WO2016058447A1 - Nanovéhicule de médicament et procédé de préparation et utilisation de celui-ci - Google Patents

Nanovéhicule de médicament et procédé de préparation et utilisation de celui-ci Download PDF

Info

Publication number
WO2016058447A1
WO2016058447A1 PCT/CN2015/087714 CN2015087714W WO2016058447A1 WO 2016058447 A1 WO2016058447 A1 WO 2016058447A1 CN 2015087714 W CN2015087714 W CN 2015087714W WO 2016058447 A1 WO2016058447 A1 WO 2016058447A1
Authority
WO
WIPO (PCT)
Prior art keywords
mesoporous silica
solution
concanavalin
particles
layer
Prior art date
Application number
PCT/CN2015/087714
Other languages
English (en)
Chinese (zh)
Inventor
刘昌胜
屈雪
李金阳
Original Assignee
华东理工大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 华东理工大学 filed Critical 华东理工大学
Publication of WO2016058447A1 publication Critical patent/WO2016058447A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein

Definitions

  • the invention belongs to the field of biotechnology, and relates to a drug delivery system, in particular to a tumor targeting and stimuli-responsive nano drug carrier regulated by a functional protein membrane, a preparation method and application thereof.
  • Nanoscale-based drug carriers are able to ooze out of tumor blood vessels by Enhanced Permeability and Retention, and the loaded drug is more highly available than free drug molecules.
  • it is necessary to give the nanocarrier its targeting and responsiveness, so as to avoid degradation or early leakage of the drug during the delivery process, so that the drug is specifically delivered to the tumor site, and its special physiology
  • the environment responds by regulating the timing and location of drug release.
  • the pH value of normal tissues is 7.4. Due to abnormal proliferation, tumor cells are in anoxic state for a long time, and anaerobic glycolysis produces lactic acid, and the pH around the tissue is about 6.8. In addition, the endosomes and lysosomes in tumor cells are more acidic.
  • the pH of early endosomes in tumor cells measured by electron and chemical probes is about 6.0, and some even lower than 5.4.
  • the pH of late endosomes is generally around 5.0, and some are even lower than 4.0.
  • Nano-mesoporous silica is an ideal intracellular drug transport carrier because of its good biocompatibility, particle size and pore size, nanometer scale, high specific surface area and good lysosomal escape ability.
  • a large number of studies have been conducted to introduce functionalized "nano-caps" on the surface of nano-mesoporous silica (MSN), giving them better drug controlled release and targeted functions.
  • Nano-mesoporous silica is used as a drug carrier according to its controlled release mechanism. It can be divided into two major categories by chemical modification. The MSN mesoporous channel is chemically modified by carboxyl group, amino group, etc., and the group is conjugated with the drug.
  • connection using the sensitivity of the linking unit to the acidic or reducing microenvironment, thereby controlling drug release;
  • loading the drug into the mesoporous channel using quantum dots, nano-ferric oxide, polyelectrolyte, bovine serum white
  • the particles or macromolecules of the protein block the mesoporous channels, and regulate the release or retention of the drug by regulating the switch of the blocking agent.
  • the latter has no requirement for the chemical structure, solubility, and electronegativity of the drug molecule.
  • the drug is stored in the mesoporous channel by the physical load, which can better preserve the chemical structure and activity of the drug, and thus has a broad Application prospects.
  • the object of the present invention is to provide a novel functional protein membrane-regulated tumor targeting and stimuli-responsive nano drug carrier in view of the deficiencies of the existing tumor-targeted drug delivery system.
  • a mesoporous silica composite particle comprising a core, a middle layer and an outer layer, wherein
  • the inner core is a nanometer mesoporous silica particle
  • the middle layer is disposed on a surface of the inner core, and includes at least one self-assembled layer, and the self-assembled layer comprises concanavalin A and a glycoside which are combined with each other;
  • the outer layer is a transferrin layer disposed on the surface of the intermediate layer.
  • a layer of concanavalin A is further disposed between the intermediate layer and the outer layer.
  • the transferrin is a human-derived iron-saturated transferrin.
  • the intermediate layer has 1-15 layers of self-assembled layers, preferably 2-10 layers of self-assembled layers.
  • the mesoporous silica composite particles dissociate at the intermediate layer and the outer layer at pH 4.0-6.0.
  • the mesoporous silica composite particles are pyrolyzed at a temperature higher than 200 ° C to 550 ° C, and the weight loss rate is 20-30%.
  • the mesoporous silica composite particles have one or more of the following characteristics:
  • the nanometer mesoporous silica particles have a pore diameter of 1.5-30 nm;
  • the nanometer mesoporous silica particles have a particle size of 50-300 nm
  • the mesoporous silica composite particles have an average particle diameter of 60-350 nm;
  • the mesoporous silica composite particles are pyrolyzed at a temperature higher than 200 ° C to 550 ° C, and the weight loss rate is 20-30%.
  • the mesoporous silica composite particles have a typical amide group vibration peak at about 1532 cm -1 and about 1468 cm -1 with respect to the nano mesoporous silica particles.
  • a method for preparing a mesoporous silica composite particle according to the first aspect comprising the steps of:
  • the nano-mesoporous silica particles are positively charged and dispersed in a solution containing a concanavalin A solution, and then dispersed into a solution containing a glycogen to form a self-assembly on the surface of the nano-mesoporous silica particles. a layer, optionally repeating the above steps to form a plurality of layers of self-assembled layers;
  • step (c) Dispersing the particles obtained in the step (b) into the solution containing the concanavalin A solution, and then dispersing into the transferrin solution to obtain the mesoporous silica composite particles.
  • the nano mesoporous silica particles used in the present invention can be produced by various methods known in the art, and are not particularly limited.
  • the nanomesoporous silica particles are prepared by the following steps: preparing an aqueous solution of cetyltrimethylammonium bromide. Adding an appropriate amount of ammonia water, adjusting the pH of the solution to above 12; adding tetraethyl orthosilicate through a separatory funnel, after completion of the reaction, extracting by filtration to obtain a white solid product; and drying the solid product by high temperature calcination to remove the template , nano-mesoporous silica particles can be obtained.
  • the mesoporous nano silica is dispersed in a polyethyleneimine solution (0.1-5 mg/mL, preferably 0.5-4.5 mg/mL) to make the nanometer mesoporous silica particles. Positively charged.
  • the method of preparation comprises one or more of the following features:
  • the concentration (or content) of the concanavalin A in the solution containing the concanavalin A in the step (b) or the step (c) is 0.2-5 mg/mL, preferably 0.5- 3 mg/mL, more preferably 0.8-2.5 mg/mL;
  • the concentration (or content) of the glycogen in the glycogen-containing solution of the step (b) is 0.2-5 mg / mL, preferably 0.5-3 mg / mL;
  • the volume ratio of the nano-mesoporous silica particles in the step (b) to the solution containing the concanavalin A solution is 1-60 mg: 1 ml, preferably 10-50 mg: 1 ml. More preferably 30-45 mg: 1 ml;
  • the volume ratio of the mass of the nano-mesoporous silica particles to the solution containing the saccharide in the step (b) is 1-60 mg: 1 ml, preferably 10-50 mg: 1 ml, more Good land is 30-45mg: 1ml;
  • the concentration (or content) of transferrin in the transferrin solution is 0.2-5 mg / mL, preferably 0.5-3 mg / mL;
  • the volume ratio of the mass of the particles obtained in the step (b) to the solution containing the concanavalin A solution is 1-60 mg: 1 ml, preferably 10-50 mg: 1 ml, more preferably 30- 45mg: 1ml;
  • the volume ratio of the mass of the particles obtained in the step (b) to the transferrin solution is 1-60 mg: 1 ml, preferably 10-50 mg: 1 ml, more preferably 30-45 mg: 1 ml. .
  • the use of the mesoporous silica composite particles of the first aspect is provided for the preparation of a pharmaceutical carrier.
  • the pharmaceutical carrier is a stimuli-responsive pharmaceutical carrier.
  • the drug carrier is a tumor-targeting drug carrier
  • the pharmaceutical carrier is a tumor targeting and stimuli responsive pharmaceutical carrier.
  • the drug carrier is capable of inhibiting drug leakage under simulated extracellular pH conditions (pH 6.8-7.4), in the middle and outer layers of the pH of the simulated intracellular endosomes (pH 4.5-6.0). Dissociation occurs, thereby inducing drug release.
  • a composite comprising:
  • the anticancer drug is selected from the group consisting of: doxorubicin, 5-fluorouracil, busulfan, bleomycin, vinblastine, docetaxel, cyclophosphamide, gemcitabine, methotrexate, Carboplatin, capecitabine, lomustine, hydroxyurea, cisplatin, mitomycin, etoposide, paclitaxel, gefitinib.
  • the mesoporous silica composite particles are dispersed in an anticancer drug solution to obtain the complex.
  • a pharmaceutical composition comprising the complex of the fourth aspect and a pharmaceutically acceptable carrier is provided.
  • a sixth aspect of the invention provides the use of the complex of the fourth aspect or the pharmaceutical composition of the fifth aspect for the preparation of a medicament for preventing and/or treating a tumor.
  • the tumor includes, but is not limited to, liver cancer, lung cancer (including mediastinal cancer), oral cavity Skin cancer, nasopharyngeal cancer, thyroid cancer, esophageal cancer, lymphoma, chest cancer, digestive tract cancer, pancreatic cancer, intestinal cancer, breast cancer, ovarian cancer, uterine cancer, kidney cancer, gallbladder cancer, cholangiocarcinoma, central nervous system cancer , testicular cancer, bladder cancer, prostate cancer, skin cancer, melanoma, meat cancer, brain cancer, blood cancer (leukemia), cervical cancer, glioma, stomach cancer, or ascites.
  • liver cancer includes, but is not limited to, liver cancer, lung cancer (including mediastinal cancer), oral cavity Skin cancer, nasopharyngeal cancer, thyroid cancer, esophageal cancer, lymphoma, chest cancer, digestive tract cancer, pancreatic cancer, intestinal cancer, breast cancer, ovarian cancer, uterine cancer, kidney cancer, gallbladder cancer, cholan
  • the mesoporous silica composite particles of the present invention are tumor targeting and stimuli-responsive nano drug carriers regulated by functional protein membranes.
  • the invention adopts nano mesoporous silica as a drug carrier, and utilizes the bioreversible bond between Concanavalin Con A and the sugar unit as a driving force, and the concanavalin A and the glycogen and transferrin are assembled units.
  • a multi-layered protein membrane structure was constructed on the surface of nano-mesoporous silica by layer-by-layer self-assembly technology. After drug loading, a nano drug delivery system with tumor targeting and stimuli responsiveness was obtained.
  • the invention has the characteristics of simple and mild preparation method, good biocompatibility, physiological response condition and high tumor targeting efficiency, and is suitable for targeted therapy of various tumors.
  • Figure 1 is a transmission electron micrograph.
  • Figure 2 is an infrared spectrum.
  • Figure 3 is a thermogravimetric map.
  • Figure 4 is a graph showing the release profile of the antitumor drug doxorubicin under different pH conditions.
  • Figure 5 is a graph showing the biospecific binding force of transferrin and concanavalin.
  • Figure 6 is a graph showing the results of specific uptake of human hepatoma cell line HepG2 against tumor targeting and stimuli-responsive nano drug carriers by confocal microscopy.
  • Figure 7 is a graph showing the selectivity of tumor targeting and stimuli-responsive nano drug carriers to human hepatoma cells HepG2 and human normal liver cells L02 by flow cytometry.
  • Figure 8 is a graph showing the results of dissociation behavior of tumor targeting and stimuli-responsive functional protein membranes in human hepatoma cells HepG2 and human normal liver cells L02 by confocal microscopy.
  • Figure 9 is a graph showing the results of drug release behavior of tumor targeting and stimuli-responsive nano drug delivery systems in human hepatoma cells HepG2 and human normal liver cells L02 by confocal microscopy.
  • Figure 10 is a MTT assay for tumor targeting and stimuli-responsive functional protein membrane anti-tumor drug doxorubicin on human hepatoma cells HepG2, human breast cancer cells MDA-MB-231, human gastric cancer cells MGC-803, human normal liver cells L02 The results of the toxicity regulation of mouse myoblast C2C12.
  • the inventors of the present application have extensively and intensively studied to develop a novel drug carrier for the first time, which is a mesoporous silica composite particle, the core is a nano mesoporous silica particle, and the nano mesoporous silica
  • the surface of the particle has one or more layers of self-assembled layers comprising Concanavalin A and a glycoside bonded to each other, and the surface of the outermost self-assembled layer has a transferrin layer.
  • the drug carrier of the invention utilizes the targeting function of the outer layer transferrin on the tumor cells, and the response dissociation function of the inner layer concanavalin A-glycan element in the low pH environment of the tumor cells can realize the carrier anti-tumor drug Targeted transmission, fixed-point release. On the basis of this, the present invention has been completed.
  • Concanavalin A is a globulin-type lectin extracted from the giant bean, which is tetramer at pH 6.8 or higher, and each subunit corresponds to a sugar binding site. Under acidic conditions, the protein depolymerizes to form a dimer, and the sugar binding site changes from four to two.
  • a glycoside is a branched polysaccharide composed of glucose, which is capable of specifically binding to concanavalin A with pH-dependent properties.
  • TfR transferrin receptor
  • CD71 transferrin receptor
  • Transferrin is a single-chain glycoprotein containing two N-oligosaccharide chains with a molecular weight of 7.7 kDa and a sugar content of about 6%. It is also capable of undergoing sugar residue-based organisms with concanavalin A. Specific binding.
  • the mesoporous material is a novel material having a large specific surface area and a three-dimensional pore structure between pores and macropores.
  • Mesoporous silica has large encapsulation, large specific surface area (>900m 2 /g), easy modification of inner and outer surfaces, orderly pores, adjustable pore size (2-10nm), non-toxic, good biocompatibility and thermodynamic stability. Highly characterized, it is an ideal nano-container storage and release carrier.
  • the invention adopts concanavalin A, glycoside and transferrin as assembly units, and uses the biospecific binding force as a driving force to form a surface on the surface of the nanometer mesoporous silica particles by using a layer-by-layer self-assembly film forming technology.
  • Layer or multi-layered concanavalin A-glycan self-assembled layer and forms a supramolecular layered membrane with transferrin as the outer layer, using the outer transferrin to target the tumor cells, concanavalin
  • the dissociation function of A-glycogen on the tumor cell internal environment enables the targeted delivery and targeted release of the anti-tumor drug.
  • the mesoporous silica composite particles of the present invention comprise a core, a middle layer and an outer layer, wherein
  • the inner core is a nanometer mesoporous silica particle
  • the middle layer is disposed on a surface of the inner core, and includes at least one self-assembled layer, and the self-assembled layer comprises concanavalin A and a glycoside which are combined with each other;
  • the outer layer is a transferrin layer disposed on the surface of the intermediate layer.
  • Construction of multi-layer self-assembled protein multilayer film Weigh a certain amount of mesoporous nano-silica and disperse it in a positively charged polyelectrolyte solution to make mesoporous nano-silica positively charged. After centrifugation washing, the nanoparticles were sequentially dispersed in the concanavalin A solution and the glycogen solution, and this step was repeated until a specified number of layered self-assembled protein multilayer films were obtained on the surface of the mesoporous nanosilica. Finally, the nanoparticles were sequentially redispersed in the concanavalin A solution and the transferrin solution, and the protein membrane was subjected to targeted modification.
  • the present invention also replaces Concanavalin A with FITC-labeled Concanavalin A to prepare a layered self-assembled protein multilayer film having a fluorescent label to study the responsiveness of the multilayer film.
  • a tumor targeting and stimuli-responsive drug delivery system Construction of a tumor targeting and stimuli-responsive drug delivery system: the above-mentioned nanoparticles coated with a protein multilayer film (ie, The mesoporous silica composite particles were dispersed in a higher concentration of doxorubicin solution and shaken overnight. The unloaded free drug molecules are centrifuged and washed, and the tumor-targeted and stimuli-responsive drug delivery system is obtained after lyophilization.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient in a safe and effective amount, together with a pharmaceutically acceptable carrier.
  • the "active ingredient" as used in the present invention means a complex according to the present invention, comprising the mesoporous silica composite particles of the present invention; and an anticancer drug.
  • the "active ingredient" and pharmaceutical composition of the present invention can be used for the preparation of a medicament for preventing and/or treating a tumor.
  • the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient per dose, more preferably from 10 to 200 mg of active ingredient per dose.
  • the "one dose” is a tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the administration form of the active ingredient or the pharmaceutical composition of the present invention is not particularly limited, and representative administration forms include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example,
  • the solid dosage forms can also be prepared with coatings and shell materials, such as casings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the complex or pharmaceutical composition of the invention may be administered alone or in combination with other therapeutic agents such as chemotherapeutic agents.
  • a safe and effective amount of the complex of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective effective administration dose, and for a person having a weight of 60 kg,
  • the daily dose is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the present invention utilizes the biospecific binding force between concanavalin and a glycosyl group to construct a concanavalin A-glycan as a middle layer and a transferrin on the surface of mesoporous nanosilica by layer self-assembly.
  • the outer layer of supramolecular layered membrane obtains a nanomedicine carrier with dual characteristics of tumor targeting and stimuli response.
  • the nano drug carrier of the invention has good biocompatibility, simple preparation, targeted selection of a plurality of tumor cells, and the response condition conforms to the cell microenvironment.
  • the preparation method of the invention is simple, and the drug or the carrier is not modified, and the protein supermolecular membrane having the dual characteristics of tumor targeting and stimulating response is prepared by using the sugar binding function of concanavalin A.
  • Con A represents concanavalin A
  • Gly represents glycoside
  • Tf represents transferrin
  • MSN mesoporous nanosilica
  • subscript n represents concanavalin A-glycan self-assembled multilayer.
  • the number of layers of the membrane the superscript D represents the antitumor drug doxorubicin loaded, and the structure of the nanoparticles is represented by sequentially arranging the constituent units from the outside to the inside, for example, targeting the nano drug-loading particles Tf/Con A (Gly /Con A) 4 -MSN D refers to the concanavalin A-glycan self-assembled multilayer membrane with outer layer of transferrin and 4 layers of middle layer, and the core is nanometer loaded with antitumor drug doxorubicin. Particles.
  • tumor targeting and stimuli-responsive drug carriers (mesoporous silica composite particles and composites)
  • concanavalin A By repeating the assembly procedure of the above-mentioned concanavalin A and glycoside, two double-layered protein supramolecular membranes can be constructed on the surface of mesoporous nanosilica. Finally, the nanoparticles were sequentially redispersed in concanavalin A (2 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+ ) and transferrin solution (2 mg/mL, 10 mM Tris). -HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+ ), slowly stirred for 30 min, centrifuged, and washed.
  • the above-mentioned protein-coated multilayered nanoparticles were dispersed in a 4 mg/mL doxorubicin solution and shaken overnight.
  • the unloaded free drug molecules are centrifuged and washed, and the tumor-targeted and stimuli-responsive mesoporous silica composite particles are obtained after lyophilization.
  • mesoporous nanosilica 150 mg was weighed and dispersed in 5 mL of polyethyleneimine solution (4 mg/mL, 0.5 M NaCl solution) to make the mesoporous nanosilica positively charged. After centrifugation, the nanoparticles were dispersed in 5 mL of concanavalin A solution (1.5 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+ ), slowly stirred for 30 min, centrifuged, and washed; 5 mL of glycoside solution (2.5 mg/mL, Tris-HCl buffer) was stirred slowly for 30 min, then centrifuged and washed.
  • concanavalin A solution 1.5 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+
  • nanoparticles were sequentially redispersed in concanavalin A (2.5 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+ ) and transferrin solution (2.5 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+ ), slowly stirred for 35 min, centrifuged, and washed.
  • concanavalin A 2.5 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+
  • transferrin solution 2.5 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+
  • the above-mentioned protein-coated multilayered nanoparticles were dispersed in a 4 mg/mL 5-fluorouracil solution and shaken overnight.
  • the unloaded free drug molecules are centrifuged and washed, and the tumor-targeted and stimuli-responsive mesoporous silica composite particles are obtained after lyophilization.
  • concanavalin A By repeating the assembly steps of the above-mentioned concanavalin A and glycoside nine times, ten double-layered protein supramolecular membranes can be constructed on the surface of mesoporous nanosilica. Finally, the nanoparticles were redispersed in concanavalin A solution (2.5 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+ ), slowly stirred for 35 min, and then centrifuged and washed. This sample is referred to as Con A(Gly/Con A) 10 -MSN, and its transmission electron micrograph is shown in Fig. 1, and has a particle diameter of about 60 to 100 nm.
  • Concanavalin A was labeled with FITC fluorescence, and the rest of the operations were the same.
  • the nanoparticles coated with four bilayer protein supramolecular membranes were prepared. The sample was recorded as (Gly). /Con A@FITC) 4 -MSN.
  • (Gly/Con A) 4 -MSN was dispersed in concanavalin A solution (2 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+ ), slowly stirred for 30 min, centrifuged, and washed. This sample is referred to as Con A(Gly/Con A) 4 -MSN.
  • Tf/Con A(Gly/Con A) 4 -MSN Distribute Con A(Gly/Con A) 4 -MSN into transferrin solution (2mg/mL, 10mM Tris-HCl buffer containing 1mM Ca 2+ , 1mM Mn 2+ ), slowly stir for 30min, then centrifuge and wash This sample is referred to as Tf/Con A(Gly/Con A) 4 -MSN.
  • Tf/Con A(Gly/Con A) 4 -MSN was dispersed in a 4 mg/mL doxorubicin solution and shaken overnight.
  • the unloaded free drug molecules were centrifuged and washed, and after lyophilization, the nano drug-loaded particles (drug-loaded complex) were obtained, and the sample was recorded as Tf/Con A(Gly/Con A) 4 -MSN D .
  • Example 2 200 mg of the mesoporous nanosilica prepared in Example 1 was weighed and dispersed in a 5 mL polyethyleneimine solution (1 mg/mL, 0.5 M NaCl solution) to bring a positive charge to the mesoporous nanosilica. After centrifugation, the nanoparticles were dispersed in 5 mL of concanavalin A solution (1 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+ ), slowly stirred for 30 min, and then centrifuged and washed.
  • concanavalin A solution (1 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+
  • (Gly/Con A) 5 -MSN was dispersed in concanavalin A solution (1 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+ ), stirred slowly for 40 min, then centrifuged and washed. This sample is referred to as Con A(Gly/Con A) 5 -MSN.
  • Tf/Con A(Gly/Con A) 5 -MSN Disperse Con A(Gly/Con A) 5 -MSN into transferrin solution (1 mg/mL, 10 mM Tris-HCl buffer containing 1 mM Ca 2+ , 1 mM Mn 2+ ), slowly stir for 40 min, centrifuge, wash This sample is referred to as Tf/Con A(Gly/Con A) 5 -MSN.
  • Tf/Con A(Gly/Con A) 4 -MSN was dispersed in a 5 mg/mL docetaxel solution and shaken overnight. The unloaded free drug molecules are centrifuged and washed, and the drug-loaded complex is obtained after lyophilization.
  • the infrared analysis spectrum of MSN, (Gly/Con A) 4 -MSN is shown in Figure 2.
  • the nanomaterials coated with the protein film are at 1532 cm -1 and 1468 cm -1 .
  • the typical amide group vibration peak further demonstrates the successful construction of the protein membrane.
  • Thermogravimetric analysis (shown in Figure 3) of MSN, (Gly/Con A) 4 -MSN shows that the middle layer and the outer layer are pyrolyzed at a temperature higher than 200 ° C to 550 ° C, and the weight loss rate is reached. 20-30% (the specific gravity of the protein film is about 20%-30%).
  • the multilayer film can be kept stable under neutral conditions; at pH 5.5, the multilayer film can be dissociated to a certain extent; at pH 5.0, the multilayer film is rapidly A response occurred, and the degree of dissociation in the first 2 hours reached about half of the first 12 hours.
  • the layer-by-layer self-assembled multilayer film has the characteristics of maintaining structural stability in a neutral environment and different degrees of dissociation under weakly acidic conditions.
  • the release behavior of the nano drug-loaded particles in the simulated intracellular weakly acidic conditions is basically consistent with the dissociation behavior of the multilayer film.
  • the degree of dissociation of the multilayer membrane is not high, but the degree of cross-linking is decreased, thus “opening” the mesoporous channel and inducing drug release.
  • the release rate after about 12 h is about 45%; at pH 5.0 Under the simulated lysosome pH environment, the multilayer film rapidly dissociated. After 7h, the release rate reached 50%, and the 12h release rate was about 70%.
  • the stimuli-responsive mesoporous silica composite particles of the present invention achieve controlled release of the drug, and the response condition is in accordance with the physiological environment, and is an ideal intracellular drug transport carrier.
  • both ligand A and ligand B are capable of binding to the receptor R and the affinity of molecule A is higher, the high affinity ligand A is first premixed with the acceptor, and then the low affinity ligand B is added. The body will preferentially interact with ligand A, and only a small fraction of ligand A is replaced by ligand B from the binding site, so there will be only a small apparent heat change.
  • the present invention firstly studied the thermodynamic binding of transferrin and concanavalin A using an isothermal titration calorimeter (ITC 200, Micarcal, Inc.) and has been conjugated to the sugar binding site of concanavalin A.
  • ITC 200 isothermal titration calorimeter
  • the high affinity ligand methyl- ⁇ -D-mannopyranoside is occupied, the competitive thermodynamic binding of transferrin to it is demonstrated, and the interaction between transferrin and Con A is based on transferrin Tf. Biospecific binding between the sugar chain and Con A.
  • transferrin (denoted as Tf) and concanavalin A were combined into a solution, which was degassed by high speed centrifugation (8000 rpm, 3 min) after passing through a 220 nm filter.
  • Set the experimental temperature to 25 ° C, the reference power 5 ⁇ cal / sec, the stirring speed of 1500 rpm; add 200 ⁇ L of Concanavalin A solution in the sample cell, 40 ⁇ L of transferrin solution in a syringe, drop one drop every 120s, 1.5 drops per drop ⁇ L, using the Origin plug provided by Microcal, Inc. for data processing, using a single binding model to calculate the thermodynamic parameters such as binding constant, number of binding sites, and molar binding enthalpy.
  • FIG. 5 The photograph of A in Fig. 5 shows that transferrin is cross-linked with concanavalin A at pH 7.4 to form a precipitate, and the process is high-affinity ligand methyl- ⁇ -D-pyridine of concanavalin A.
  • C in Figure 5 indicates that methyl- ⁇ -D-mannopyranoside (Me- ⁇ -man) is a high-affinity ligand for concanavalin A.
  • mesoporous silica was fluorescently labeled with FITC, mesoporous silica (MSN) and unmodified transferrin mesoporous silica composite particles (Con A(Gly) /Con A) 4 -MSN) is a control group, and pre-incubation by adding free transferrin to the culture medium to occupy the cell surface transferrin receptor binding site by confocal microscopy and flow cytometry Semi-quantitative and quantitative analysis were performed separately to further investigate the specific recognition of tumor-targeted mesoporous silica composite particles by transferrin receptor.
  • the specific operation was as follows: HepG2 cells were seeded at a density of 2 ⁇ 10 4 /well in a NEST laser confocal special glass bottom petri dish to grow adherently.
  • Tf/Con A(Gly/Con A) 4 -MSN+ competition factor Tf group one group (named Tf/Con A(Gly/Con A) 4 -MSN+ competition factor Tf group) was removed after co-culture for 22 h, and the addition of 200 ⁇ g/mL was added. The cell culture medium of ferritin is pre-incubated. After 2 h, the wells were removed and cell culture media containing 50 ⁇ g/mL of different functionalized nano drug carriers were added.
  • the cell culture medium containing nanoparticles was removed, washed 3 times with PBS, the unintaked nanoparticles were removed, fixed in 1% glutaraldehyde solution for 15 min, labeled with DAPI, and passed through a confocal microscope. (Nikon A1R) Observed the intracellular distribution of nanoparticles and drugs.
  • the wavelength is set as follows: DAPI channel excitation at 404.3 nm, reception at 450.0 nm; FITC channel (ie MSN) excitation at 488.0 nm, reception at 525.0 nm, observation under 60 times oil mirror, as shown in Figure 6, respectively, from left to right
  • a human liver cancer cell line HepG2 and a human normal liver cell L02 are used as a cell model.
  • HepG2 cells and L02 cells were seeded in a 6-well plate at a density of 40 ⁇ 10 4 /well to grow adherently.
  • one group of HepG2 cells designated Tf/Con A (Gly/Con A) 4 -MSN+ competition factor Tf group
  • Tf/Con A Gly/Con A 4 -MSN+ competition factor
  • the cell culture medium containing the nanoparticles was removed, washed twice with PBS, digested with trypsin for 1-2 minutes, and the cells were collected into a centrifuge tube, centrifuged at 1000 rpm/5 min, and washed twice with PBS.
  • extracellular fluorescence was quenched by adding 1 mL of 0.4% trypan blue solution, and the residual trypan blue flow cytometry was washed away with PBS. The results are shown in Fig. 7. Show.
  • the system After the outermost layer of the multilayer film (self-assembled layer) was connected to Tf, the system was given The excellent targeting performance, the surface of HepG2 cells due to the presence of a large number of TfR1 and TfR2, and the specific recognition of Tf on the surface of nanoparticles mediated a large number of endocytosis, the uptake rate reached 60%. At the same time, since the sugar binding site of Con A on the surface of the nanoparticle is mostly occupied by Tf, the specific binding of the particle to the glycoprotein on the cell membrane surface no longer exists, and the uptake rate of L02 cells is reduced to about 25%.
  • the mesoporous silica was labeled with a red fluorescent probe, Texas Red, and the concanavalin A was labeled with a green fluorescent probe FITC to synthesize a dual fluorescently labeled nano drug carrier, and the nanoparticles were co-cultured with the cells. Confocal fluorescence microscopy was used to study the uptake of nano drug carriers and the dissociation behavior of multilayer films.
  • the specific operation was as follows: HepG2 and L02 cells were seeded at a density of 2 ⁇ 10 4 /well in a special glass-bottomed Petri dish of NEST laser confocal, and the cell culture medium was removed after adherent growth for 24 hours, and a double fluorescence of 20 ⁇ g/mL was added.
  • the cell culture medium of the labeled nano drug carrier was incubated for 3 h, 8 h, and 24 h, respectively, and washed with PBS three times to remove the unintaked nanoparticles, and fixed in a 1% glutaraldehyde solution for 15 min, and the nuclei were labeled with DAPI.
  • Laser confocal microscopy (Nikon A1R) was used to observe the intracellular distribution of nanoparticles and drugs.
  • the wavelength settings are as follows: DAPI channel excitation at 404.3 nm, reception at 450.0 nm; FITC channel (ie Con A) excitation at 488.0 nm, reception at 525.0 nm; Texas Red channel (ie MSN) excitation at 561.0 nm, reception at 595.0 nm, Observed under a 60-fold oil microscope, the results are shown in Fig. 8.
  • mesoporous silica was labeled with the red fluorescent probe Texas Red, and a multi-layered targeting protein membrane was constructed on the surface (MSN drug-loaded with uncoated protein membrane)
  • the particles, MSN D were used as the control group. After the drug was loaded, the cells were co-cultured, and the uptake and drug release behavior of the drug-loaded nanoparticles were observed under a confocal fluorescence microscope.
  • HepG2 and L02 cells were inoculated into the NEST laser confocal special glass bottom culture dish at a density of 2 ⁇ 10 4 /well, and the cell culture medium was removed after adherent growth for 24 hours, and the doxorubicin content was 0.5 ⁇ g/mL.
  • the cells of the above-mentioned fluorescently labeled drug-loaded nanoparticles were incubated for 3 or 8 hours respectively, and then washed three times with PBS to remove the unintaked nanoparticles, and fixed in a 1% glutaraldehyde solution for 15 minutes, and the nuclei were labeled with DAPI.
  • the intracellular distribution of nanoparticles and drugs was observed by laser confocal microscopy (Nikon A1R).
  • the wavelength settings are as follows: DAPI channel excitation at 404.3 nm, reception at 450.0 nm; DOX channel excitation at 488.0 nm, reception at 525.0 nm; Texas Red channel (ie MSN) excitation at 561.0 nm, reception at 595.0 nm, 60 times under oil mirror Observed, the results are shown in Figure 9.
  • HepG2 cells were co-cultured with the material for 3 h, and it was found that the MSN drug-loaded particles were significantly higher in the uptake amount and intracellular drug level of the targeted nano drug-loaded particles than the unmodified protein film.
  • the drug was uniformly dispersed in the cytoplasm at 3 h, and the cells showed green fluorescence; and at this time, since the MSN particles still coexisted with the drug, they exhibited superimposed yellow fluorescence.
  • the nano drug-loaded particles showed red fluorescence due to the large amount of drug escaping; and the behavior of nuclear concentration and cell shrinkage and rounding was observed, indicating that the cells undergo apoptosis under the action of drugs.
  • the uptake of the two nanoparticles was small, and the intake did not increase with time. However, some of the nanoparticles are still taken up by the clathrin-mediated pathway, and drug leakage occurs under the stimulation of intracellular lysosomes.
  • Targeted drug-loaded nanoparticles Tf/Con A(Gly/Con A) 4 -MSN D
  • different tumor cell lines human hepatoma cell HepG2, human breast cancer cell MDA-MB-231, human gastric cancer cell MGC-
  • normal cell line human normal liver cell L02, mouse myoblast C2C12
  • mesoporous silica drug-loaded particles MSN D
  • the cells were seeded at a density of 2 ⁇ 10 4 /well in 24-well plates (6 parallel experiments in each set of experiments), and after 24 hours of adherent growth, one of them (Tf/Con A(Gly/Con A) 4 -MSN D + competition factor Tf) was preincubated with 1 mL of cell culture medium containing 200 ⁇ g/mL transferrin for 30 min to occupy the TfR1 and TfR2 binding sites on the cell membrane surface.
  • the targeting drug-loaded nanocarrier Tf/Con A(Gly/Con A) 4 -MSN D can increase the inhibition rate of tumor cells, which is normal.
  • the toxicity of the cells is greatly reduced. This is because the mesoporous silica composite particles are rapidly endocytosed by the tumor cells mediated by the transferrin receptor, and rapidly release the drug under the stimulation of the intracellular microenvironment of the tumor, so that the inhibition of the tumor cells is stronger;
  • normal cells can only target drug-loaded nanoparticles through clathrin-mediated non-specific endocytic uptake, and the toxicity of the drug-loading system is greatly reduced.
  • the competitive factor Tf the toxicity of the targeted drug-loaded nanoparticles on tumor cells decreased, and it was confirmed that the inhibition rate of the tumor cells was based on the transferrin receptor-mediated active targeting.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nanovéhicule de médicament et un procédé de préparation et une utilisation de celui-ci. Le nanovéhicule de médicament est constitué de particules de composite de dioxyde de silicium mésoporeux, comprenant un noyau interne, une couche intermédiaire et une couche externe, le noyau interne et étant constitué de particules d'oxyde de silicium nano-mésoporeux; la couche intermédiaire est située sur la surface du noyau interne, et comprend au moins une couche d'auto-assemblage, les couches d'auto-assemblage comprenant de la concavaline A et du glycogène qui sont mutuellement combinés; et la couche externe est une couche de transferrine disposée sur la surface de la couche intermédiaire. Le procédé de préparation est : l'utilisation de la technologie de fabrication de membrane par auto-assemblage de couche, la formation d'au moins une couche d'auto-assemblage de concavaline A et de glycogène sur la surface des particules d'oxyde de silicium nano-mésoporeux, et la formation finale d'une membrane de couche supramoléculaire utilisant la transferrine en tant que couche externe. Le nano-véhicule de médicament de l'invention possède les doubles caractéristiques de ciblage tumoral et de réponse aux stimuli.
PCT/CN2015/087714 2014-10-17 2015-08-20 Nanovéhicule de médicament et procédé de préparation et utilisation de celui-ci WO2016058447A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410499726.4 2014-10-17
CN201410499726.4A CN104324380B (zh) 2014-10-17 2014-10-17 一种纳米药物载体及其制备方法和应用

Publications (1)

Publication Number Publication Date
WO2016058447A1 true WO2016058447A1 (fr) 2016-04-21

Family

ID=52399265

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/087714 WO2016058447A1 (fr) 2014-10-17 2015-08-20 Nanovéhicule de médicament et procédé de préparation et utilisation de celui-ci

Country Status (2)

Country Link
CN (1) CN104324380B (fr)
WO (1) WO2016058447A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112450222A (zh) * 2019-12-20 2021-03-09 华中师范大学 一种纳米农药控释剂及其制备方法
CN112618789A (zh) * 2020-12-08 2021-04-09 西安理工大学 一种温度-磁场协同响应释药磷酸钙基骨水泥的制备方法
CN113134012A (zh) * 2021-03-04 2021-07-20 江苏大学 一种CaO2/Fe3O4@OA纳米复合物及其制备方法与应用
CN113149022A (zh) * 2021-04-30 2021-07-23 南昌大学 一种二氧化硅@硅酸钙中空纳米球及其制备方法和应用
CN113559084A (zh) * 2021-07-09 2021-10-29 东华大学 一种基于微流控芯片的载药超小四氧化三铁纳米团簇及其制备方法和应用
CN113633762A (zh) * 2021-06-25 2021-11-12 中国矿业大学 一种介孔硅负载SARS-CoV-2 S蛋白B细胞抗原的纳米颗粒的制备方法及其应用
CN113768903A (zh) * 2021-09-10 2021-12-10 浙江海洋大学 一种褐藻寡糖修饰的氨基化介孔二氧化硅纳米颗粒
CN114010619A (zh) * 2021-11-30 2022-02-08 江南大学 一种功能性纳米平台的构建及应用

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104324380B (zh) * 2014-10-17 2017-08-01 华东理工大学 一种纳米药物载体及其制备方法和应用
CN113058028A (zh) * 2021-03-31 2021-07-02 福建农林大学 一种复合纳米药物的制备及应用
CN115590835B (zh) * 2022-10-25 2023-12-05 宁波高新区美诺华医药创新研究院有限公司 一种鲁拉西酮的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051278A2 (fr) * 2001-07-10 2003-06-26 North Carolina State University Vehicule d'administration de nanoparticules
CN103463639A (zh) * 2012-06-08 2013-12-25 华东理工大学 一种控制释放系统及其制备方法
CN104324380A (zh) * 2014-10-17 2015-02-04 华东理工大学 一种纳米药物载体及其制备方法和应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101773813B (zh) * 2010-03-12 2011-12-21 浙江大学 一种基于伴刀豆球蛋白与糖原特异相互作用制备中空微胶囊的方法
CN103272241A (zh) * 2013-05-20 2013-09-04 东南大学 一种pH敏感释药特性的靶向SERS探针及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051278A2 (fr) * 2001-07-10 2003-06-26 North Carolina State University Vehicule d'administration de nanoparticules
CN103463639A (zh) * 2012-06-08 2013-12-25 华东理工大学 一种控制释放系统及其制备方法
CN104324380A (zh) * 2014-10-17 2015-02-04 华东理工大学 一种纳米药物载体及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WANG, XIN ET AL.: "Mesoporous silica nanoparticles for cancer theranostic drug delivery", ACTA PHARMACEUTICA SINICA, vol. 48, no. 1, 31 January 2013 (2013-01-31), pages 8 - 13, ISSN: 0513-4870 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112450222A (zh) * 2019-12-20 2021-03-09 华中师范大学 一种纳米农药控释剂及其制备方法
CN112450222B (zh) * 2019-12-20 2023-09-15 华中师范大学 一种纳米农药控释剂及其制备方法
CN112618789A (zh) * 2020-12-08 2021-04-09 西安理工大学 一种温度-磁场协同响应释药磷酸钙基骨水泥的制备方法
CN112618789B (zh) * 2020-12-08 2022-06-10 西安理工大学 一种温度-磁场协同响应释药磷酸钙基骨水泥的制备方法
CN113134012A (zh) * 2021-03-04 2021-07-20 江苏大学 一种CaO2/Fe3O4@OA纳米复合物及其制备方法与应用
CN113149022B (zh) * 2021-04-30 2022-07-22 南昌大学 一种二氧化硅@硅酸钙中空纳米球及其制备方法和应用
CN113149022A (zh) * 2021-04-30 2021-07-23 南昌大学 一种二氧化硅@硅酸钙中空纳米球及其制备方法和应用
CN113633762A (zh) * 2021-06-25 2021-11-12 中国矿业大学 一种介孔硅负载SARS-CoV-2 S蛋白B细胞抗原的纳米颗粒的制备方法及其应用
CN113633762B (zh) * 2021-06-25 2023-10-13 中国矿业大学 一种介孔硅负载SARS-CoV-2 S蛋白B细胞抗原的纳米颗粒的制备方法及其应用
CN113559084A (zh) * 2021-07-09 2021-10-29 东华大学 一种基于微流控芯片的载药超小四氧化三铁纳米团簇及其制备方法和应用
CN113768903A (zh) * 2021-09-10 2021-12-10 浙江海洋大学 一种褐藻寡糖修饰的氨基化介孔二氧化硅纳米颗粒
CN113768903B (zh) * 2021-09-10 2022-12-13 浙江海洋大学 一种褐藻寡糖修饰的氨基化介孔二氧化硅纳米颗粒
CN114010619B (zh) * 2021-11-30 2022-07-19 江南大学 一种功能性纳米平台的构建及应用
CN114010619A (zh) * 2021-11-30 2022-02-08 江南大学 一种功能性纳米平台的构建及应用

Also Published As

Publication number Publication date
CN104324380B (zh) 2017-08-01
CN104324380A (zh) 2015-02-04

Similar Documents

Publication Publication Date Title
WO2016058447A1 (fr) Nanovéhicule de médicament et procédé de préparation et utilisation de celui-ci
Samadi et al. Ameliorating quercetin constraints in cancer therapy with pH-responsive agarose-polyvinylpyrrolidone-hydroxyapatite nanocomposite encapsulated in double nanoemulsion
Song et al. An oral drug delivery system with programmed drug release and imaging properties for orthotopic colon cancer therapy
Rahmani et al. Preparation of a pH‐responsive chitosan‐montmorillonite‐nitrogen‐doped carbon quantum dots nanocarrier for attenuating doxorubicin limitations in cancer therapy
Xie et al. Hybrid nanoparticles for drug delivery and bioimaging: mesoporous silica nanoparticles functionalized with carboxyl groups and a near-infrared fluorescent dye
Tang et al. Facile synthesis of pH sensitive polymer-coated mesoporous silica nanoparticles and their application in drug delivery
Gao et al. Mesoporous silica nanoparticles capped with graphene quantum dots as multifunctional drug carriers for photo-thermal and redox-responsive release
Chang et al. A pH-responsive mesoporous silica nanoparticle-based drug delivery system for targeted breast cancer therapy
Yue et al. Cancer cell membrane-modified biodegradable mesoporous silica nanocarriers for berberine therapy of liver cancer
Kong et al. Polyethyleneimine-stabilized hydroxyapatite nanoparticles modified with hyaluronic acid for targeted drug delivery
Leporatti Halloysite clay nanotubes as nano‐bazookas for drug delivery
Anirudhan et al. Synthesis characterization and biological evaluation of alginate nanoparticle for the targeted delivery of curcumin
Guo et al. Overcoming drug resistance with functional mesoporous titanium dioxide nanoparticles combining targeting, drug delivery and photodynamic therapy
KR101580251B1 (ko) Tpp-pcl-tpp 고분자 및 상기 고분자를 이용한 미토콘드리아 표적 나노약물전달용 조성물
CN104523723A (zh) 一种可逆转肿瘤耐药的线粒体靶向胶束递药系统
Liu et al. Inhibition of growth and metastasis of breast cancer by targeted delivery of 17-hydroxy-jolkinolide B via hyaluronic acid-coated liposomes
Zhou et al. Drug-mediation formation of nanohybrids for sequential therapeutic delivery in cancer cells
Zhang et al. Chitosan and dextran stabilized GO-iron oxide nanosheets with high dispersibility for chemotherapy and photothermal ablation
Zhao et al. Magnetic mesoporous silica nanoparticles mediated redox and pH dual-responsive target drug delivery for combined magnetothermal therapy and chemotherapy
Wu et al. Mesoporous iron-carboxylate metal–organic frameworks synthesized by the double-template method as a nanocarrier platform for intratumoral drug delivery
CN113384530B (zh) 一种多糖核心Nanocells及其制备方法与应用
Guan et al. Multifunctional Fe3O4@ SiO2-CDs magnetic fluorescent nanoparticles as effective carrier of gambogic acid for inhibiting VX2 tumor cells
Karimi et al. Fabrication of biocompatible magnetic maltose/MIL-88 metal–organic frameworks decorated with folic acid-chitosan for targeted and pH-responsive controlled release of doxorubicin
Liu et al. Mouse model to explore the therapeutic effect of nano-doxorubicin drug delivery system on bladder cancer
Tavakolizadeh et al. Green modified-UiO-66/MXene sandwich composites for gene-chemotherapy synergistic cancer suppression: Co-delivery of doxorubicin and pCRISPR

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15850806

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15850806

Country of ref document: EP

Kind code of ref document: A1