (0.0103 mmoles) of FITC has been introduced in a suspension obtained mixing 700 mg of an 3-aminopropyl mesoporous silica obtained according procedure B in 5.5 ml of ethanol. The whole mixture has been stirred for two days at room temperature.
  • Procedure E Triethylamine (0.25 ml) and folic acid (0.5 g) are dissolved in dimethylsulfoxide (15 ml). Aftercomplete dissolution, nitromethane (3 ml) and 3- aminopropyl mesoporous silica fluorescent or not fluorescent (3,6 g) obtained according to procedure B 1 C or D and previously activated in oven at 110 0 C for 2 hours, are added.
  • Procedure F Triethylamine (0.25 ml) and folic acid (0.5 g) are dissolved in dimethylsulfoxide (15 ml). After complete dissolution, nitromethane (3 ml) and 3- aminopropyl mesoporous silica fluorescent or not fluorescent (3,6 g) obtained according to procedure B 1 C or D and previously activated in oven at 110 0 C for 2 hours, are added.
  • Mesoporous silica microspheres have been obtained starting from biphasic emulsions according a synthesis methodology recently reported (Pasqua L, Testa F and Aiello R 2005 Stud. Surf. Sci. Catal. 158, 2005, 557-564). In this case decane has been used as organic phase.
  • the synthesis procedure is aimed to produce mesoporous silica particles with controlled diameter and morphology important parameters in the field of drug targeting because they affect suspendibility in water and other biological fluids.
  • the resulting material has been modified to produce systems potentially useful for drug targeting. To this aim free amino-propyl groups and a fluorescent marker obtained by coupling of FITC with APTES have been introduced on the mesoporous silica surface before surfactant extraction.
  • the covalent anchoring of folic acid, a receptor-specific ligand able to be recognized from specific tissue completed the functionalization of mesoporous silica.
  • Figure 2 shows the X-ray powder diffraction pattern of as-synthesised mesoporous materials obtained from the biphasic system decane-water.
  • Data obtained from XRD of as-synthesized material evidence that the properties of the interfacial region affect the size of the channels of the MSM.
  • the double peak XRD pattern of as-synthesized material shows that micelles with different size are formed during the assembly of the material.
  • XRD pattern of calcined material (not shown) evidences that two main reflecting elements are present.
  • Some coexistence of two templating systems, constituted by micelles with different diameters, is in accordance with the nitrogen adsorption of calcined material that is a reversible type IV isotherm presenting some nitrogen uptake corresponding to capillary condensation also at higher relative pressure where a hysteresis loop can be noted.
  • the occurrence of heterogeneous formation of surfactant templating- micelles can be explained on the basis of solvent inclusion in the hydrophobic core of the micelles.
  • Fluoresceine isothiocyanate isomer I used as fluorescence label was covalently linked to amino-propyltriethoxysilane (APTES) in ethanol.
  • the fluorescent silicon alkoxide was successively grafted at room temperature to the external surface of mesoporous silica microsphere using the as-synthesized material before surfactant extraction to produce FITC-MSM material.
  • Folic acid a receptor specific ligand able to be recognized from specific tissues, was then coupled to free amino groups on FITC-MSM in DMSO using diisopropylcarbodiimide as condensing agent to produce FITC-MSM-FOL material.
  • FITC-MSM-FOL was characterized by XRD and nitrogen adsorption-desorption to investigate its porous structure.
  • Powder XRD of FITC-MSM and FITC-MSM-FOL shows a low-order single reflection pattern evidencing a silica reorganization during FITC coupling and ethanol soaking. Both samples evidence a single reflection pattern and the intensity of the reflection is further decreased after folic acid coupling
  • Figure 3 shows DRFT-IR spectra of as-synthesized MSM materials, FITC-MSM and FITC-MSM-FOL.
  • the first one presents a very important surfactant contribution in the region around 2900 cm "1 while the second one shows vibrations in the region 1020-1560 cm “1 , as expected for thiourea derivatives, but shows decreased intensity for surfactant vibrations probably because soaking in ethanol for a long time during FITC coupling partially removes surfactant; this is confirmed by thermogravimetric analysis which shows a decrease in total mass loss from 48.62 % for MSM material to 25.8 % for the corrispondent FITC-MSM material.
  • DRIFT spectrum of material FITC-MSM-FOL Figure 3 c shows typical vibrations of folic acid.
  • 29 Si-NMR spectra (not shown) unambiguously demonstrate the change in the support during the various treatments.
  • the initial mesoporous material is characterized by three 29 Si-NMR lines; the -110 ppm line stems from the Si(OSi) 4 group, the one at -101 ppm is due to SiOH groups, while that at -91 ppm stems from Si(OH) 2 groups.
  • the average pore diameter is considerably larger compared to the isotherm of calcined MSM material ( Figure 4).
  • Synthesis procedure A allows to obtain ordered mesoporous materials that after removal of surfactant show a specific surface around 1000 m 2 /g and very large pore volume.
  • Post-synthesis functionalization is carried out on the silica- micelles composite material to preferentially address the functionalizing agent on the external surface of the particle.
  • the functionalizing agent can migrate through the micelles and condense on the internal pore walls as already-seen in the open literature for some kind of mesoporous silica.

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  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)

Abstract

L'invention concerne un procédé modulaire pour la préparation de micro- et de nanodispositifs à base d'oxydes inorganiques avec une porosité régulière d'une utilisation potentielle en tant que supports d'espèces biologiques actives ou activables. Les composites micellaires inorganiques obtenus par les modes opératoires de synthèse sont fonctionnalisés, à l'aide de réactifs appropriés selon des modes opératoires de greffe post-synthétique ou en partant directement du mélange de synthèse. Successivement, des fonctions biologiques de différentes propriétés chimiques sont ancrées sur la première fonction, lesquelles visent à permettre la détection des systèmes dans des fluides biologiques (marqueur) et le ciblage actif du système par reconnaissance moléculaire ou biologique (ciblage). Le marqueur et les espèces de ciblage peuvent faire partie des systèmes de façon jointe ou séparée sans affecter la particularité de l'invention concernant les systèmes avec le ciblage intra- ou extracellulaire de substances biologiquement actives. Le greffage du marqueur et des fonctions de ciblage a lieu sélectivement sur la surface externe du fait qu'il est réalisé en partant du matériau composite micellaire inorganique initial. L'étape suivante consiste à retirer le modèle réalisé à l'aide de traitements qui n'affectent pas l'activité biologique du marqueur et des fonctions de ciblage. Le volume de pore obtenu est utilisé pour l'immobilisation et la libération ultérieure de substances actives ou d'agents thérapeutiques de nature et de dimension différentes.
PCT/IT2008/000533 2007-08-03 2008-08-04 Préparation de micro- ou nanosystèmes détectables dans des environnements biologiques basés sur des oxydes inorganiques avec une porosité contrôlée pour transporter des substances biologiquement actives ou activables WO2009040843A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000038A ITCS20070038A1 (it) 2007-08-03 2007-08-03 Preparazione di micro- o nanosistemi rivelabili in ambienti biologici a base di ossidi inorganici a porosita controllata per il veicolamento di sostanze biologicamente attive o attivabili
ITCS2007A000038 2007-08-03

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WO2009040843A2 true WO2009040843A2 (fr) 2009-04-02
WO2009040843A3 WO2009040843A3 (fr) 2009-11-19

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IT (1) ITCS20070038A1 (fr)
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CN103179955A (zh) * 2010-09-14 2013-06-26 纳诺洛吉卡股份公司 用于不良水溶性的药物和化妆活性成分的过饱和释放赋形剂
US9119875B2 (en) 2013-03-14 2015-09-01 International Business Machines Corporation Matrix incorporated fluorescent porous and non-porous silica particles for medical imaging
CN110862568A (zh) * 2019-12-04 2020-03-06 石河子大学 一种用于分离苯乙醇苷类的分子印迹膜的制备方法和应用
CN113941005A (zh) * 2021-10-29 2022-01-18 上海唯可生物科技有限公司 二硫键功能化的二氧化硅纳米粒子、制备、复合物、用途

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Publication number Priority date Publication date Assignee Title
US7563451B2 (en) * 2003-07-22 2009-07-21 Iowa State University Research Foundation, Inc. Capped mesoporous silicates

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103179955A (zh) * 2010-09-14 2013-06-26 纳诺洛吉卡股份公司 用于不良水溶性的药物和化妆活性成分的过饱和释放赋形剂
CN103179955B (zh) * 2010-09-14 2016-08-03 纳诺洛吉卡股份公司 用于不良水溶性的药物和化妆活性成分的过饱和释放赋形剂
US9119875B2 (en) 2013-03-14 2015-09-01 International Business Machines Corporation Matrix incorporated fluorescent porous and non-porous silica particles for medical imaging
US9549996B2 (en) 2013-03-14 2017-01-24 International Business Machines Corporation Matrix incorporated fluorescent porous and non-porous silica particles for medical imaging
CN110862568A (zh) * 2019-12-04 2020-03-06 石河子大学 一种用于分离苯乙醇苷类的分子印迹膜的制备方法和应用
CN113941005A (zh) * 2021-10-29 2022-01-18 上海唯可生物科技有限公司 二硫键功能化的二氧化硅纳米粒子、制备、复合物、用途

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WO2009040843A3 (fr) 2009-11-19

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