CN111297829A - Modified glucan-coated core-shell composite nanoparticle and preparation method thereof - Google Patents
Modified glucan-coated core-shell composite nanoparticle and preparation method thereof Download PDFInfo
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- 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
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Abstract
The invention relates to a modified glucan coated core-shell type composite nano particle and a preparation method thereof, wherein the modified glucan coated core-shell type composite nano particle comprises the following components: the composite material comprises an inorganic porous material loaded with an anti-cancer drug as an inner core and an acetalized and modified glucan polymer coated on the surface of the inner core as an outer shell.
Description
Technical Field
The invention relates to a core-shell type composite nano particle coated by modified glucan and a preparation method thereof, belonging to the field of nano material manufacturing.
Background
Cancer has become a public health problem worldwide. In recent years, the incidence of malignant tumors has a significantly increasing trend in China. Malignant tumors exceed cardiovascular diseases, become the leading cause of death of human beings, and seriously threaten the life and health of human beings. Chemotherapy is still one of the most clinically significant tumor treatment methods at present. However, only a very small amount of traditional chemotherapy drugs can reach the tumor focus area of a patient through blood circulation, most of the drugs are phagocytized by normal tissues such as liver, spleen and the like, and the traditional chemotherapy drugs have the defects of low curative effect and large toxic and side effects. According to statistics, almost all patients have serious toxic and side effects, 90 percent of the patients have drug resistance with different degrees, and more than half of patients in initial diagnosis have tumor metastasis.
The appearance of the nano biotechnology provides a new way for the efficient treatment of tumors and the reduction of toxic and side effects. The emergence and successful application of Drug Delivery systems (DDS for short) provides a new strategy for targeted Delivery and controlled release of drugs. The carrier material of the drug plays a very important role in the drug transportation process, and drug carriers with different properties have different release behaviors. For example, inorganic porous silica nanospheres have attracted much attention in the field of drug carrier development due to their unique structure and properties, as well as their advantages of good stability, monodispersity, high yield, low cost, etc. Then, the inorganic material carrier has poor degradability in the organism, and cannot be clinically applied. The organic acetalized dextran polymer is amphiphilic macromolecule prepared by acetalization reaction of hydrophilic natural dextran as substrate. The nano-drug carrier formed by self-assembly of the polymer has multiple advantages of good biocompatibility and degradability, easy functionalization of molecular structure, pH response performance and the like, but the problem of poor stability of the organic carrier generally exists. Thereby, an organic/inorganic composite support is produced. Compared with the traditional pure organic material or inorganic material, the organic/inorganic composite material can effectively adjust the stability, degradation speed and material size of the material through regulating and controlling the structure and composition, and overcomes the defects of poor stability of the organic material and poor degradability of the inorganic material.
At present, the research on organic/silicon dioxide drug carrier systems is increased at home and abroad, and a batch of known high-toxicity drugs can be safely and effectively applied to disease treatment. For example, Zhu et al (Angew Chem Int Ed., 2005; 44: 5083-. However, the nano-carriers also have the problems of low encapsulation efficiency, easy drug leakage, complex preparation process and the like, and limit industrial production and market popularization and application.
Disclosure of Invention
Aiming at the problems, the invention aims to provide the core-shell organic-inorganic composite nano-particle which has high drug loading, good biocompatibility, pH response performance, simple, convenient and quick preparation process and accurate and controllable technical parameters and the preparation method thereof, and has important research significance and popularization value.
In one aspect, the present invention provides a modified glucan-coated core-shell composite nanoparticle comprising: the composite material comprises an inorganic porous material loaded with an anti-cancer drug as an inner core and an acetalized and modified glucan polymer coated on the surface of the inner core as an outer shell.
In the present invention, an inorganic porous material using porous silica nanospheres or the like can be loaded with an anticancer drug (e.g., a hydrophilic anticancer drug or a hydrophobic anticancer drug) as an inner core, and an acetalized modified polymer as an outer shell. The acetalization modified polymer shell has an acidic response degradation property, and can realize acidic response release of the anticancer drug loaded in the inorganic porous material, namely acid response controllable release of the anticancer drug. In addition, the core-shell type composite nano-particles coated by the modified glucan have better structural stability in blood circulation, effectively improve the utilization rate of anticancer drugs, reduce the toxic and side effects of chemotherapy, are expected to realize the inhibition effect on the metastasis and recurrence of tumors and improve the treatment effect of the tumors. Preferably, the surface of the shell is also loaded with hydrophobic anticancer drugs.
Preferably, the anticancer drug is a hydrophilic anticancer drug or a hydrophobic anticancer drug; the hydrophilic anticancer drug is selected from at least one of doxorubicin hydrochloride, cyclytidine hydrochloride, cytarabine and hydroxyurea; the hydrophobic anticancer drug is at least one selected from IR-780 iodide, camptothecin, paclitaxel, cisplatin, vincristine, fluorouracil, methotrexate, mitoxantrone, adenosine cyclophosphate, cyclophosphamide and pelomycin.
Preferably, the loading capacity of the anticancer drug in the modified glucan-coated core-shell composite nanoparticle is 10-40 wt%.
Preferably, the inorganic porous material is selected from zeolite nanoparticles, metal organic framework materials, microporous molecular sieves, prussian blue nanoparticles, or porous silica nanoparticles; preferably, the porous silica nanoparticles are pure porous silica nanoparticles, or hollow porous silica nanoparticles.
Preferably, the particle size of the inorganic porous material is 50-1000 nm, and the diameter of the pore diameter is 1-50 nm; preferably, the particle size of the inorganic porous material is 100 nm-200 nm; the diameter of the aperture is 5 nm-10 nm.
Preferably, the acetalized modified glucan polymer has a thickness of 1 to 50nm, preferably 3 to 15 nm.
Preferably, the acetalization modified glucan polymer is a glucan compound containing an acetal group; the content of the acetal group in the acetal group-containing glucan compound is 0.5 to 30 wt%.
Preferably, the mass ratio of the inner core to the acetalized modified glucan polymer is 1: 0.2 to 100, preferably 1: 1 to 10.
In another aspect, the present invention further provides a preparation method of the modified glucan-coated core-shell composite nanoparticle, including:
(1) mixing an anticancer drug and an inorganic porous material to obtain an inorganic porous material loaded with the anticancer drug;
(2) dispersing an inorganic porous material loaded with an anti-cancer drug and an acetalized modified glucan polymer in an organic solvent solution to obtain a mixed solution;
(3) and placing the obtained mixed solution as a micro-fluidic inner phase and an aqueous solution containing a surfactant as an outer phase in a micro-fluidic chip, and obtaining the modified glucan-coated core-shell composite nano-particle by a micro-fluidic technology.
In the invention, the inorganic porous material loaded with the anti-cancer drugs is used as an inner core, the acetalization modified glucan polymer is adopted, and the batch and stable preparation is realized by the microfluidic technology. Specifically, the anticancer drug and the inorganic porous material are mixed so that the anticancer drug is loaded in the pore structure of the inorganic porous material. Then, the mixed solution containing the inorganic porous material loaded with the anti-cancer drug and the acetalized modified glucan polymer is used as a micro-fluidic internal phase, the aqueous solution containing the surfactant is used as an external phase, the mixed solution is placed in a micro-fluidic chip, the internal phase and the external phase are respectively injected through a micro-fluidic technology, when the two phases meet at a convergence port, the acetalized glucan is uniformly wrapped on the surface of the inorganic porous material due to the sudden reduction of the solubility of the acetalized glucan and high-speed shearing force, and meanwhile, the hydrophobic drug is wrapped in a core-shell structure. After the core-shell structure is formed, the surfactant in the aqueous solution can improve the dispersibility of the nano-particles, so that the purpose that the acetalized modified glucan polymer is coated on the inorganic porous material loaded with the anti-cancer drugs is realized. The microfluidic technology can realize the advantages of simple, convenient and quick preparation process and accurate and controllable technical parameters.
Preferably, in the step (1), the mass ratio of the anticancer drug to the inorganic porous material is 1-100 mg: 100 mg; in the step (2), the acetalization modified glucan is polymerized from a glucan compound through acetalization reaction, preferably, a hydrophobic anticancer drug is additionally added into the mixed solution, and the addition amount of the hydrophobic anticancer drug is 0.5-4 times of the mass of the inorganic porous material loaded with the anticancer drug. Preferably, the hydrophobic anticancer drug is additionally added into the microfluidic internal phase ethanol solution, and when the shell is formed by microfluidic control, the hydrophobic interaction force and the physical adsorption effect of the hydrophobic drug and the acetalization modified glucan polymer are utilized to realize the loading of the hydrophobic anticancer drug on the surface of the shell, so that the overall drug loading capacity of the core-shell type composite nanoparticle is greatly improved.
Preferably, the microfluidic chip is provided with an inner phase outlet and an outer phase outlet which are coaxial and in the same direction, and the diameter of the inner phase outlet is 0.5-10 μm. Wherein the pipe for receiving and outputting the inner phase is located inside the pipe for receiving and outputting the outer phase.
Preferably, the injection speed of the inner phase is 1-5 mL/h, and the injection speed of the outer phase is 20-100 mL/h; the ratio of the injection speeds of the internal phase and the external phase is 1: 15-40, preferably 1: 18 to 25. The invention regulates and controls the injection speed ratio of the inner phase and the outer phase by a microfluidic technology, thereby realizing that the acetalization modified glucan polymer is coated on the surface of the inorganic porous material loaded with the anti-cancer drugs. If the injection speed of the inner phase is too high, the core-shell composite nanoparticles coated by the modified glucan are agglomerated and have poor dispersibility. If the injection speed of the external phase is too high, the shell layer of the core-shell composite nanoparticle coated by the modified glucan is not uniformly or completely coated, so that the drug loading efficiency of the nanoparticle is reduced.
Preferably, the surfactant is at least one selected from the group consisting of polyvinyl alcohol, polyoxyethylene polyoxypropylene ether block copolymer P188, polyoxyethylene sorbitan fatty acid ester P80, phospholipids PE80, polypropylene glycol and ethylene oxide addition polymer F127.
Preferably, the concentration of the acetalized modified dextran polymer in the mixed solution is 0.1-2 mg/mL.
Preferably, the concentration of the aqueous solution containing the surfactant is 0.1 to 1 wt%.
Advantageous effects
In the invention, the obtained modified glucan-coated core-shell composite nano-particles have amino groups, polyethylene glycol containing functional groups (including but not limited to carboxyl, epoxy, isocyanate and the like) and phospholipid molecules can be further modified for surface modification, so that the composite of the modified glucan-coated core-shell composite nano-particles and various materials including polymers, proteins, other functional nano-particles, dispersing agents and biological coatings is realized, and the stability under the in vivo environment and the tumor targeted drug delivery performance are improved.
According to the invention, the particle size of the core-shell composite nanoparticle coated by the modified glucan can be controlled within 100-200 nm, and meanwhile, the material is good in biological safety and compatibility and high in drug loading (about 30 wt%), so that the material serving as a nano-drug carrier can effectively improve the enrichment and treatment effects of drugs in a tumor region.
In the invention, the obtained core-shell composite nano-particles coated by the modified glucan have good dispersibility, biocompatibility and nontoxicity, and can be used for loading various hydrophilic/hydrophobic medicaments and realizing the controllable release of the medicaments under the stimulation of pH. Meanwhile, the preparation technology of the invention has high yield, simple preparation process and strong repeatability, thereby being suitable for industrialized large-scale production.
Drawings
Fig. 1 is a schematic view of a microfluidic chip device of example 1;
FIG. 2 is a transmission electron microscope image of the porous silica nanoball of example 1, from which it can be seen that the diameter of the porous silica nanoball is about 120 nm;
FIG. 3 is a scanning electron microscope image of the porous silica nanospheres of example 1, from which it can be seen that the diameter of the porous silica nanospheres is about 120nm, the diameter of the pore channels is about 10nm, and the pore channel structure is clearly visible;
FIG. 4 is the NMR spectrum of the acetalized modified dextran polymer of example 1, from which the characteristic hydrogen peak of the acetalized group and the characteristic hydrogen peak of the modified spermine are both shown, indicating that the acetalized modified dextran polymer was successfully synthesized;
FIG. 5 is a TEM image of the modified glucan-coated core-shell composite nanoparticle of example 1, wherein it can be seen that the pore structure disappears when the diameter of the nanoparticle is about 140 nm;
fig. 6 is a scanning electron microscope image of the modified dextran-coated core-shell composite nanoparticle of example 1, from which it can be seen that the pore structure of the porous silica nanosphere clearly seen disappears since the nanoparticle is directly about 140nm and the surface is a modified dextran shell layer;
fig. 7 is a transmission electron micrograph of the modified glucan-coated core-shell type composite nanoparticle in comparative example 1, from which it can be seen that the modified glucan-coated core-shell type composite nanoparticle was strongly adhered, was unevenly coated, and had a large number of modified glucan vacuoles;
fig. 8 is an in vitro cytotoxicity diagram of the modified glucan-coated core-shell composite nanoparticle in example 1 under different concentration conditions, and it can be seen from the diagram that the cell survival rate is greater than 95% under the given nanoparticle concentration condition, which proves that the biosafety of the material is good.
Detailed Description
The present invention is further illustrated by the following examples, which are to be understood as merely illustrative and not restrictive.
Aiming at the technical problems of low encapsulation efficiency, easy drug leakage, complex preparation process and the like of a nano-drug carrier in the prior art, the invention firstly selects an inorganic porous material (called a drug-loaded inorganic porous material for short) loaded with an anti-cancer drug as a core, and selects an acetalization modified glucan polymer to coat the surface of the core, thereby finally obtaining the modified glucan-coated core-shell type composite nano-particle. Wherein, the acetalization modified glucan polymer is a glucan compound containing acetal groups, and the mass proportion of the acetal groups in the total polymer is about 0.5-30%.
In alternative embodiments, the inorganic porous material includes, but is not limited to, zeolite nanoparticles, metal organic framework materials, microporous molecular sieves, prussian blue nanoparticles, or porous silica nanoparticles, among others. The porous silica nanoparticles comprise pure porous silica nanoparticles, hollow porous silica nanoparticles, porous silica nanoparticles compounded with other functional particles and functional molecules, and the like.
In an alternative embodiment, the particle size of the inorganic porous material is 50 to 1000nm, preferably 100 to 200 nm. Furthermore, the inorganic porous material has a nanopore having a pore diameter of about 1nm to 50nm, preferably 5nm to 10 nm.
In an alternative embodiment, the mass ratio of the inorganic porous material loaded with the anticancer drug to the acetalized modified glucan polymer is 1: 0.2 to 100, preferably 1: 1 to 10. Wherein the thickness of the outer shell formed by the acetalization modified glucan polymer can be 1-50 nm, and preferably 3-15 nm.
In an alternative embodiment, the anticancer drug in the inorganic porous material loaded with the anticancer drug may be a hydrophilic anticancer drug or a hydrophobic anticancer drug, such as camptothecin, paclitaxel, cisplatin, vincristine, fluorouracil, methotrexate, mitoxantrone, adenosine cyclophosphamide, perlomycin, nitrocarb, doxorubicin hydrochloride, and the like. Preferably, the surface of the shell is also loaded with hydrophobic anticancer drugs. The load capacity of the anticancer drug in the integrally modified glucan-coated core-shell composite nano-particles can be up to 10-40 wt%.
In one embodiment of the invention, the preparation of the modified glucan-coated core-shell composite nanoparticle having a core-shell structure and acid-responsive drug release properties is realized by a microfluidic confocal flow technology. The method has mild preparation conditions, is simple and feasible, has no pollution and high yield, and is suitable for industrial large-scale production. The preparation method of the modified glucan-coated core-shell composite nanoparticle is exemplarily illustrated with porous silica nanospheres as the inorganic porous material.
Hydrophilic anticancer drugs or hydrophobic anticancer drugs are mixed with the porous silicon dioxide nanospheres to obtain the drug-loaded porous silicon dioxide nanospheres. Wherein, the mixing mode can be magnetic stirring and the like. The temperature of mixing may be room temperature, for example, 25 to 30 ℃. The particle size of the porous silicon dioxide nanospheres is 50-1000 nm, preferably 100-200 nm. The porous silica nanospheres have nanopores with a pore size of about 1nm to 50nm, preferably 5nm to 10 nm. The mass ratio of the anticancer drug to the inorganic porous material can be 1-100 mg: 100mg, for example 10-60 mg: 100 mg. As a detailed example, the porous silica nanospheres are added to a phosphate buffer solution containing an anticancer drug, magnetically stirred at room temperature, and then centrifuged, washed and dried to obtain drug-loaded porous silica nanospheres.
The acetalized modified glucan polymer is obtained by acetalization reaction by using a commercialized glucan compound as a raw material. In the present invention, acetalized modified dextran polymers include, but are not limited to, those obtainable by acetalization of dextran compounds, and also those that are prepared as commercial products. The mass ratio of acetal groups in the acetalized and modified glucan polymer to the total polymer is ensured to be between 0.5 and 30 percent.
The drug-loaded porous silica nanospheres and the acetalized modified glucan polymer are dispersed in an organic solvent solution according to a certain mass ratio to obtain a mixed solution which is used as a micro-fluidic internal phase. Preferably, the hydrophobic anticancer drug is additionally added into the mixed solution, and the addition amount of the hydrophobic anticancer drug is 0.5-4 times of the mass of the inorganic porous material loaded with the anticancer drug. An aqueous solution containing a surfactant was used as an external phase. Surfactants include, but are not limited to, polyvinyl alcohol, polyoxyethylene polyoxypropylene ether block copolymer P188, polyoxyethylene sorbitan fatty acid ester P80, phospholipids PE80, polypropylene glycol and ethylene oxide addition polymer F127, and the like. And obtaining the core-shell type composite nano-particles coated with the modified glucan by a microfluidic technology. In the preparation process of the microfluidic technology, a specific microfluidic chip is used, the core-shell type composite nano-particles coated by the modified glucan are rapidly prepared in batches with the assistance of two injection pumps, and the acetalized modified glucan polymer is uniformly and completely coated on the outer surface of the medicine-carrying porous silica nanospheres. In the process of preparing the microfluidic technology, the temperature is generally room temperature, for example, 25-30 ℃, and preferably 25 ℃. The preparation condition is mild, and the preparation process is simple and easy to operate.
As an example of a structure for preparing a microfluidic chip, as shown in fig. 1, the structure includes:
a pipe 4 for receiving and outputting the external phase, one end of the pipe 4 being closed and the other end being an external phase outlet 3;
an external phase inlet 1 provided on the pipe 4;
a pipe located inside the pipe 4 for receiving and outputting the internal phase;
one end of the pipeline is closed, and an inner phase inlet 2 is arranged on the pipeline; or one end of the pipeline is directly arranged as an inner phase inlet 2;
and one end of the inner phase outlet 4, which is arranged in the pipeline and is consistent with the output direction of the outer phase, is arranged as an inner phase outlet, and the diameter of the inner phase outlet can be 0.5-10 mu m. Wherein, the pipeline can directly adopt a uniform pipeline with the diameter of 1-100 mu m. Of course, in the present invention, the diameters and the cross-sectional shapes of the other inlets, outlets, the conduit 4 and the conduit are not particularly limited, and it is only required to ensure that the microfluidic chip has an inner phase outlet and an outer phase outlet which are coaxial and in the same direction, and the diameter of the inner phase outlet is 0.5 to 10 μm. In the invention, the materials such as glass sheets, glass capillaries, glue and the like are assembled into the microfluidic chip, and the chip is provided with an outlet of the coaxial inner phase and an outlet of the coaxial outer phase.
In an alternative embodiment, the injection rates of the inner and outer phases are controlled by microfluidic techniques. The injection process is controlled by an injection pump. Preferably, the ratio of the injection rates of the internal phase and the external phase may be 1: 15-40, preferably 1: 18 to 25.
In an alternative embodiment, the concentration of the acetalized modified dextran polymer in the mixed solution may be 0.1 to 2 mg/mL. The concentration of the aqueous solution containing the surfactant may be 0.1 to 1 wt%.
In the invention, the core-shell composite nano-particles coated by the modified glucan have controllable particle size and high structural stability in physiological environment, and the acetalized modified glucan polymer shell has acidic response degradation property, can be used in the fields of medical diagnosis, catalyst protection, analysis and detection and the like, and particularly has wide application prospect in the aspect of drug delivery.
The present invention will be described in detail by way of examples. It is also to be understood that the following examples are illustrative of the present invention and are not to be construed as limiting the scope of the invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art may be made in light of the above teachings. The specific process parameters and the like of the following examples are also only one example of suitable ranges, i.e., those skilled in the art can select the appropriate ranges through the description herein, and are not limited to the specific values exemplified below.
Example 1
50mg of the porous silica nanospheres were uniformly dispersed in a phosphate buffer solution (6mL, 5mg/mL) of doxorubicin hydrochloride, and magnetically stirred at room temperature for 24 hours in the absence of light. And (3) centrifugally collecting the material loaded with the drug, washing the material for 2 times by using a phosphate buffer solution, and drying the material overnight in vacuum to obtain the drug-loaded porous silicon dioxide nanospheres.
Dissolving dextran (5.0g, 30.9mmol, Mw 9-11000g/mol) in 20mL water, adding sodium periodate (1.1g, 514mmol), stirring at 25 deg.C for 5h, selecting dialysis membrane with molecular weight cutoff of 3500g/mol, dialyzing in distilled water, purifying, replacing water five times, and vacuum drying to obtain white powder. 3g of partially oxidized dextran powder was dissolved in 30mL of dimethyl sulfoxide, followed by addition of 2-methoxypropene (10.6mL, 11mmol), pyridinium p-toluenesulfonate (46.8mg, 0.186mmol), stirring at 25 ℃ for 3h, addition of triethylamine (3mL, 21mmol) to terminate the reaction, precipitation of the product in 300mL of deionized water, centrifugation at 4600g (RCF) for 10 minutes, 2 times, and lyophilization to a powder. Nitrogen was introduced throughout the reaction. The acetylated dextran was finally obtained, and the acetylated dextran (20g, 12.3mmol) and arginine (40g, 19.8mmol) were dissolved in 10mL of dimethyl sulfoxide and stirred at 55 ℃ for 22 h. Then naturally cooling, at 25 deg.C adding NaBH4(2.0g, 529mmol) to dimethyl sulfoxide and stirring for 18 h; the product was precipitated in 40mL of distilled water and centrifuged at 4000g (RCF) for 5 minutesCentrifuging for 5 times, and performing cold drying to obtain the acetalized modified glucan polymer, wherein the content of acetal groups is 5-10 wt%.
1mg of drug-loaded porous silica nanosphere, 2mg of hydrophobic anticancer drug IR780 iodide and 2mg of acetalized modified glucan polymer are dispersed in 4mL of absolute ethanol solution to serve as a microfluidic internal phase; and (3) taking a 0.5 wt% F127 aqueous solution as an external phase, and obtaining the core-shell composite nano-particles coated with the modified glucan by a microfluidic technology, wherein the injection speeds of the internal phase and the external phase are respectively 2mL/h and 40 mL/h. The loading capacity of the anti-cancer drug in the modified glucan coated core-shell composite nano-particle is about 28 wt%, wherein the thickness of the acetalized modified glucan polymer is about 10 nm.
Example 2
50mg of the porous silica nanospheres were uniformly dispersed in a phosphate buffer solution (6mL, 5mg/mL) of doxorubicin hydrochloride, and magnetically stirred at room temperature for 24 hours in the absence of light. And (3) centrifugally collecting the material loaded with the drug, washing the material for 2 times by using a phosphate buffer solution, and drying the material overnight in vacuum to obtain the drug-loaded porous silicon dioxide nanospheres.
Dissolving dextran (5.0g, 30.9mmol, Mw 9-11000g/mol) in 20mL water, adding sodium periodate (1.1g, 514mmol), stirring at 25 deg.C for 5h, selecting dialysis membrane with molecular weight cutoff of 3500g/mol, dialyzing in distilled water, purifying, replacing water five times, and vacuum drying to obtain white powder. 3g of partially oxidized dextran powder was dissolved in 30mL of dimethyl sulfoxide, followed by addition of 2-methoxypropene (10.6mL, 11mmol), pyridinium p-toluenesulfonate (46.8mg, 0.186mmol), stirring at 25 ℃ for 3h, addition of triethylamine (3mL, 21mmol) to terminate the reaction, precipitation of the product in 300mL of deionized water, centrifugation at 4600g (RCF) for 10 minutes, 2 times, and lyophilization to a powder. Nitrogen was introduced throughout the reaction. The acetylated dextran was finally obtained, and the acetylated dextran (20g, 12.3mmol) and arginine (40g, 19.8mmol) were dissolved in 10mL of dimethyl sulfoxide and stirred at 55 ℃ for 22 h. Then naturally cooling, at 25 deg.C adding NaBH4(2.0g, 529mmol) to dimethyl sulfoxide and stirring for 18 h; precipitating the product in 40mL of distilled water, centrifuging for 5 minutes at 4000g (RCF), centrifuging for 5 times, and cold drying to obtain acetalized modified glucanA polymer having an acetal group content of 5 to 10 wt%.
1mg of drug-loaded porous silica nanosphere, 1mg of hydrophobic anticancer drug IR780 iodide and 1mg of acetalized modified glucan polymer are dispersed in 4mL of absolute ethanol solution to serve as a microfluidic internal phase; and (3) taking a 0.5 wt% F127 aqueous solution as an external phase, and obtaining the core-shell composite nano-particles coated with the modified glucan by a microfluidic technology, wherein the injection speeds of the internal phase and the external phase are respectively 2mL/h and 40 mL/h. The loading capacity of the anti-cancer drug in the modified glucan-coated core-shell composite nano-particle is about 22 wt%, and the thickness of the acetalized modified glucan polymer is about 6 nm.
Example 3
50mg of the porous silica nanospheres were uniformly dispersed in a phosphate buffer solution (6mL, 5mg/mL) of doxorubicin hydrochloride, and magnetically stirred at room temperature for 24 hours in the absence of light. And (3) centrifugally collecting the material loaded with the drug, washing the material for 2 times by using a phosphate buffer solution, and drying the material overnight in vacuum to obtain the drug-loaded porous silicon dioxide nanospheres.
Dissolving dextran (5.0g, 30.9mmol, Mw 9-11000g/mol) in 20mL water, adding sodium periodate (1.1g, 514mmol), stirring at 25 deg.C for 5h, selecting dialysis membrane with molecular weight cutoff of 3500g/mol, dialyzing in distilled water, purifying, replacing water five times, and vacuum drying to obtain white powder. 3g of partially oxidized dextran powder was dissolved in 30mL of dimethyl sulfoxide, followed by addition of 2-methoxypropene (10.6mL, 11mmol), pyridinium p-toluenesulfonate (46.8mg, 0.186mmol), stirring at 25 ℃ for 3h, addition of triethylamine (3mL, 21mmol) to terminate the reaction, precipitation of the product in 300mL of deionized water, centrifugation at 4600g (RCF) for 10 minutes, 2 times, and lyophilization to a powder. Nitrogen was introduced throughout the reaction. The acetylated dextran was finally obtained, and the acetylated dextran (20g, 12.3mmol) and arginine (40g, 19.8mmol) were dissolved in 10mL of dimethyl sulfoxide and stirred at 55 ℃ for 22 h. Then naturally cooling, at 25 deg.C adding NaBH4(2.0g, 529mmol) to dimethyl sulfoxide and stirring for 18 h; precipitating the product in 40mL of distilled water, centrifuging 4000g (RCF) for 5 minutes, centrifuging 5 times, and performing cold drying to obtain the acetalized modified glucan polymer, wherein the content of acetal groups is 5-10 wt%.
1mg of drug-loaded porous silica nanosphere, 2mg of hydrophobic anticancer drug IR780 iodide and 4mg of acetalized modified glucan polymer are dispersed in 4mL of absolute ethanol solution to serve as a microfluidic internal phase; and (3) taking a 0.5% F127 aqueous solution as an external phase, and obtaining the core-shell composite nano-particles coated with the modified glucan by a microfluidic technology, wherein the injection speeds of the internal phase and the external phase are respectively 2mL/h and 40 mL/h. The loading capacity of the anti-cancer drug in the modified glucan coated core-shell composite nano-particle is about 33 wt%, wherein the thickness of the acetalized modified glucan polymer is about 13 nm.
Example 4
50mg of the porous silica nanospheres were uniformly dispersed in a phosphate buffer solution (6mL, 5mg/mL) of doxorubicin hydrochloride, and magnetically stirred at room temperature for 24 hours in the absence of light. And (3) centrifugally collecting the material loaded with the drug, washing the material for 2 times by using a phosphate buffer solution, and drying the material overnight in vacuum to obtain the drug-loaded porous silicon dioxide nanospheres.
Dissolving dextran (5.0g, 30.9mmol, Mw 9-11000g/mol) in 20mL water, adding sodium periodate (1.1g, 514mmol), stirring at 25 deg.C for 5h, selecting dialysis membrane with molecular weight cutoff of 3500g/mol, dialyzing in distilled water, purifying, replacing water five times, and vacuum drying to obtain white powder. 3g of partially oxidized dextran powder was dissolved in 30mL of dimethyl sulfoxide, followed by addition of 2-methoxypropene (10.6mL, 11mmol), pyridinium p-toluenesulfonate (46.8mg, 0.186mmol), stirring at 25 ℃ for 3h, addition of triethylamine (3mL, 21mmol) to terminate the reaction, precipitation of the product in 300mL of deionized water, centrifugation at 4600g (RCF) for 10 minutes, 2 times, and lyophilization to a powder. Nitrogen was introduced throughout the reaction. The acetylated dextran was finally obtained, and the acetylated dextran (20g, 12.3mmol) and arginine (40g, 19.8mmol) were dissolved in 10mL of dimethyl sulfoxide and stirred at 55 ℃ for 22 h. Then naturally cooling, at 25 deg.C adding NaBH4(2.0g, 529mmol) to dimethyl sulfoxide and stirring for 18 h; precipitating the product in 40mL of distilled water, centrifuging 4000g (RCF) for 5 minutes, centrifuging 5 times, and performing cold drying to obtain the acetalized modified glucan polymer, wherein the content of acetal groups is 5-10 wt%.
Dispersing 1mg of drug-loaded porous silica nanosphere and 8mg of acetalized modified glucan polymer in 4mL of absolute ethanol solution to serve as a microfluidic internal phase; and (3) taking a 0.5% F127 aqueous solution as an external phase, and obtaining the core-shell composite nano-particles coated with the modified glucan by a microfluidic technology, wherein the injection speeds of the internal phase and the external phase are respectively 2mL/h and 40 mL/h. The loading capacity of the anti-cancer drug in the modified glucan coated core-shell composite nano-particle is about 20 wt%, wherein the thickness of the acetalized modified glucan polymer is about 18 nm.
Example 5
50mg of the porous silica nanospheres were uniformly dispersed in a phosphate buffer solution (6mL, 5mg/mL) of doxorubicin hydrochloride, and magnetically stirred at room temperature for 24 hours in the absence of light. And (3) centrifugally collecting the material loaded with the drug, washing the material for 2 times by using a phosphate buffer solution, and drying the material overnight in vacuum to obtain the drug-loaded porous silicon dioxide nanospheres.
Dissolving dextran (5.0g, 30.9mmol, Mw 9-11000g/mol) in 20mL water, adding sodium periodate (1.1g, 514mmol), stirring at 25 deg.C for 5h, selecting dialysis membrane with molecular weight cutoff of 3500g/mol, dialyzing in distilled water, purifying, replacing water five times, and vacuum drying to obtain white powder. 3g of partially oxidized dextran powder was dissolved in 30mL of dimethyl sulfoxide, followed by addition of 2-methoxypropene (10.6mL, 11mmol), pyridinium p-toluenesulfonate (46.8mg, 0.186mmol), stirring at 25 ℃ for 3h, addition of triethylamine (3mL, 21mmol) to terminate the reaction, precipitation of the product in 300mL of deionized water, centrifugation at 4600g (RCF) for 10 minutes, 2 times, and lyophilization to a powder. Nitrogen was introduced throughout the reaction. The acetylated dextran was finally obtained, and the acetylated dextran (20g, 12.3mmol) and arginine (40g, 19.8mmol) were dissolved in 10mL of dimethyl sulfoxide and stirred at 55 ℃ for 22 h. Then naturally cooling, at 25 deg.C adding NaBH4(2.0g, 529mmol) to dimethyl sulfoxide and stirring for 18 h; precipitating the product in 40mL of distilled water, centrifuging 4000g (RCF) for 5 minutes, centrifuging 5 times, and performing cold drying to obtain the acetalized modified glucan polymer, wherein the content of acetal groups is 5-10 wt%.
0.8mg of drug-loaded porous silica nanosphere and 2mg of acetalized modified glucan polymer are dispersed in 4mL of absolute ethanol solution to serve as a microfluidic internal phase; and (3) taking a 0.5% F127 aqueous solution as an external phase, and obtaining the core-shell composite nano-particles coated with the modified glucan by a microfluidic technology, wherein the injection speeds of the internal phase and the external phase are respectively 2mL/h and 30 mL/h. The loading capacity of the anti-cancer drug in the modified glucan coated core-shell composite nano-particle is about 18 wt%, wherein the thickness of the acetalized modified glucan polymer is about 12 nm.
Example 6
50mg of the porous silica nanospheres were uniformly dispersed in a phosphate buffer solution (6mL, 5mg/mL) of doxorubicin hydrochloride, and magnetically stirred at room temperature for 24 hours in the absence of light. And (3) centrifugally collecting the material loaded with the drug, washing the material for 2 times by using a phosphate buffer solution, and drying the material overnight in vacuum to obtain the drug-loaded porous silicon dioxide nanospheres.
Dissolving dextran (5.0g, 30.9mmol, Mw 9-11000g/mol) in 20mL water, adding sodium periodate (1.1g, 514mmol), stirring at 25 deg.C for 5h, selecting dialysis membrane with molecular weight cutoff of 3500g/mol, dialyzing in distilled water, purifying, replacing water five times, and vacuum drying to obtain white powder. 3g of partially oxidized dextran powder was dissolved in 30mL of dimethyl sulfoxide, followed by addition of 2-methoxypropene (10.6mL, 11mmol), pyridinium p-toluenesulfonate (46.8mg, 0.186mmol), stirring at 25 ℃ for 3h, addition of triethylamine (3mL, 21mmol) to terminate the reaction, precipitation of the product in 300mL of deionized water, centrifugation at 4600g (RCF) for 10 minutes, 2 times, and lyophilization to a powder. Nitrogen was introduced throughout the reaction. The acetylated dextran was finally obtained, and the acetylated dextran (20g, 12.3mmol) and arginine (40g, 19.8mmol) were dissolved in 10mL of dimethyl sulfoxide and stirred at 55 ℃ for 22 h. Then naturally cooling, at 25 deg.C adding NaBH4(2.0g, 529mmol) to dimethyl sulfoxide and stirring for 18 h; precipitating the product in 40mL of distilled water, centrifuging 4000g (RCF) for 5 minutes, centrifuging 5 times, and performing cold drying to obtain the acetalized modified glucan polymer, wherein the content of acetal groups is 5-10 wt%.
Dispersing 1mg of drug-loaded porous silica nanosphere and 2mg of acetalized modified glucan polymer in 4mL of absolute ethanol solution to serve as a microfluidic internal phase; and (3) taking a 0.5% F127 aqueous solution as an external phase, and obtaining the core-shell composite nano-particles coated with the modified glucan by a microfluidic technology, wherein the injection speeds of the internal phase and the external phase are respectively 2mL/h and 50 mL/h. The loading capacity of the anti-cancer drug in the modified glucan coated core-shell composite nano-particle is about 19 wt%, wherein the thickness of the acetalized modified glucan polymer is about 8 nm.
Example 7
The preparation process of the modified dextran-coated core-shell composite nanoparticle in this example 7 is as described in example 1, except that: 50mg of the porous silica nanosphere was uniformly dispersed in a phosphate buffer solution (6mL, 5mg/mL) of Cytidine hydrochloride, and magnetically stirred at room temperature for 24 hours in the absence of light. And (3) centrifugally collecting the material loaded with the drug, washing the material for 2 times by using a phosphate buffer solution, and drying the material overnight in vacuum to obtain the drug-loaded porous silicon dioxide nanospheres. The loading capacity of the anti-cancer drug in the modified glucan coated core-shell composite nano-particle is about 24 wt%, wherein the thickness of the acetalized modified glucan polymer is about 10 nm.
Example 8
The injection speeds of the internal phase and the external phase are respectively 2mL/h and 60mL/h, and other preparation conditions are the same as example 1, so that the modified glucan coated core-shell type composite nano-particle with incomplete acetalized modified glucan polymer coating is obtained.
Example 9
The injection speeds of the internal phase and the external phase are respectively 2mL/h and 80mL/h, and other preparation conditions are the same as example 1, so that the modified glucan coated core-shell type composite nano-particle with incomplete acetalized modified glucan polymer coating is obtained.
Comparative example 1
The injection speeds of the internal phase and the external phase are respectively 2mL/h and 10mL/h, and other preparation conditions are the same as those of example 1, so that the modified glucan coated core-shell type composite nano-particle with incomplete acetalized modified glucan polymer coating is obtained, as shown in FIG. 7.
Comparative example 2
The injection speeds of the internal phase and the external phase are respectively 2mL/h and 90mL/h, and other preparation conditions are the same as example 1, so that the modified glucan coated core-shell type composite nano-particle with incomplete acetalized modified glucan polymer coating is obtained.
Table 1 shows the raw materials and preparation parameters of the modified glucan-coated core-shell composite nanoparticle prepared in the present invention:
effects of the embodiment
The core-shell type organic-inorganic composite nanospheres of example 1 and HeLa cells were incubated for 24 hours, and then the cell viability was measured using the CCK-8 method. The test process is as follows: 100 μ L of cell suspension was prepared in a 96-well plate, and the plate was pre-cultured in an incubator for 24 hours (37 ℃ C., 5% CO)2). 10 μ L of the test substances at different concentrations were then added to the plates and incubated in an incubator for 24 hours. Subsequently, 10. mu.L of CCK-8 solution was added to each well and incubation in the incubator was continued for 2 hours. Finally, absorbance at 450nm is measured by a microplate reader, and the result shown in FIG. 8 is obtained by analysis. The core-shell organic-inorganic composite nano-particles are proved to have good biological safety.
Claims (14)
1. A modified glucan-coated core-shell composite nanoparticle, comprising: the composite material comprises an inorganic porous material loaded with an anti-cancer drug as an inner core and an acetalized and modified glucan polymer coated on the surface of the inner core as an outer shell.
2. The modified glucan-coated core-shell composite nanoparticle according to claim 1, wherein the surface of the shell is further loaded with a hydrophobic anticancer drug.
3. The modified glucan-coated core-shell composite nanoparticle according to claim 1 or 2, wherein the anticancer drug is a hydrophilic anticancer drug or a hydrophobic anticancer drug; the hydrophilic anticancer drug is selected from at least one of doxorubicin hydrochloride, cyclytidine hydrochloride, cytarabine and hydroxyurea; the hydrophobic anticancer drug is at least one selected from IR-780 iodide, camptothecin, paclitaxel, cisplatin, vincristine, fluorouracil, methotrexate, mitoxantrone, adenosine cyclophosphate, cyclophosphamide and pelomycin.
4. The modified glucan-coated core-shell composite nanoparticle according to any one of claims 1 to 3, wherein the loading amount of the anticancer drug in the modified glucan-coated core-shell composite nanoparticle is 10 to 40 wt%.
5. The modified glucan-coated core-shell composite nanoparticle according to any one of claims 1 to 4, wherein the inorganic porous material is selected from a zeolite nanoparticle, a metal organic framework material, a microporous molecular sieve, a Prussian blue nanoparticle, or a porous silica nanoparticle; preferably, the porous silica nanoparticles are pure porous silica nanoparticles, or hollow porous silica nanoparticles.
6. The modified glucan-coated core-shell composite nanoparticle according to any one of claims 1 to 5, wherein the inorganic porous material has a particle size of 50 to 1000nm and a pore diameter of 1 to 50 nm; preferably, the particle size of the inorganic porous material is 100 nm-200 nm; the diameter of the aperture is 5 nm-10 nm.
7. The modified glucan-coated core-shell composite nanoparticle according to any one of claims 1 to 6, wherein the acetalized modified glucan polymer has a thickness of 1 to 50nm, preferably 3 to 15 nm.
8. The modified glucan-coated core-shell composite nanoparticle according to any one of claims 1 to 7, wherein the acetalized modified glucan polymer is a glucan compound containing an acetal group; the content of the acetal group in the acetal group-containing glucan compound is 0.5 to 30 wt%.
9. The modified glucan-coated core-shell composite nanoparticle according to any one of claims 1 to 8, wherein the mass ratio of the core to the acetalized modified glucan polymer is 1: 0.2 to 100, preferably 1: 1 to 10.
10. A method of preparing the modified glucan-coated core-shell composite nanoparticle of any one of claims 1 to 9, comprising:
(1) mixing an anticancer drug and an inorganic porous material to obtain an inorganic porous material loaded with the anticancer drug;
(2) dispersing an inorganic porous material loaded with an anti-cancer drug and an acetalized modified glucan polymer in an organic solvent solution to obtain a mixed solution;
(3) and placing the obtained mixed solution as a micro-fluidic inner phase and an aqueous solution containing a surfactant as an outer phase in a micro-fluidic chip, and obtaining the modified glucan-coated core-shell composite nano-particle by a micro-fluidic technology.
11. The preparation method according to claim 10, wherein in the step (1), the mass ratio of the anticancer drug to the inorganic porous material is 1-100 mg: 100 mg; in the step (2), the acetalization modified glucan is polymerized by acetalization reaction of a glucan compound; preferably, the hydrophobic anticancer drug is additionally added into the mixed solution, and the addition amount of the hydrophobic anticancer drug is 0.5-4 times of the mass of the inorganic porous material loaded with the anticancer drug.
12. The preparation method according to claim 10 or 11, wherein the microfluidic chip has an inner phase and an outer phase which are coaxial and equidirectional, and the diameter of the convergence port of the inner phase and the outer phase is 0.5-10 μm.
13. The method according to any one of claims 10 to 12, wherein the injection rate of the inner phase is 1 to 5mL/h, and the injection rate of the outer phase is 20 to 100 mL/h; the ratio of the injection speeds of the internal phase and the external phase is 1: 15-40, preferably 1: 18 to 25.
14. The method according to any one of claims 10 to 13, wherein the surfactant is at least one selected from the group consisting of polyvinyl alcohol, polyoxyethylene polyoxypropylene ether block copolymer P188, polyoxyethylene sorbitan fatty acid ester P80, phospholipids PE80, polypropylene glycol and ethylene oxide addition polymer F127.
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