WO2010150036A1 - Sol-gel nano-structuré et biocompatible, et biocatalyseurs platine-oxyde de titane et platine-silice nano-structurés et biocompatibles pour utilisation dans le traitement du cancer - Google Patents

Sol-gel nano-structuré et biocompatible, et biocatalyseurs platine-oxyde de titane et platine-silice nano-structurés et biocompatibles pour utilisation dans le traitement du cancer Download PDF

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WO2010150036A1
WO2010150036A1 PCT/IB2009/006079 IB2009006079W WO2010150036A1 WO 2010150036 A1 WO2010150036 A1 WO 2010150036A1 IB 2009006079 W IB2009006079 W IB 2009006079W WO 2010150036 A1 WO2010150036 A1 WO 2010150036A1
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platinum
nanostructured
silica
nanoparticles
titania
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PCT/IB2009/006079
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Tessy Maria Lopez Goerne
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Universidad Autonoma Metropolitana - Xochimilco
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • This invention is related to the synthesis of nanostructured inorganic nanostructured and biocompatible biocatalysts defined as M n O 2n - ( ⁇ + y )/2 (OH) v (S ⁇ 4 )w(P ⁇ 4 ) ⁇ (OR) y (CI) z
  • M stands for silicon, titanium or a mixture of both and R for an organic ligand, preferably C n H n+ i, either linear or branched to which Pt-based compounds, in II, III or IV oxidation state, having cytotoxic activity (i.e. cisplatin, carboplatin, Pt(IV) based drugs).
  • the matrix acidity, structure, electronic density, pore size distribution, matrix particle size, platinum particle size, platinum dispersion on the support (silica or titania), crystallite size and oxidation state of platinum are controlled. These anticancer biocatalyst formulations will be delivered directly into the tumor.
  • BACKGROUND FOR THE INVENTION Cancer is one of the leading causes of death all over the world.
  • the treatment use is surgery, radiotherapy, chemotherapy or a combination of them.
  • Chemotherapy uses chemical agents (anticancer drugs) to kill cancer cells, is one of the primary methods to cancer treatment.
  • anticancer drugs have limited selectivity for cancer and are inherently toxic to both cancer and normal tissues.
  • compounds that exhibit high antitumor activity such as cis-platin are typically highly toxic.
  • the main disadvantages of cis-platin are its extreme nephrotoxicity and neurotoxicity, which is an important limiting factor to use.
  • inorganic oxides nanoparticles offer a suitable mean to deliver drugs to tissues or cells.
  • Their submicrometric size favors the taken up by cells via endocytosis/phagocytosis, the hydrophilic character of their surfaces allows evading the recognition by the reticuloendothelial systems and their intrinsic stability prevents the breakage in the bloodstream.
  • they may have high surface area a controlled pore size distribution and if required tailored surface acid-base properties for adapting them to site specificity.
  • the sol-gel technique with or without the use of templates can be used as a good method by which the various solid phases can be controlled (T.Lopez et.al., Catalysis Today 35,293.1997 y otras mas). A greater degree of control can be achieved in comparison to other methods of synthesis. One can tailor make the reservoir to fit specific applications by using this method.
  • Advances include: Superior homogeneity and purity; High solid acidity; High biocompatibility with any tissue; Better nano and microstructural control of the inorganic oxide matrices; Greater BET surface area; High dispersion of the platinum on the matrices; Improved thermal stability of the drugs attached to the transporter; Well-defined mean pore size distributions; Inorganic chain structures can be generated in solution; A finer degree of control over the hydroxylation of the transporter can be achieved.
  • a sol is a fluid, colloidal dispersion of solid particles in a liquid phase where the particles are sufficiently small to stay suspended in Brownian motion.
  • a "gel” is a solid consisting of at least two phases wherein a solid phase forms a network that entraps and immobilizes a liquid phase (ref).
  • the dissolved or "solution” precursors can include metal alkoxides, alcohol, water, acid or basic promoters and on occasion salt solutions.
  • Metal alkoxides are commonly employed as high purity solution precursors. When they react with water through a series of hydrolysis and condensation reactions they yield amorphous metal oxides or oxo-hydroxide gels. When the volatile alcohol molecules are removed the result is the formation of crystalline solid compounds. This solid can be modified by adding suitable amounts of desired molecules during the synthesis process whose amount an stability are determined by the stability constant (ref).
  • the materials that are used as colloid precursors can be metals, metal oxides, metal oxo-hydroxides or other insoluble compounds.
  • the degree of aggregation or flocculation in the colloidal precursor can be adjusted in such a way that the pore size distribution can be controlled.
  • Dehydration, gelation, chemical cross-linking and freezing can be used to form the shape and appearance of the final product.
  • M can be in the form, M n O 2n -(x+y) /2 (OH) x OR)y, M stands for silicon, titanium or a mixture of both and R for an organic fragment, preferably C n H n+I , either linear or branched, where n is the number of titanium atoms polymerized in the polymer molecule and x and y is the number of terminal OH and OR groups respectively.
  • R for an organic fragment, preferably C n H n+I , either linear or branched, where n is the number of titanium atoms polymerized in the polymer molecule and x and y is the number of terminal OH and OR groups respectively.
  • sol-gel structures attain their highest coordination state through intermolecular links (Sankar G., Vasureman S, and Rao C. N. R., J.Phys. Chem, 94,1879 (1988)y otras mas modemas). Because there are strong chemical interaction forces between the drugs and the inorganic nanop
  • U.S.Pat.No. 6 124 367 This patent protects reservoirs used in the Fischer Tropsch reactions from sintering by imparting a higher degree of mechanical strength to the reservoir. It incorporates SiO 2 and AI 2 O 3 into the reservoir and claims a rutile-anatase ratio of 1/9. It is a porous reservoir with either a spherical or a cylindrical shape. It is made by extrusion, spray drying or tableting.
  • the present invention includes a novel nano-material (silica, titania and silica-titania) obtained by the sol-gel process to which platinum compounds are bound.
  • the support particle size ranges between 10 nm to 1 Dm.
  • the platinum metal is either bound as metallic nanoparticles or covalently bound platinum complexes.
  • the metal nanoparticle size ranges from atomic dispersion to 100 nm.
  • This nanomaterial consists of partially hydrolyzed oxides having a Ti:Si range of compositions between (100:0 and 0:100). These materials were prepared using a sol-gel process, which has been used to synthesize ceramic and glass materials.
  • the titania, silica and titania-silica xerogels (100:0, 0:100) materials are found to be biocompatible with surrounding tissue.
  • the synthesis of the platinum containing drug is carried out by adding the platinum compound during the gelation process or by grafting the platinum compound to the sol-gel obtained oxides. The total amount of platinum can be as high as 10% by weight.
  • Mesoporous sol-gel oxides can be synthesized, in reactive (i.e. air, carbon dioxide, etc.) or inert atmosphere (i.e nitrogen, argon, etc.) at pH ranging from 2 to 12 using water: alkoxide ratio ranging from 2 to 64. Water, Ci to C 5 primary, secondary or tertiary alcohols, acetyl acetone, acetone or a mixture alcohol-water or acetone- acetyl acetone was used as solvent for the synthesis.
  • the gelation process was carried out from room temperature to 8O 0 C in the presence or absence of organic templates or modifiers (i.e. P 123, acetylacetone, CTAB, etc).
  • organic templates or modifiers i.e. P 123, acetylacetone, CTAB, etc.
  • Platinum compound precursors are HaPtCI 6 cis-Pt or PtAcAc or Pt(NHs) 4 CI 2 .
  • Pore volumes and pore diameters are not strongly affected by platinum compound loadings.
  • the administration form can be: a) nanoparticle suspension in physiological compatible fluids; b) extrudates, in this case biocompatible binders might be used (i.e. poly[bis(p- carboxypenoxy)]propane-sebacic acid, PLGA, methylcellulose,
  • Biocatalysts platinum compound-sol-gel synthesis In the three-necked flask, a mixture consisting of deionized water, platinum compound, base or acid and solvent were refluxed. Prior to initiating the reflux, the pH of the solution was adjusted. In either case, the acid or the base was added drop by drop manner until the desired pH was obtained. The pH was monitored continually using a potentiometer throughout the entire process. Using a funnel, metal alkoxide or a mixture of metal alkoxides was added to the solution being refluxed. The dropwise addition was performed over a four-hour period in order to enhance nucleation and functionalization. Following the addition of the alkoxide, the colloidal suspension was refluxed over a period from 24 to 240 hours.
  • the samples were dried under vacuum conditions in a roto-vapor (10 ⁇ 3 mm of Hg) in order to remove excess water and alcohol. Finally the samples were dried at 3O 0 C for 72 hours. In order to reach the final drying temperature of 3O 0 C, the temperature was increased at a rate of 0.25°C/min to 5C/min using a conventional furnace.
  • the synthesis procedure respected the known synthesis procedures for obtaining the adequate micelle concentration.
  • the inorganic oxides were synthesized following the same procedure but in the absence of the platinum compound.
  • the desired amount of platinum is added by: a) A solution containing the platinum compound is added to the inorganic alkoxide in such a way that the solution volume matches the pore volume of the inorganic oxide. b) A solution containing the platinum compound is added to the inorganic alkoxide at pH above or below the isoelectric point of the surface. In every case, the pH is adjusted to either preserve or decompose the platinum compound. For example for grafting [Pt (NHs) 4 ]CI 2 to a titania surface, a chloride rich solution at low pH is used.
  • the sample was prepared as follow: Pt(NHs) 4 CI 2 was dissolved in ethanol and distilled water. The solution was stirred continuously under constant reflux. After the salt was completely dissolved, gamma-aminobutyric acid and TEOS were added. The resulting sol was maintained under constant flux and continuous stirring until the gel was formed. The evaporation of the solvent and water was performed at room temperature. The dry solid was crushed and later characterized.
  • the sample was prepared as follow: H 2 PtCI 6 .6H 2 O was dissolved in distilled water. The solution was stirred continuously under constant reflux. After the salt was completely dissolved, ethanol, gamma-aminobutyric acid and TEOS were added. The resulting sol was maintained under constant flux and continuous stirring until the gel was formed. The evaporation of the solvent and water was performed at room temperature. The dry solid was crushed and later characterized.
  • FIG 1a an x-ray diffraction pattern, (obtained using a Brucker D-5000 instrument equipped with Cu-Ka radiation with a wavelength of 1.5418 A (45kV and 4OmA)), in which an undefined broad band characteristic of amorphous silica is shown.
  • Several small bands, which are reflections from the Pt (NHs) 4 CI, centered at 12° and 24°(2 theta) are also observed.
  • Figure 1 (a) X-ray diffraction pattern and, (b) FTIR spectrum of Pt/SiO 2 - Pt(NHs) 4 CI 2
  • FIG 3 Transmission electron microscopy of the nanostructured particles, which comprise the PI- 7 SiO 2 -Pt(NHs) 4 Cl 2 biocatalyst Histological studies using hematoxiline-eosine were performed on the tissue surrounding the trajectory of the injection of the suspension of Pt/SiO2-H 2 PtCI 6 nanoparticles Figure 4.
  • the micrographs pertaining to this study tunel are shown in figure4.
  • Fig 4a an interface clearly shows a line of demarcation between two zones, one in which the tumor cells are clearly visible and the other, visibly showing the cell damage.
  • a higher magnification is used to examine the damaged area.
  • figure 4c the absence of growth in the tumoral tissue is apparent.
  • the white dots are DNA fragments.
  • FIG. 5 Photomicrographs of hematoxylin and eosin stained sections of (a) tumor treated with PIZSiO 2 -Pt (NH 3 ) 4 CI2 nanoparticles, (b) higher amplification, and, (c) TUNEL analysis
  • Table 1 shows the final volume of the tumours as a function of treatment. From this data it is clear that both the platinum coordination compound and the Ti ⁇ 2 carrier produce a significant reduction of the tumour volume. This effect is greatly enhanced in the case of the groups treated with the TiO 2 and TiO 2 -Pt nanodevices. In this later case, the tumour volume is just 44% of the volume achieved by the control group.
  • Table 1 Average tumour volume for the four designed groups of Wistar rats.
  • CISPLATIN ® in the silica matrix is by impregnation: 100 g of silica are mixed with water and HCI 1M. The platinum salt is dissolved in the HCI solution (0,5% wt of Pt). The mixture was stirred at 30 0 C, during 72 h. The sample is dried with vacuum and is maintained at ambient temperature.
  • the sample was prepared as follow: Pt(NHs) 4 CI 2 was dissolved in ethanol and distilled water. The solution was stirred continuously under constant reflux. After the salt was completely dissolved, gamma-aminobutyric acid and TEOS were added. The resulting sol was maintained under constant flux and continuous stirring until the gel was formed. The evaporation of the solvent and water was performed at room temperature. The dry solid was crushed and later characterized. The final platinum concentration was 1 mol%.
  • FIG 1a an x-ray diffraction pattern, (obtained using a Brucker D-5000 instrument equipped with Cu-Ka radiation with a wavelength of 1.5418 A (45kV and 4OmA)), in which an undefined broad band characteristic of amorphous silica is shown.
  • Several small bands, which are reflections from the Pt (NH 3 ) 4 Cl 2 , centered at 12° and 24°(2 theta) are also observed.
  • C6 glioma cells (benda et al. 1968), obtained from the American Tissue Culture Collection (Rockville, MD) were cultured under sterile conditions at 37 0 C in a humid environment with 5% of CO 2 in Ham F-10 medium supplemented with bovine foetal serum (2.5%) and horse serum (15%). After the cultures became confluent, the cells were washed with saline solution, harvested and counted; 1x10 7 C6 cells were inoculate intraperitoneal ⁇ in a male Wistar rat. Twenty days later, a large peritoneal tumor developed.
  • the tumor was mechanically dissociated at 4 0 C and 1x10 r cells, suspended in 500 ⁇ L of saline solution, were inoculated subcutaneously into the left thighs of 12-week-old Wistar rats.
  • a subcutaneous tumour developed in 80% of animals (Arrieta et al. 1998; Guevara and Sotelo 1999).
  • Histological studies using hematoxiline-eosine were performed on the tissue surrounding the trajectory of the injection of the suspension of PtZSiO 2 - Pt(NHs) 4 CI 2 nanoparticles. The micrographs pertaining to this study are shown in figure 3.
  • Fig 3a an interface clearly shows a line of demarcation between two zones, one in which the tumor cells are clearly visible and the other, visibly showing the cell damage.
  • figure 3b a higher magnification is used to examine the damaged area.
  • figure 3c the absence of growth in the tumoral tissue is apparent.
  • the white dots are DNA fragments.
  • H 2 PtCI 6 xH 2 O was incorporated to a mixture containing of ethanol and deionized water and ⁇ -amminobutyric acid, under constant stirring at 343K. This mixture was refluxed for 10 minutes at 343K prior to the addition of the titanium alkoxide. Then titanium n-butoxide, was added dropwise over a 4 h period. The resulting sols were maintained under constant stirring until gelation occurs. The total molar ratio water:alkoxide:alcohol was 8:1 :16. Alter and aging period of 72 hours at room temperature xerogel samples were obtained by oven drying the obtained solids at 343K.
  • Table 1 shows the final volume of the tumours as a function of treatment. From this data it is clear that both the platinum coordination compound and the TiO 2 carrier produce a significant reduction of the tumour volume. This effect is greatly enhanced in the case of the groups treated with the TiO 2 and TiO 2 -Pt nanodevices.
  • H2PtCI6/SiO2 biocatalysts exhibit a type I isotherm, according to the IUPAC classification, characteristic of microporous materials.
  • H 2 PtCI 6 ZTiO 2 biocatalyst exhibits a type IV isotherm, characteristic of porous materials with bimodal pore size distribution (presence of both micro and mesopores).
  • the presence of a hysteresis loop on the H2PtCI6/TiO2 biocatalysts above p/p o ⁇ O.4 reflects the capillary condensation of nitrogen molecules in the mesopores (figure 4).
  • the BET surface area for both samples is 416 m 2 /g and 250 m 2 /g, for H 2 PtCl6/Si ⁇ 2 and H 2 PtCI 6 ZTiO 2 , respectively, whilst the micropore volume (Vo) is 0.14 and 0.08 ccZg, respectively.
  • the average pore size is 1.4 and 3.1 nm for H 2 PtCI 6 ZSiO 2 and H 2 PtCI 6 ZTiO 2 , respectively, which is in agreement with the analysis done on their isotherms.
  • X-ray photoelectron spectroscopy According to the XPS spectra, Pt nanoparticles are well-dispersed on the surface of the TiO 2 support, as it can be inferred from the PtZTi atomic ratio (this ratio can be used as a rough estimation of the Pt dispersion on the surface of the catalyst).
  • the Pt 4f level X-ray photoelectron spectra for H 2 PtCI 6 ZTiO 2 biocatalyst shows the presence of two broad bands which corresponds to the Pt 4f 7 / 2 and Pt 4f 5/2 levels (see Figure 5). The binding energy (eV) corresponding to these two levels are 72.2 eV and 75.5 eV, respectively.
  • Figure 6 shows TEM images of both (a) H 2 PtCI 6 /Ti0 2 and (b) H 2 PtCVSiO 2 biocatalysts.
  • TiO 2 support ( Figure 6b) exhibits a high degree of crystallinity in accordance with previous observations using raman.
  • a close inspection through the whole biocatalyst does not allow discerning any spot attributed to Pt nanoparticles.
  • the absence of any observation attributed to the platinum nanoparticles is usually attributed to the lower density of the oxide nanoparticles (compared to the pure metal), together with the presence of spectators (organic precursor).
  • the situation is different.
  • TEOS tetraethoxysilane

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Abstract

L'invention porte sur un nouveau matériau nano-structuré comprenant de la silice et de l'oxyde de titane fonctionnalisés et partiellement hydroxylés ayant une plage Ti:Si de composition allant d'environ 100:0 à 0:100, sur des nanoparticules de taille comprise entre 1 nm et 30 nm de platine coordonné (II) dispersées sur la surface et liées dans le réseau du matériau, et sur leur processus de fabrication et d'utilisation.
PCT/IB2009/006079 2009-06-24 2009-06-24 Sol-gel nano-structuré et biocompatible, et biocatalyseurs platine-oxyde de titane et platine-silice nano-structurés et biocompatibles pour utilisation dans le traitement du cancer WO2010150036A1 (fr)

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Cited By (9)

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US8729286B2 (en) 2012-05-10 2014-05-20 Massachusetts Institute Of Technology Platinum compounds as treatment for cancers, and related methods, kits, and compositions
US9034862B2 (en) 2011-06-21 2015-05-19 Massachusetts Institute Of Technology Compositions and methods for the treatment of cancer
US9133225B2 (en) 2013-03-13 2015-09-15 Massachusetts Institute Of Technology Dual targeting anticancer agents
US9265747B2 (en) 2008-08-26 2016-02-23 Massachusetts Institute Of Technology Platinum (IV) complexes for use in dual mode pharmaceutical therapy
US9593139B2 (en) 2013-04-05 2017-03-14 Massachusetts Institute Of Technology Compositions, methods, and kits comprising platinum compounds associated with a ligand comprising a targeting moiety
WO2019016723A3 (fr) * 2017-07-20 2019-02-28 GÓMEZ-LÓPEZ, Wenceslao Biocatalyseurs nanostructurés et biocompatibles utilisables dans le traitement du cancer
CN111093631A (zh) * 2017-07-20 2020-05-01 文塞斯劳·戈麦斯-洛佩斯 包含纳米结构的颗粒的表面、材料和个人的清洁制剂
CN111093630A (zh) * 2017-07-20 2020-05-01 文塞斯劳·戈麦斯-洛佩斯 用于治疗创伤和感染的包含纳米结构、生物可相容且生物催化的材料的制剂
WO2022129983A1 (fr) 2020-12-14 2022-06-23 LÓPEZ MACÍAS, Javier Eduardo Nanosystèmes basés sur des nanocomposites et des extraits naturels

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WO2007141590A1 (fr) * 2006-06-06 2007-12-13 Universidad Autonoma Metropolitana Réservoirs en dioxyde de titane nanostructuré obtenu par voie sol-gel destinés à être utilisés dans la libération contrôlée de médicaments dans le système nerveux central et procédé de synthèse

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Publication number Priority date Publication date Assignee Title
WO2001062232A1 (fr) * 2000-02-21 2001-08-30 Australian Nuclear Science & Technology Organisation Particules de ceramique a liberation lente, compositions correspondantes et procedes de preparation et d'utilisation correspondants
WO2007141590A1 (fr) * 2006-06-06 2007-12-13 Universidad Autonoma Metropolitana Réservoirs en dioxyde de titane nanostructuré obtenu par voie sol-gel destinés à être utilisés dans la libération contrôlée de médicaments dans le système nerveux central et procédé de synthèse

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9265747B2 (en) 2008-08-26 2016-02-23 Massachusetts Institute Of Technology Platinum (IV) complexes for use in dual mode pharmaceutical therapy
US9034862B2 (en) 2011-06-21 2015-05-19 Massachusetts Institute Of Technology Compositions and methods for the treatment of cancer
US8729286B2 (en) 2012-05-10 2014-05-20 Massachusetts Institute Of Technology Platinum compounds as treatment for cancers, and related methods, kits, and compositions
US9133225B2 (en) 2013-03-13 2015-09-15 Massachusetts Institute Of Technology Dual targeting anticancer agents
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CN111093636A (zh) * 2017-07-20 2020-05-01 文塞斯劳·戈麦斯-洛佩斯 用于癌症治疗的纳米结构且生物可相容的生物催化剂
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CN111093631A (zh) * 2017-07-20 2020-05-01 文塞斯劳·戈麦斯-洛佩斯 包含纳米结构的颗粒的表面、材料和个人的清洁制剂
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US20200147259A1 (en) * 2017-07-20 2020-05-14 Wenceslao GÓMEZ-LÓPEZ Formulation comprising nanostructured, biocompatible and biocatalytic material for the treatment of wounds and infections
JP2020528084A (ja) * 2017-07-20 2020-09-17 ゴメス − ロペス、ベンセスラオ 創傷および感染症を治療するためのナノ構造の生体適合性および生体触媒性材料を含む製剤
EP3654943A4 (fr) * 2017-07-20 2021-08-18 Gómez-López, Wenceslao Formulation de nettoyage personnel, de matériau et de surface comprenant des particules nanostructurées
WO2022129983A1 (fr) 2020-12-14 2022-06-23 LÓPEZ MACÍAS, Javier Eduardo Nanosystèmes basés sur des nanocomposites et des extraits naturels

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