CN107551271B - magnetic-ROS dual intelligent targeting nanoparticle and preparation method thereof - Google Patents
magnetic-ROS dual intelligent targeting nanoparticle and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, in particular to a magnetic-ROS dual intelligent targeting nanoparticle which takes thiol ketal polymer (PPADT) as a basic nanomaterial and wraps Fe3O4Superparamagnetic nano magnetic cores. The invention also discloses a preparation method of the nanoparticle, characterization of nanoparticle character, safety, in-vivo targeting property and the like. The product of the invention has good double-targeting effect, good drug encapsulation efficiency and stability and low biological toxicity.
Description
Technical Field
The invention relates to the field of burn basic research and medicine technology, in particular to a magnetic-ROS dual intelligent targeting nanoparticle and a preparation method thereof.
Background
In recent years, with the development of nanotechnology, functional nanomaterials have attracted more and more extensive attention in the fields of bioengineering and medicine. The gene medicine or the protein polypeptide medicine is wrapped in the biodegradable nano microsphere material for administration, so that the degradation of the medicine in vivo can be obviously reduced, and the nanoparticles can be connected with an antibody, a ligand and an enzyme by controlling the particle size of the nanoparticles to enable the nanoparticles to have active targeting and passive targeting functions.
ROS is used as pathogenic factor of pathological existence in organism, mainly includes hydroxyl free radical, hydrogen peroxide, nitrite anion and superoxide anion, and the ROS concentration is obviously raised in the disease position of trauma, inflammation, ischemia and tumor, etc., and is nanoThe particles carry important targets for targeted release of the drug. A method for preparing ROS sensitive nanoparticles using thiol ketal polymer PPADT as a material was introduced in Nature Materials by Wilson et al in 2010 (Wilson DS, Dalmasso G, Wang L, Sitaraman SV, Merlin D, Murthy N.Oraly transmitted thiol nanoparticles loaded with TNF- α siRNA target injection and inhibition gene expression in the Nature Materials 2010; 9: 923-8.). A Magnetic Targeted Drug Delivery System (MTDDS) refers to a drug delivery system in which a drug is targeted to be released to a diseased part under the action of an external Magnetic field. Wherein, magnetic Fe4O3As a Magnetic nucleus, the compound has the characteristics of sensitive Magnetic targeting, high safety, no immunogenicity and the like, has mature synthesis technology, can be eliminated from the body along with metabolism, and is one of the materials which are closest to industrialization and have the greatest development prospect in MTDDS (Mou X, Ali Z, Li S, He N.applications of Magnetic Nanoparticles in Targeted Drug Delivery System J Nanosci nanotechnol.2015Jan; 15(1): 54-62.). When Fe4O3When the magnetic core particle size of the nanoparticles is less than 20nm, the magnetic nanoparticles have superparamagnetism, and when the nanoparticles are in a magnetic field, the magnetic properties of the magnetic nanoparticles disappear immediately after the magnetic field is removed, so that the side effects of gathering, blocking blood vessels and the like cannot be caused.
In 2015, royal resol and the like of second military medical university report a pure ROS-targeted intelligent nanoparticle (see the Chinese patent application for invention, "a nanoparticle sensitive to active oxygen and capable of promoting vascularization of wound surface", with publication number CN 104587449A). The invention realizes the intellectualization of the nanoparticles to a certain extent and can carry the medicine to the target wound surface. However, the nanoparticle has the following defects: the ROS single-targeting sensitive nanoparticles carry a drug and have a 'false positive release' phenomenon in vivo, namely, the ROS sensitive nanoparticles can target to not only damaged tissues with high ROS, but also high ROS areas of the liver and the like. In 2016, Fe was reported in Wang Xiu Yu3O4Application of magnetic nanoparticles in preparation of anti-aging agent (see Chinese patent application' Fe3O4Application of magnetic nanoparticles in preparation of anti-aging agents ", publication number CN 106176809A). Said Fe3O4The magnetic nanoparticles are primarily coated externally with edible nutrients, followed by Fe3O4The magnetic nano-particles are taken as therapeutic drugs to be orally administered into the body, and play a role in resisting aging. However, in the present invention Fe3O4The magnetic nanoparticles are a component for constructing drug-loaded intelligent nanoparticles, and mainly have the effect of enabling the nanoparticles to have magnetic responsiveness and Fe3O4The nanoparticles themselves do not play a therapeutic role.
So far, no magnetic-ROS dual intelligent targeting nanoparticle exists, and can safely, targetedly and efficiently carry a medicament to a target area in vivo, so that the medicament can conveniently pass through a biological barrier and the degradation of the medicament in vivo is reduced.
Disclosure of Invention
The invention aims to provide a magnetic-ROS dual-sensitive targeting nano drug delivery system with relatively simple structure, stable performance and good wrapping performance, and particularly relates to a magnetic-ROS dual-sensitive targeting nano drug delivery system which takes thiol ketal polymer (PPADT) as a basic structural material and wraps Fe3O4Superparamagnetic nanoparticles and a process for their preparation are described.
The invention provides a magnetic-ROS dual intelligent targeting nanoparticle, which takes thiol ketal polymer (PPADT) as a drug-loaded nanomaterial to wrap Fe3O4Superparamagnetic nano magnetic cores.
The drug-loaded nano material is thiol ketal polymer (PPADT), the thiol ketal polymer has the characteristic of being sensitive to ROS, and the chemical structural formula of the thiol ketal polymer is shown as formula I:
fe according to the invention3O4Superparamagnetic nanoparticles, the synthesis of which is of formula 2Fe3++Fe2++8OH-→Fe3O4+4H2O is the basis.
Preferably, said Fe3O4The nano magnetic core is prepared by a coprecipitation method.
Preferably, said Fe3O4The diameter of the nano magnetic core is less than 20nm, and the nano magnetic core has superparamagnetism.
Preferably, the particle size range of the magnetic-ROS dual intelligent targeting nanoparticle is 70-130 nm.
The second aspect of the invention provides a preparation method of the magnetic-ROS dual intelligent targeting nanoparticle, wherein the preparation method is a multiple emulsion solvent evaporation/extraction method.
The preparation method comprises the following steps:
A. synthesis of thiol ketal polymer PPADT;
B. superparamagnetic Fe3O4Construction of the nanoparticles: adding fresh solution FeCl2With FeCl3Adding the mixture according to the molar ratio of 1:2, and adding NH into the mixed solution4OH liquid and surfactant (oleic acid or citric acid) in a molar ratio of FeCl2：FeCl3：NH4OH: surfactant 1:2:8: 0.6. Continuously introducing nitrogen into the reaction liquid in the reaction process, fully and mechanically stirring until the liquid changes color to black and bright after reaction, ultrasonically dispersing, washing with deionized water, and obtaining superparamagnetic Fe with the diameter of less than 20nm, namely the superparamagnetic Fe obtained by the coprecipitation method3O4Nanoparticles;
C、PPADT-Fe3O4construction of nanoparticles: adopting a multiple emulsion solvent evaporation/extraction method, dissolving 10mg PPADT in 1ml dichloromethane as an oil phase, and 2mg Fe3O4Dissolving nanoparticles in 100ul PBS solution as an inner water phase, fully mixing the two phases, performing ultrasonic emulsification to form a primary emulsion, and performing ultrasonic emulsification with 1ml of an outer water phase 1% cholate solution to form a W/O/W multiple emulsion suspension; placing the W/O/W multiple emulsion suspension into 35ml of 0.5% cholic acid salt solution, fully mixing, completely volatilizing the organic solvent, and drying at low temperature to obtain PPADT-Fe3O4And (3) nanoparticles.
In the step A, the synthesis method of the thiol ketal polymer PPADT comprises the following steps: the mercaptan ketal polymer (PPADT) is synthesized by catalyzing 1, 4-dimethyl mercaptan phenol and 2, 2-dimethoxy propane to react by utilizing toluenesulfonic acid, and the reaction formula is as follows;
the method specifically comprises the following steps: stirring phenol, 1, 4-dimethylmercaptan phenol and 2, 2-dimethoxypropane, heating to 95 ℃, adding a methanol solution of toluenesulfonic acid for catalytic reaction, reacting at 107 ℃ for 24h to obtain a mercaptan ketal compound PPADT, and freeze-drying and storing. Thiol ketal groups in the PPADT molecular structure are sensitive to oxygen radical concentration, only degrade in an environment with higher oxygen radical concentration, and have ROS sensitive characteristics. The method comprises the following specific steps:
the third aspect of the invention provides an application of the magnetic-ROS dual intelligent targeting nanoparticle in preparation of a drug carrier.
The magnetic-ROS dual-targeting drug-loaded nanoparticle provided by the invention is subjected to targeting action on an in-vivo target region under the dual actions of an in-vitro magnetic field and high ROS in vivo through intravenous injection.
The invention has the advantages that:
the product of the invention has good double-targeting effect, good drug encapsulation efficiency and stability and low biological toxicity.
Drawings
Fig. 1 is a schematic diagram of the construction and principle of the magnetic-ROS dual intelligent targeting nanoparticle.
Fig. 2 is an electron microscopy image of the magnetic-ROS dual intelligent targeting nanoparticle.
Fig. 3 is a particle size analysis diagram of the magnetic-ROS dual intelligent targeting nanoparticle.
Fig. 4 is a nuclear magnetic spectrum of the magnetic-ROS dual intelligent targeting nanoparticle, confirming that the molecular structure of the synthesized product is the same as expected.
Fig. 5 shows that the magnetic-ROS dual intelligent targeting nanoparticle distribution with Cy5 fluorescence was observed with a small animal living body imager 12h after injection.
Fig. 6 is an in vitro safety test of the magnetic-ROS dual intelligent targeting nanoparticle.
Fig. 7 is a detection of the in vivo safety of the magnetic-ROS dual intelligent targeting nanoparticle.
Detailed Description
The following examples are provided to illustrate specific embodiments of the present invention.
Example 1 construction of magnetic-ROS Dual Intelligent targeting nanoparticles
Stirring phenol, 1, 4-dimethylmercaptan phenol and 2, 2-dimethoxypropane, heating to 95 ℃, adding a methanol solution of toluenesulfonic acid for catalytic reaction, reacting at 107 ℃ for 24h to obtain a mercaptan ketal compound PPADT, and freeze-drying and storing.
Adding fresh solution FeCl2With FeCl3Proportionally adding NH into the mixed solution4And (2) introducing nitrogen into the reaction liquid continuously in the reaction process of the OH liquid and the surfactant (oleic acid and citric acid), fully and mechanically stirring until the liquid changes color to black and bright after reaction, ultrasonically dispersing, washing with deionized water, and obtaining the superparamagnetic nanofluid with the diameter of less than 20nm, namely the superparamagnetic nanofluid obtained by the coprecipitation method.
The magnetic-ROS double-targeting nanoparticle is constructed by adopting a multiple emulsion solvent evaporation/extraction method, and specifically comprises the following steps: dissolving PPADT in dichloromethane as oil phase, Fe3O4Dissolving the nano particles in PBS solution as an inner water phase, fully mixing the nano particles and the PBS solution, performing ultrasonic emulsification to form a primary emulsion, and performing ultrasonic emulsification with 1% cholate solution of an outer water phase to form W/O/W multiple emulsion suspension. Placing the W/O/W multiple emulsion suspension into 35ml of 0.5% cholic acid salt solution, fully mixing, completely volatilizing the organic solvent, and drying at low temperature to obtain PPADT-Fe3O4And (3) nanoparticles.
The magnetic-ROS dual intelligent targeting nanoparticles disclosed by the invention are constructed and have a schematic diagram shown in figure 1.
Example 2 identification of characterization characteristics of magnetic-ROS dual intelligent targeting nanoparticles
Detection of Fe by Scanning Electron Microscope (SEM) and High Resolution Transmission Electron Microscope (HRTEM)3O4Microscopic characterization of magnetic nano particle in dispersing degree, geometric shape and particle size, etc. and utilizes super-high propertyQuantum guided interferometer for detecting Fe3O4The magnetic properties of the nanoparticles, such as Curie temperature, a magnetic hysteresis loop, magnetic strength and the like, the chemical structure of the nanoparticles is represented and analyzed by an X-ray photoelectron spectrum, a laser particle analyzer is used for measuring the particle size distribution and the Zeta potential of the material, and a superconducting quantum interferometer is used for detecting the magnetism strength and the superparamagnetic property of the nanoparticles. The diameter of the synthesized magnetic-ROS dual intelligent targeting nanoparticle is about 100nm as shown in FIG. 2 and FIG. 3, and the nuclear magnetic spectrum shown in FIG. 4 confirms that the molecular structure of the synthesized product is the same as expected.
Example 3 magnetic-ROS Dual Intelligent Targeted in vivo tracking of nanoparticles
The double sensitive nanoparticles carrying SDF-1 were labeled with the fluorescent dye Cy 5. 10 nude mice were randomly divided into 2 groups of 5 rats each, and both groups of rats were shocked for 2 s. After 12h, tail vein injection: group a, 10mg SDF-1 protein + Cy 5; group b, 10mg of double sensitive nanoparticles carrying SDF-1 + Cy 5. At 12h after injection, the distribution of Cy5 fluorescence in the animals was observed with a small animal Living body imager (IVIS LaminqII, Caliper Life sciences, USA) at 649nm excitation wavelength. The results are shown in fig. 5, the fluorescence of the dual intelligent nanoparticle injection group is concentrated on the wound surface, and the intelligent targeting property of the nanoparticles is proved to be ideal.
Example 4 magnetic-ROS Dual Intelligent Targeted nanoparticle safety assessment
In vitro drug toxicity test: RAW264.7 cells were cultured in a 96-well plate, DMEM medium and 10% Fetal Bovine Serum (FBS) were added thereto, and the mixture was incubated at 37 ℃ and 5% CO2Culturing in an incubator. Nanoparticles with different concentrations and 10ul CCK8 solution +90ul (DMEM + 10% FBS) are added into each hole, the cell adherence and survival conditions are observed under a microscope of 12h, 24h and 48h, the absorbance of the mixed culture medium at 450nm is measured by using an enzyme labeling instrument, and the cell activity is calculated. The results are shown in fig. 6, which proves that the nanoparticles with different concentrations have no obvious influence on the proliferation capacity of RAW264.7 cells (P is more than 0.05), and proves that the nanoparticles have no obvious toxicity on in vitro cell growth and proliferation.
In vivo drug toxicity test: male rats are randomly divided into four groups, 1mg/kg, 10mg/kg, 100mg/kg nanoparticle solution and 0.9% physiological saline are respectively injected into tail veins, blood is respectively taken through orbital venous plexus for 12h, 24h and 48h, the change of serum liver enzymes is detected, and the survival rate of the rats is calculated. The results are shown in fig. 7, when nanoparticles with different concentrations were injected into rats, there was no statistical difference (P > 0.05) between CK enzyme, ALT enzyme and AST enzyme among the groups compared to the saline injection group, which proves that the nanoparticles were not significantly toxic to rats when injected into rats.
While the preferred embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that the invention is not limited thereto, and that various changes and modifications may be made without departing from the spirit of the invention, and the scope of the appended claims is to be accorded the full range of equivalents.
Claims (4)
1. The magnetic-ROS dual intelligent targeting nanoparticle is characterized in that thiol ketal polymer PPADT is used as a drug-loaded nanomaterial to wrap Fe3O4Superparamagnetic nano magnetic cores; the particle size range of the magnetic-ROS dual intelligent targeting nanoparticle is 70-130 nm; the chemical structural formula of the thiol ketal polymer PPADT is shown as formula I:
the preparation method of the magnetic-ROS dual intelligent targeting nanoparticle comprises the following steps:
A. synthesis of thiol ketal polymer PPADT;
B. superparamagnetic Fe3O4Construction of the nanoparticles: adding fresh solution FeCl2With FeCl3Adding the mixture according to the molar ratio of 1:2, and adding NH into the mixed solution4OH liquid and surfactant oleic acid or citric acid with the molar ratio of FeCl2：FeCl3：NH4OH: surfactant 1:2:8: 0.6; continuously introducing nitrogen into the reaction liquid in the reaction process, fully and mechanically stirring until the liquid changes color to black and bright after reaction, ultrasonically dispersing, washing with deionized water to obtain the nano particlesThe diameter is less than 20nm, namely the superparamagnetic Fe obtained by the coprecipitation method3O4Nanoparticles;
C、PPADT-Fe3O4construction of nanoparticles: adopting a multiple emulsion solvent evaporation/extraction method, dissolving 10mg PPADT in 1ml dichloromethane as an oil phase, and 2mg Fe3O4Dissolving nanoparticles in 100ul PBS solution as an inner water phase, fully mixing the two phases, performing ultrasonic emulsification to form a primary emulsion, and performing ultrasonic emulsification with 1ml of an outer water phase 1% cholate solution to form a W/O/W multiple emulsion suspension; placing the W/O/W multiple emulsion suspension into 35ml of 0.5% cholic acid salt solution, fully mixing, completely volatilizing the organic solvent, and drying at low temperature to obtain PPADT-Fe3O4And (3) nanoparticles.
2. A method for preparing the magnetic-ROS dual intelligent targeting nanoparticle of claim 1, wherein the method comprises the following steps:
A. synthesis of thiol ketal polymer PPADT;
B. superparamagnetic Fe3O4Construction of the nanoparticles: adding fresh solution FeCl2With FeCl3Adding the mixture according to the molar ratio of 1:2, and adding NH into the mixed solution4OH liquid and surfactant oleic acid or citric acid with the molar ratio of FeCl2：FeCl3：NH4OH: surfactant 1:2:8: 0.6; continuously introducing nitrogen into the reaction liquid in the reaction process, fully and mechanically stirring until the liquid changes color to black and bright after reaction, ultrasonically dispersing, washing with deionized water, and obtaining superparamagnetic Fe with the diameter of less than 20nm, namely the superparamagnetic Fe obtained by the coprecipitation method3O4Nanoparticles;
C、PPADT-Fe3O4construction of nanoparticles: adopting a multiple emulsion solvent evaporation/extraction method, dissolving 10mg PPADT in 1ml dichloromethane as an oil phase, and 2mg Fe3O4Dissolving nanoparticles in 100ul PBS solution as an inner water phase, fully mixing the two phases, performing ultrasonic emulsification to form a primary emulsion, and performing ultrasonic emulsification with 1ml of an outer water phase 1% cholate solution to form a W/O/W multiple emulsion suspension; placing the W/O/W multiple emulsion suspension into 35ml of 0.5% cholate solutionFully mixing, completely volatilizing the organic solvent, and drying at low temperature to obtain PPADT-Fe3O4And (3) nanoparticles.
3. The method for preparing the magnetic-ROS dual intelligent targeting nanoparticle according to claim 2, wherein in the step A, the synthesis method of thiol ketal polymer PPADT comprises the following steps: the mercaptan ketal polymer PPADT is synthesized by catalyzing 1, 4-dimethyl mercaptan phenol and 2, 2-dimethoxy propane to react by utilizing toluenesulfonic acid.
4. Use of the magnetic-ROS dual intelligent targeting nanoparticle of claim 1 for the preparation of a pharmaceutical carrier.
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