CN111166728B - Tumor-targeted composite nano-drug carrier, drug, preparation method and application - Google Patents
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- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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Abstract
The invention relates to a tumor-targeted composite nano-drug carrier, a drug, a preparation method and application thereof. The nano hydrogel can effectively load iron ions, and the dissipation speed of the ions can be reduced by modifying a hydrophobic membrane outside the nano hydrogel, so that the high-efficiency ion transportation of the targeted tumor cells is realized. The nanometer hydrogel inner core, the hydrophobic layer, the functional group layer and the RNA nanoflower are compounded to form the carrier with efficient targeted drug delivery.
Description
Technical Field
The invention belongs to the technical field of nano-drugs, and particularly relates to a tumor-targeted composite nano-drug carrier, a drug, a preparation method and application.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
The nano material has become a powerful tool for cancer imaging, diagnosis and treatment due to unique physicochemical properties such as small-size effect, surface effect, volume effect, quantum size effect, macroscopic quantum tunneling effect and the like, and has good application prospect in the field of biomedicine. However, the existing nano materials still face many challenges in the field of cancer treatment, such as poor active targeting of tumors, single function, undesirable treatment effect and the like. The multifunctional integrated nano-therapeutic system can effectively overcome the defects, such as combination of tumor targeting and treatment, combination of different treatment methods, multifunctional integrated treatment and the like.
Nanomaterial-based combination therapies are the focus of research. The combined treatment of drug therapy and photodynamic therapy, thermal therapy, radiotherapy and other methods by using the nano material has been developed to a certain extent, but the nano material loaded ions are easy to lose through diffusion in the transportation process.
Ferrous ions have a very unique effect in cancer treatment, because ferrous ions can generate fenton reaction with peroxide to kill cells, and the characteristic of high expression of peroxide in tumor cells makes the killing effect more obvious. However, the method for directly transporting ferrous ions into cells is less, most of the methods are to label ferrocene and the like on nucleic acid chains or generate the ferrous ions through chemical reaction of iron-containing nano materials, the transportation efficiency is difficult to improve, and the release process needs exogenous stimulation.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a tumor-targeted composite nano-drug carrier, a drug, a preparation method and application.
In order to solve the technical problems, the technical scheme of the invention is as follows:
in a first aspect, the tumor-targeted composite nano-drug carrier is a spherical structure and sequentially comprises a nano-hydrogel inner core, a hydrophobic layer, a functional group layer and an RNA nanoflower from inside to outside, wherein the nano-hydrogel inner core is a spherical core, and the hydrophobic layer, the functional group layer and the RNA nanoflower are sequentially coated on the outer surface of the spherical core.
The carrier forms a form of an inner core and an outer coating RNA nanoflower, the RNA nanoflower is loaded with anticancer drugs, the inner core of the nano hydrogel can be effectively loaded with iron ions, and the escape speed of ions can be reduced by modifying a hydrophobic membrane outside the nano hydrogel, so that efficient ion delivery of targeted tumor cells is realized. The nanometer hydrogel inner core, the hydrophobic layer, the functional group layer and the RNA nanoflower are compounded to form the carrier with efficient targeted drug delivery. The composite nano-drug carrier is a carrier for targeted drug delivery or a targeted nano-drug carrier.
In some embodiments, the diameter of the nanohydrogel core is 80-120 nm.
In some embodiments, the hydrophobic layer and the functional group layer are comprised of iodohexadecane and behenic acid, the functional group layer is comprised of carboxyl groups of behenic acid exposed on the outside, and the hydrophobic layer is located on the inside of the functional group. The combination of iodohexadecane and behenic acid exposes the functional layer to the outside, providing sites for binding RNA nanoflowers.
In some embodiments, the RNA nanoflower is composed of RNA1 and RNA2 strands complementary to DNA1 and DNA2, respectively, and a biotin-modified Primer strand Primer1 and a Primer strand Primer2 that modifies a folate targeting group, the sequence of DNA1 is shown in SEQ ID No.1, the sequence of DNA2 is shown in SEQ ID No.2, the sequence of Primer1 is shown in SEQ ID No.3, and the sequence of Primer2 is shown in SEQ ID No. 4.
In some embodiments, the RNA nanoflower layer is 50nm to 80nm thick.
In a second aspect, the preparation method of the composite nano-drug carrier comprises the following specific steps:
mixing the oil phase, the water phase and potassium persulfate, and preparing the nano hydrogel by using a two-phase synthesis method;
modifying the hydrophobic layer through halogenation reaction of the nano hydrogel, and then modifying the functional group layer through a self-assembly process;
and covalently combining the functional group layer with streptavidin to obtain the composite nano hydrogel, combining a primer chain by taking the streptavidin as a starting point, combining the primer chain with a template chain, and wrapping the RNA nanoflower through a rolling circle amplification reaction to obtain the composite nano drug carrier.
In some embodiments, the process for preparing the nanohydrogel is: and mixing the oil phase, the water phase and potassium persulfate, removing oxygen in the mixed solution, heating for reaction, cooling, dripping tetrahydrofuran in the mixed solution to separate out a product, washing and dialyzing to obtain the nano hydrogel. Preferably, the oil phase comprises n-hexane, Tween-80 and Span-80, and the mass of 1mL of n-hexane dissolved Tween-80 and Span-80 in the oil phase is 0.035-0.036g:0.04-0.05 g. Preferably, the water phase comprises water, AMA and PEGDA, and the mass ratio of the water to the AMA to the PEGDA to the KPS is 20-22: 10-12: 1: 0.7-0.8. Preferably, the heating reaction temperature is 50-70 ℃, and the reaction time is 1-3 h; preferably, the dialysis time is 20-28 h.
In some embodiments, the process of modifying the hydrophobic layer and the functional group layer by the nano hydrosol is as follows: mixing the nano hydrosol and the iodohexadecane to perform substitution reaction, standing for layering, taking supernate, adding docosanoic acid to perform self-assembly, and obtaining the nano hydrosol modified by the hydrophobic layer and the functional group layer. Preferably, the iodohexadecane incubation concentration is 0.8-1.2g/mL, and the behenic acid incubation concentration is 0.05-0.15 g/mL. The incubation concentration refers to the concentration of the solution added during the reaction.
In some embodiments, the method for modifying RNA nanoflowers by composite nanohydrogels is: and mixing the composite nano hydrogel with primer1, DNA1, DNA2 and primer2, adding DNA T4 ligase after mixing, adding an ATP solution and T7 RNA polymerase for reaction to obtain the composite nano drug carrier.
Modifying streptavidin under the catalytic action of EDC/NHS by taking the exposed carboxyl group of the functional group layer as a starting point; the biotin-modified Primer1 can be combined with streptavidin, and after the Primer1 is combined with the template strand DNA1, RCA circulation is carried out under the action of RNA polymerase, so that long-chain RNA1 with a repetitive sequence complementary to the sequence of the DNA1 can be obtained; similarly, after primer2 modified with a folate targeting group is combined with template strand DNA2, RCA cycling occurs with RNA polymerase to obtain long-chain RNA2 with a repeat sequence complementary to the sequence of DNA 1. And RNA1 and RNA2 can be complementarily paired to form RNA nanoflower. And, end-modified folic acid of primer2 becomes a targeting group. EDC/NHS is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; n-hydroxysuccinimide.
In a second aspect, the tumor-targeted composite nano-drug carrier is applied to an anti-tumor targeted drug.
In a third aspect, the anti-tumor targeted drug comprises the composite nano drug carrier, an anti-tumor drug and a ferrous ion salt, wherein the anti-tumor drug is combined with the RNA nanoflower, and the ferrous ion is positioned in the nano hydrogel.
Preferably, the weight percentage of the loading amount of the antitumor drug in the antitumor targeting drug is 2-10%;
preferably, the antitumor drug is adriamycin Dox and the like. The anti-tumor drug is a drug capable of being combined with the composite nano-drug carrier through electrostatic adsorption.
Preferably, the ferrous ion salt is ferrous sulfate, ferrous chloride, or the like.
In a fourth aspect, the preparation method of the anti-tumor targeted drug comprises the step of mixing and incubating the composite nano-drug carrier, the anti-tumor drug and a ferrite solution to obtain the anti-tumor targeted drug. The adriamycin is embedded in the middle of the nucleic acid chain by the electrostatic adsorption effect of the composite nano-drug carrier.
In some embodiments, the antitumor drug is incubated at a concentration of 8-12 μ g/ml and the ferrous salt solution is incubated at a concentration of 2-10 μ M.
The invention has the beneficial effects that:
the invention realizes the efficient targeted delivery of ferrous ions to tumor cells and reduces the oxidation of the ferrous ions in the transmission process;
the invention provides a new drug release mode, which accelerates the release of the loaded drug through the release of ferrous ions;
ferrous ions respectively loaded by the two parts of the core shell and the anti-cancer drug can generate synergistic effect, more efficiently kill tumor cells, and are expected to have positive influence on the drug treatment of tumors.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description, serve to explain the invention and not to limit the invention.
FIG. 1 is a schematic diagram of a targeted nano-drug carrier structure and a particle size characterization diagram;
FIG. 2 is the differential identification of tumor cells and non-tumor cells by targeting nano-drug carriers; a picture is that a nano targeting drug carrier acts on tumor cells Hela; wherein A1 is adriamycin fluorescence picture, A2 is Hochest staining indicating cell nucleus, and A3 is superposition picture indicating adriamycin distribution position; the B picture is that the nano targeting drug carrier is used for acting on non-tumor cells MCF-10A, B1 is an adriamycin fluorescence picture, B2 is a Hochestt staining indicating cell nucleus, and B3 is a superposition picture indicating the distribution position of adriamycin;
FIG. 3 shows the effect of the targeted nano-drug carrier on the enrichment of tumor sites in mice;
FIG. 4 shows the effect of tumor treatment in mice with targeted nano-drug carriers; group A is tumor-bearing mice injected with PBS blank reagent; group B is tumor-bearing mice injected with conventional anticancer drug adriamycin; group C is tumor-bearing mice treated with the anti-tumor targeted drug combination of the invention.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
The first embodiment is as follows: preparation steps of composite nano-drug carrier
Preparation of Nanogel 0.71g Tween-80 and 0.82g Span-80 dissolved in 20mL n-hexane, 162mg 2-aminoethylmethacrylate hydrochloride (AMA) dissolved in 300mg water; 13.9mg Poly (ethylene glycol) diacrylate (PEGDA); 10.8mg of Potasssium perffate (KPS), mixing the two solutions, introducing nitrogen to remove oxygen, stirring and heating to 60 ℃, reacting for 2h, and cooling to room temperature. And dripping tetrahydrofuran to separate out a sample, centrifuging and collecting, washing with tetrahydrofuran three times, and dialyzing for 24 hours to obtain the nano hydrogel nanogel.
Modification of nano hydrogel to the nano hydrogel product obtained in the above step, 0.5mL of 1g/mL of 1-iodohexadecane was added, the mixture was allowed to stand for layering, 100uL of 0.1g/mL behenic acid (dissolved in dichloromethane) was added to the supernatant, and the mixture was stirred for 3 hours. EDC/NHS was used for activation for 30min each (400mg/ml,200 ul). Streptavidin was added at 400ul, 100. mu.g/ml for modification for 2 h. Centrifuging and dialyzing to obtain FA-nanogel.
Encapsulation of RNA nanoflower 30. mu.L of 2.5. mu.M biotinylated primer1, DNA1, DNA2 and primer2 modified with folate targeting group were added to 50. mu.L of FA-nanogel. mu.L of 5U/. mu.L DNA T4 ligase was added thereto, and the reaction was carried out at 25 ℃ for 12 hours. mu.L of 25mM ATP solution and 6. mu.L of 50U/. mu. L T7 RNA polymerase were added, reacted at 37 ℃ for 12 hours, centrifuged, and stored in pure water for further use.
The structure and TEM representation of the composite nano-drug carrier prepared by the invention can be obtained from FIG. 1, and the transmission electron microscope image shows that the composite nano-drug carrier prepared by the invention is of a sphere-like structure.
DNA1, DNA2, primer1, primer2 are shown below:
DNA1:
5’–ATAGTGAGTCGTATTAACTTACGCTGAGTACTTCGATTCAAGTCCAGTCCATAATACTGCGTGTGCGTTGGTACGTTAATACGACTCCCTCCCTCCCTCCCTACACCCTCCCTCCCTCCCATCCCT-3’。
DNA2:
5’-ATAGTGAGTCGTATTAACGTACCAACGCACACGCAGTATTATGGACTGGACTTGAATCGAAGTACTCAGCGTAAGTTTAGAGGCATCCCTCCCTCCCTCCCTACACCCTCCCTCCCTCCCATCCCT-3’。
primer1:5’-TTTTTTTTTTAATACGACTCACTATAGGGAT。
primer2:
5’-TTTTTTTTTTTTTTTTTTTAATACGACTCACTATAGGGAT-3’。
example two: treatment of tumor cells using targeted nano-drug carriers
Preparing a targeted nano-drug carrier according to the embodiment one;
and co-culturing a proper amount of the carrier for targeted drug delivery and tumor cells for 72 hours, inspecting the cell death rate condition, and evaluating the biocompatibility of the carrier. The carrier for targeted drug delivery has good biocompatibility.
100 μ L of 10 μ g/ml Dox, 10 μ M ferrous sulfate was added to the carrier for targeted drug delivery prepared by the method of example 1, and incubated for 6 hours to obtain the antitumor targeted drug.
HeLa cells in exponential growth phase were cultured in six-well plates, and 5. mu.L of drug-loaded product (anti-tumor targeting drug) was added to each well and incubated for 24 hours.
And (3) inspecting the killing effect of the drug-loaded product on Hela under an FITC/PI double-staining model by a flow cytometer. As a result, as shown in fig. 2, A3 in fig. 2 shows the effect of the superposition of a1 and a2, and B3 does not show the effect of the superposition of B1 and B2. From FIG. 2, it can be seen that the anti-tumor targeting drug prepared by the present invention has an identifying effect on tumor cells, and can distinguish tumor cells from non-tumor cells.
Example three: treatment of in vivo tumor models using targeted nano-drug carriers
Preparing a targeted nano-drug carrier according to the embodiment one;
loading a drug: adding 100 mu L of Dox with the concentration of 10 mu g/ml and 10 mu M ferrous sulfate into the carrier for targeted drug delivery obtained by the method in example 1, and incubating for 6 hours to obtain the anti-tumor targeted drug;
the injection method comprises the following steps: 60 μ L of each injection was given every 72 hours for a total of 7 injections. Body weight and tumor volume were observed daily (in vitro measurements), and tumors were dissected out of mice after 7 injections.
In the two mice in fig. 3, the left side is a normal mouse, the right side is a tumor-bearing mouse, and after a targeted drug carrier (rhodamine marker) is injected through tail vein, the tumor part of the tumor-bearing mouse can see obvious enrichment effect.
The tumor-bearing mice targeted in fig. 4 are divided into A, B, C three groups, each group is provided with three tumor-bearing mice, the mice injected with the three groups of tumor-bearing mice for 7 times are dissected to take out tumors, A, B, C three groups of injected substances are different, group A is injected with PBS blank reagent, group B is injected with conventional anticancer drug adriamycin, group C is injected with the antitumor targeted drug of the invention, and the injection method is as shown above. The results show that the antitumor targeting drug of the present invention has a smaller tumor site in mice by injection from group A, B, C in fig. 4, which indicates that the antitumor targeting drug of the present invention has a better therapeutic effect on tumor sites than the antitumor drug used directly, and that the vector of the present invention has a better release effect on antitumor drugs.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
SEQUENCE LISTING
<110> Linyi university
<120> tumor-targeted composite nano-drug carrier, drug, preparation method and application
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Claims (18)
1. A tumor-targeted composite nano-drug carrier is characterized in that: the nano hydrogel is a spherical core, and the outer surface of the spherical core is sequentially coated with the hydrophobic layer, the functional group layer and the RNA nanoflower;
the hydrophobic layer and the functional group layer are composed of iodohexadecane and behenic acid, the functional group layer is composed of carboxyl groups exposed outside of the behenic acid, and the hydrophobic layer is positioned on the inner side of the functional group;
the RNA nanoflower consists of an RNA1 chain and an RNA2 chain which are respectively complementary with DNA1 and DNA2, a biotin-modified Primer chain Primer1 and a biotin-modified Primer chain Primer2 for modifying a folic acid targeting group, wherein the sequence of the DNA1 is shown as SEQ ID NO.1, the sequence of the DNA2 is shown as SEQ ID NO.2, the sequence of the Primer1 is shown as SEQ ID NO.3, and the sequence of the Primer2 is shown as SEQ ID NO. 4;
the preparation method of the tumor-targeted composite nano-drug carrier comprises the following steps:
mixing the oil phase, the water phase and potassium persulfate, and preparing the nano hydrogel by using a two-phase synthesis method;
modifying the hydrophobic layer through halogenation reaction of the nano hydrogel, and then modifying the functional group layer through a self-assembly process;
covalently combining the functional group layer with streptavidin to obtain composite nano hydrogel, combining a primer chain with the streptavidin as a starting point, combining the primer chain with a template chain, and wrapping the RNA nanoflower through a rolling circle amplification reaction to obtain a composite nano drug carrier;
the tumor-targeted composite nano-drug carrier also comprises ferrous ions, and the ferrous ions are positioned in the nano-hydrogel.
2. The tumor-targeted composite nano-drug carrier according to claim 1, characterized in that: the diameter of the nano hydrogel inner core is 80-120 nm.
3. The tumor-targeted composite nano-drug carrier according to claim 1, characterized in that: the thickness of the RNA nanoflower is 50nm-80 nm.
4. The method for preparing the tumor-targeted composite nano-drug carrier of any one of claims 1 to 3, which is characterized in that: the method comprises the following specific steps:
mixing the oil phase, the water phase and potassium persulfate, and preparing the nano hydrogel by using a two-phase synthesis method;
modifying the hydrophobic layer through halogenation reaction of the nano hydrogel, and then modifying the functional group layer through a self-assembly process;
and covalently combining the functional group layer with streptavidin to obtain the composite nano hydrogel, combining a primer chain by taking the streptavidin as a starting point, combining the primer chain with a template chain, and wrapping the RNA nanoflower through a rolling circle amplification reaction to obtain the composite nano drug carrier.
5. The method for preparing the composite nano-drug carrier according to claim 4, wherein: the preparation process of the nano hydrogel comprises the following steps: and mixing the oil phase and the water phase, removing oxygen in the mixed solution, heating for reaction, cooling, dripping tetrahydrofuran in the mixed solution to separate out a product, washing and dialyzing to obtain the nano hydrogel.
6. The method for preparing the composite nano-drug carrier according to claim 5, wherein: tween-80 and Span-80 with the mass of 0.035-0.036g and 0.04-0.05g are dissolved in 1mL of solvent in the oil phase solution.
7. The method for preparing the composite nano-drug carrier according to claim 5, wherein: the mass ratio of water to AMA to PEGDA in the aqueous phase solution is 20-22: 10-12: 1.
8. the method for preparing the composite nano-drug carrier according to claim 5, wherein: the heating reaction temperature is 50-70 ℃, and the reaction time is 1-3 h.
9. The method for preparing the composite nano-drug carrier according to claim 5, wherein: the dialysis time is 20-28 h.
10. The method for preparing the composite nano-drug carrier according to claim 5, wherein: the process of modifying the hydrophobic layer and the functional group layer by the nano hydrosol comprises the following steps: mixing the nano hydrosol and iodohexadecane to perform substitution reaction, standing for layering, taking supernate, adding docosanoic acid into the supernate to perform self-assembly to obtain a hydrophobic layer and a functional group layer modified nano hydrosol;
or the method for modifying the RNA nanoflower by the composite nano hydrogel comprises the following steps: and mixing the composite nano hydrogel with primer1, DNA1, DNA2 and primer2, adding DNA T4 ligase after mixing, adding an ATP solution and T7 RNA polymerase for reaction to obtain the composite nano drug carrier.
11. The method for preparing a composite nano-drug carrier according to claim 10, characterized in that: the iodohexadecane incubation concentration is 0.8-1.2g/mL, and the behenic acid incubation concentration is 0.05-0.15 g/mL.
12. The use of the tumor-targeted composite nano-drug carrier of any one of claims 1 to 3 for the preparation of an anti-tumor targeted drug.
13. An anti-tumor targeted drug, characterized in that: the tumor-targeted composite nano-drug carrier and the anti-tumor drug which are combined with the RNA nanoflower according to any one of claims 1 to 3.
14. The anti-tumor targeting agent according to claim 13, wherein the loading of anti-tumor agent in the anti-tumor targeting agent is 2-10% by weight.
15. The anti-tumor targeted drug of claim 13, wherein the anti-tumor drug is doxorubicin Dox.
16. The anti-tumor targeting agent according to claim 13, wherein the ferrous ion salt is ferrous sulfate or ferrous chloride.
17. The process for the preparation of an anti-tumor targeted drug according to any of claims 13 to 16, characterized in that: the composite nano-drug carrier is mixed with an anti-tumor drug and a ferrite solution for incubation to obtain the anti-tumor targeted drug.
18. The process for preparing an anti-tumor targeted drug of claim 17, characterized in that: the incubation concentration of the antitumor drug is 8-12 mu g/ml, and the concentration of the ferrite solution is 2-10 mu M.
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