CN103263673B - Polysaccharide-gold-nanoparticle supermolecule assembled body as well as preparation method and application thereof - Google Patents
Polysaccharide-gold-nanoparticle supermolecule assembled body as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a polysaccharide-gold-nanoparticle supermolecule assembled body. Supermolecule nanoparticles in which hydrophilic transparent hyaluronic acid is used as a shell and hydrophobic gold nanoparticles which is modified by N-adamantyl-lipoamide is used as a kernel are formed under the strong non-covalent interaction between cyclodextrin and adamantine; and according to a three-dimensional cavity structure and the static-electricity action, various anti-cancer medicines can be loaded and targeted to conveyed. The polysaccharide-gold-nanoparticle supermolecule assembled body has the advantages that a target medicine conveying system has a simple synthesis line and is low in production cost, high in yield and suitable for amplification synthesis and actual production application; under the endocytosis action of a transparent hyaluronic acid acceptor on the surface of a malignant cell serving as a medium, the anti-cancer medicine supermolecule assembled body is targetedly brought into the cancer cell and then slowly releases the anti-cancer medicines, so that targeted selective killing for the cancer cell is realized; and moreover, the toxic and side effects on normal cells are obviously reduced.
Description
Technical field
The present invention relates to cancer therapy drug targeted delivery technical field, particularly a kind of polysaccharide-golden nanometer particle super-molecule assembling body and its preparation method and application.
Background technology
Nano material has important effect due to the physics of its uniqueness, chemical property in drug delivery and therapeutic treatment.In nano material, golden nanometer particle has hypotoxicity and good biocompatibility, and its preparation is simple, and size is easy to control, and several functions molecule is also easily modified in surface, the carrier therefore as bioactive molecule especially cancer therapy drug has potential application in treatment of cancer.There is the relation of obvious dosage and curative effect in the medicine of clinical cancer therapy, escalated dose meeting normal tissue and cell produce significant toxic and side effects, therefore strengthen medicine to the selectivity of cancer site, reducing its accumulation that distributes in normal structure and cell is the key improving cancer therapy drug curative effect.At present one of most effective method is exactly utilize the specific Nano medication delivery system of targeting principle design, reduces its toxic and side effects while target tissue and cell drug concentration are raised.In recent years, a kind of hydrophilic polysaccharide macromolecule-hyaluronic acid (HA) is subject to paying close attention to more and more widely as the targeting agent of drug delivery.It can normally be absorbed by the body and metabolism, has good bio-compatibility, and surface has the chemical modification after the modifiable group such as hydroxyl and carboxyl is convenient to.The more important thing is there is excessive expression at the hyaluronic receptor of tumor surface CD44 and RHAMM, so specific binding strong between hyaluronic acid and receptor makes it have target function in Nano medication delivery system, the utilization rate of cancer therapy drug can be improved.Therefore, both advantages can be played in the delivery system applying to cancer therapy drug that golden nanometer particle and hyaluronic acid combined simultaneously, there is good application prospect.
Summary of the invention
The object of the invention is for above-mentioned technical Analysis, a kind of polysaccharide-golden nanometer particle super-molecule assembling body and its preparation method and application is provided, this super-molecule assembling body can the hydrophilic and hydrophobic anticancer drug of the multiclass such as targeted delivery multiclass cancer therapy drug example hydrochloric acid amycin, irinotecan hydrochloride, topotecan hydrochloride, camptothecine and paclitaxel, and toxic and side effects is low, preparation method simple, productive rate is higher, is suitable for amplifying synthesis and production application.
Technical scheme of the present invention:
A kind of polysaccharide-golden nanometer particle super-molecule assembling body, for the binary supermolecule nano assembly of the golden nanometer particle modified based on N-adamantyl thioctamide and HACD synthesis, wherein the size of the golden nanometer particle of N-adamantyl thioctamide modification is 2.2 nm, and each golden nanometer particle finishing has 19 amantadines and the occupation rate of each amantadine on the surface of golden nanometer particle is 3.20 nm
2the average macromolecular chain of HACD modifies 11 cyclodextrin units, this binary super-molecule assembling body is with cyclodextrin and the strong noncovalent interaction of amantadine, formed with hydrophilic hyaluronic acid as shell, the golden nanometer particle that hydrophobic N-adamantyl thioctamide is modified is the supermolecule nano particle of kernel, its size is 200 nm, this nano supermolecule assembly surface band negative electricity and have three-dimensional loose structure, can the multiple cancer therapy drug of load.
A kind of preparation method of described polysaccharide-golden nanometer particle super-molecule assembling body, comprises the following steps:
1) synthesis of N-adamantyl thioctamide
Under nitrogen atmosphere, thioctic acid is dissolved in dry N, in dinethylformamide, add I-hydroxybenzotriazole stir-activating half an hour at 0 DEG C again, then 1-amantadine and N will be dissolved with, the N of N-dicyclohexyl phosphinylidyne diimine, dinethylformamide dropwise joins in above-mentioned solution, keep 0 DEG C, continue under nitrogen protection after stirring reaction 24 h, 24 h are reacted again at 18-25 DEG C, insoluble matter in reaction solution is crossed after filtering, solvent is removed in filtrate distilling under reduced pressure under vacuum is 0.1Pa and obtains solid a, gained solid a is dissolved in chloroform, three times are extracted again with water, collect organic facies with after anhydrous sodium sulfate drying, concentrated by distilling under reduced pressure under being 0.1Pa in vacuum, then be the petroleum ether of 100:1 and the mixed liquor of chloroform with volume ratio be developing solvent, be separated with 200-300 order silicagel column and can obtain N-adamantyl thioctamide,
2) synthesis of the golden nanometer particle (AuNPs) of N-adamantyl thioctamide modification
Under nitrogen atmosphere, four hydration gold chlorides are dissolved in dry N, in dinethylformamide, add the N of the drying being dissolved with sodium borohydride and N-adamantyl thioctamide more fast, dinethylformamide solution, reactant liquor becomes dark brown by light yellow, continue nitrogen protection stirring reaction 24 h at 18-25 DEG C, then acetonitrile precipitation product is added, the black solid b that collected by centrifugation obtains, be first acetonitrile and the N of 1:1 by volume ratio, dinethylformamide mixed solution washs, use washing with alcohol again, collected by centrifugation solid b under vacuum is 0.1Pa after drying, obtain the golden nanometer particle (AuNPs) that N-adamantyl thioctamide is modified,
3) preparation of polysaccharide-golden nanometer particle super-molecule assembling body (HACD-AuNPs)
Solution is obtained by soluble in water for HACD (HACD), the amount ratio of HACD and water is 0.05 mmol/L, the golden nanometer particle (AuNPs) that N-adamantyl thioctamide is modified is added in above-mentioned solution super molten, the polysaccharide-golden nanometer particle super-molecule assembling body (HACD-AuNPs) of the multiple cancer therapy drug of targeted delivery can be obtained.
Described thioctic acid and N, the amount ratio of dinethylformamide is 0.1 mol/L, 1-amantadine and N, N-dicyclohexyl phosphinylidyne diimine and N, the amount ratio of dinethylformamide is respectively 0.12 mol/L and 0.1 mol/L, and the amount ratio of solid a and chloroform is 3mg/mL.
Described gold chloride and N, the amount ratio of dinethylformamide is 7.4 mmol/L, the amount ratio of sodium borohydride and N-adamantyl thioctamide and DMF is respectively 10 mmol/L and 0.81 mmol/L, and the consumption volume ratio of acetonitrile and reactant liquor is 1:1.
The application of prepared polysaccharide-golden nanometer particle super-molecule assembling body, for load cancer therapy drug, the preparation method of the aqueous solution of the load golden nanometer particle super-molecule assembling body of cancer therapy drug (Anticancer Drug@HACD-AuNPs) is as follows:
In obtained polysaccharide-golden nanometer particle super-molecule assembling body (HACD-AuNPs), the aqueous solution of slow dropping cancer therapy drug, at 18-25 DEG C, lucifuge stirs collected by centrifugation solid after 24 h, the solids washed with water obtained 3-5 time, collected by centrifugation solid, and the aqueous solution obtaining the golden nanometer particle super-molecule assembling body (Anticancer Drug@HACD-AuNPs) of load cancer therapy drug under vacuum is 0.1Pa after drying.
The solution of described cancer therapy drug is doxorubicin hydrochloride aqueous solution, irinotecan hydrochloride aqueous solution, topotecan hydrochloride aqueous solution, camptothecine DMF solution and paclitaxel DMF solution; The concentration of the solution of cancer therapy drug is 3mg/mL.
Described polysaccharide-golden nanometer particle super-molecule assembling body (HACD-AuNPs) is 9.26:1 with the mass ratio of cancer therapy drug.
Advantage of the present invention is: the golden nanometer particle super-molecule assembling body of this targeted delivery cancer therapy drug can the multiple cancer therapy drug of payload by its three-dimensional hole and electrostatic interaction, and utilize Ag-Ab effect strong between the hyaluronic acid receptor of hyaluronic acid and cancer cell surfaces overexpression, the super-molecule assembling body being loaded with cancer therapy drug to be brought in the middle of cancerous cell specifically by the endocytosis of cell and to respond slow releasing medicine according to pH, thus realizing the selective killing to cancerous cell; This drug delivery system has suitable active anticancer with directly using compared with cancer therapy drug, but toxic and side effects obviously reduces; The preparation technology of this drug delivery system is simple, easy to implement and the cost of material is low, has larger application prospect in the targeted therapy field of cancer.
[accompanying drawing explanation]
Fig. 1 is the synthetic route chart of the golden nanometer particle (AuNPs) that N-adamantyl thioctamide and N-adamantyl thioctamide are modified.
Fig. 2 is the transmission electron microscope figure of AuNPs.
Fig. 3 be this nano supermolecule assembly HACD-AuNPs and absorption cancer therapy drug synthetic route schematic diagram.
Fig. 4 is the transmission electron microscope figure of golden nanometer particle super-molecule assembling body HACD-AuNPs.
Fig. 5 is the gold content comparison diagram of different time interval MCF-7 cell and NIH3T3 cellular uptake.
Fig. 6 is the cytotoxicity experiment result of MCF-7 cell.
Fig. 7 is the cytotoxicity experiment result of NIH3T3 cell.
[detailed description of the invention]
Below by example, the present invention is described further:
Embodiment:
A preparation method for the polysaccharide-golden nanometer particle super-molecule assembling body of the multiple cancer therapy drug of described targeted delivery, step is as follows:
1) synthesis of N-adamantyl thioctamide
Under nitrogen protection, by 206.3 mg(1 mmol) thioctic acid is dissolved in the DMF of 10 mL dryings, adds 162.5 mg(1.2 mmol) I-hydroxybenzotriazole is 0 oC stir-activating half an hour.165.3 mg(1 mmol will be dissolved with) 1-amantadine and 247.6 mg(1.2 mmol) 10 mL DMF dropwise of N, N-dicyclohexyl phosphinylidyne diimine join in above-mentioned solution.Keep 0 oC, continue under nitrogen protection after stirring reaction 24 h, more at room temperature react 24 h.Insoluble matter in reaction solution is crossed after filtering, filtrate is removed solvent through distilling under reduced pressure and obtains solid a, gained solid a is dissolved in chloroform, the amount ratio of solid a and chloroform is 3mg/mL, three times are extracted again with 50 mL water, collect organic facies with after anhydrous sodium sulfate drying, concentrated by distilling under reduced pressure under being 0.1Pa in vacuum, then with the volume ratio of petroleum ether and the chloroform mixed liquor that is 100:1 for developing solvent, be separated with 200-300 order silicagel column and can obtain N-adamantyl thioctamide.
The nuclear-magnetism of N-adamantyl thioctamide prepared by detection display the present invention, elementary analysis and mass spectral characteristi are as follows:
1h NMR (400 MHz, CDCl
3, TMS, ppm): δ 5.08 (s, 1H), 3.63 – 3.52 (m, 1H), 3.23 – 3.06 (m, 2H), 2.46 (td, 1H), 2.10 (dd, 5H), 2.02 – 1.87 (m, 6H), 1.76 – 1.56 (m, 12H), 1.51 – 1.39 (m, 2H)..C
18h
29nOS
2: measured value: C, 63.51%; H, 8.66%; N, 4.13%.Theoretical value: C, 63.67%; H, 8.61%; N, 4.12%.ESI-MS：340.17 [M+H]
+。
2) synthesis of the golden nanometer particle (AuNPs) of N-adamantyl thioctamide modification
Under nitrogen atmosphere, 50 mg tetra-hydration gold chlorides are dissolved in the DMF of 20 mL dryings, add the DMF solution of the 20 mL dryings being dissolved with 75.5 mg sodium borohydrides and 5.5 mg N-adamantyl thioctamide fast.Reactant liquor is very fast becomes dark brown by light yellow, continues stirring at room temperature under nitrogen protection and reacts 24 h.Then add acetonitrile precipitation product, the consumption volume ratio of acetonitrile and reactant liquor is 1:1, collected by centrifugation solid b, and the black solid b obtained is first that 60 mL washing with alcohol are used in the acetonitrile of 1:1 and the washing of DMF mixed solution again by 60 mL volume ratios.Collected by centrifugation solid b is dry under vacuum is 0.1Pa, obtains the golden nanometer particle (AuNPs) that N-adamantyl thioctamide is modified.Fig. 1 is the synthetic route chart of this golden nanometer particle (AuNPs), and Fig. 2 is the transmission electron microscope figure of AuNPs.
Infrared, elementary analysis and the inductively coupled plasma atomic emission of the golden nanometer particle that N-adamantyl thioctamide prepared by detection display the present invention is modified characterize as follows: FT-IR (KBr)
v3325,2906,2852,1662,1537,1448,1343,1242,1156,1038,811 cm
-1.Elemental analysis data: C, 12.00%; H, 1.49%, N, 0.24%.ICP (%): Au，44.88。
3) preparation of polysaccharide-golden nanometer particle super-molecule assembling body (HACD-AuNPs)
HACD (HACD) by 24.78 is dissolved in 8 mL water and obtains aqueous solution, then the golden nanometer particle (AuNPs) that 3 mg N-adamantyl thioctamide are modified is dissolved in the super-molecule assembling body (HACD-AuNPs) that can obtain the multiple cancer therapy drug of targeted delivery in this aqueous solution.
The application of prepared polysaccharide-golden nanometer particle super-molecule assembling body, for load cancer therapy drug, the preparation method of the aqueous solution of the load golden nanometer particle super-molecule assembling body of cancer therapy drug (Anticancer Drug@HACD-AuNPs) is as follows
Be dissolved in 8 mL water by 24.78 mg HACDs (HACD), the golden nanometer particle (AuNPs) adding 3 mg N-adamantyl thioctamide modifications makes HACD-AuNPs aqueous solution.Then the solution that concentration is the cancer therapy drug of 3mg/mL is slowly dripped respectively, the solution of cancer therapy drug is: doxorubicin hydrochloride aqueous solution, irinotecan hydrochloride aqueous solution, topotecan hydrochloride aqueous solution, camptothecine N, dinethylformamide solution and paclitaxel DMF solution.Under 22 oC, lucifuge stirs collected by centrifugation solid after 24 h, the solids washed with water obtained four times.Collected by centrifugation solid is the dry polysaccharide-golden nanometer particle super-molecule assembling body (Anticancer Drug@HACD-AuNPs) that can obtain load cancer therapy drug under vacuum is 0.1 Pa again.Fig. 3 be this nano supermolecule assembly and absorption cancer therapy drug synthetic route schematic diagram.Fig. 4 is the transmission electron microscope figure of this golden nanometer particle super-molecule assembling body.
Polysaccharide prepared by the detection display the present invention-load capacity of golden nanometer particle super-molecule assembling body to various cancer therapy drug is as shown in the table:
| Doxorubicin hydrochloride | Irinotecan hydrochloride | Topotecan hydrochloride | Camptothecine | Paclitaxel | |
| Load factor (%) | 11.02 | 7.51 | 4.98 | 5.04 | 19.29 |
Embody rule effect of the present invention is as follows:
For cancer therapy drug doxorubicin hydrochloride (DOX), add HACD-AuNPs after MCF-7 cell (mankind mastopathy cell) and NIH3T3 cell (l cell) are cultivated 24 hours in 24 orifice plates being covered with the DMEM culture medium containing 10 % hyclones, enter the gold content of cell in different time interval measurements.As shown in Figure 5, the gold content entering MCF-7 cell at different intervals is all higher than the gold content entering NIH3T3 cell, shows that HACD-AuNPs utilizes interaction strong between the hyaluronic acid receptor of hyaluronic acid and cancer cell surfaces overexpression can the entering in the middle of cancerous cell of targeting.Afterwards MCF-7 cell and NIH3T3 cell are cultivated 24 hours in 96 orifice plates being covered with the DMEM culture medium containing 10 % hyclones.Add DOX respectively, HACD-AuNPs, DOX-HACD-AuNPs, continuous culture 48 hours, measure the cells survival rate under each experiment condition with mtt assay.Result shows, as shown in Figure 6, in 48 hours window, the inhibitory action of DOX-HACD-AuNPs to MCF-7 cell is equivalent to DOX; And for NIH3T3 cell, as shown in Figure 7, DOX is lethal very large to it, but be far smaller than cancerous cell due to the expression of normal cell surface hyaluronic acid receptor, therefore DOX-HACD-AuNPs is very little for Normocellular toxic and side effects.Above result shows that DOX-HACD-AuNPs achieves Normocellular protection and the targeting selective killing to cancerous cell.
Claims (6)
1. the preparation method of polysaccharide-golden nanometer particle super-molecule assembling body, described polysaccharide-golden nanometer particle super-molecule assembling body be based on N-adamantyl thioctamide modify golden nanometer particle and HACD synthesis binary supermolecule nano assembly, wherein the size of the golden nanometer particle of N-adamantyl thioctamide modification is 2.2 nm, and each golden nanometer particle finishing has 19 amantadines and the occupation rate of each amantadine on the surface of golden nanometer particle is 3.20 nm
2the average macromolecular chain of HACD modifies 11 cyclodextrin units, this binary supermolecule nano assembly is with cyclodextrin and the strong noncovalent interaction of amantadine, formed with hydrophilic hyaluronic acid as shell, the golden nanometer particle that hydrophobic N-adamantyl thioctamide is modified is the supermolecule nano particle of kernel, its size is 200 nm, this nano supermolecule assembly surface band negative electricity and there is three-dimensional loose structure, can the multiple cancer therapy drug of load, it is characterized in that comprising the following steps:
1) synthesis of N-adamantyl thioctamide
Under nitrogen atmosphere, thioctic acid is dissolved in dry N, in dinethylformamide, add I-hydroxybenzotriazole stir-activating half an hour at 0 DEG C again, then 1-amantadine and N will be dissolved with, the N of N-dicyclohexyl phosphinylidyne diimine, dinethylformamide dropwise joins in above-mentioned solution, keep 0 DEG C, continue under nitrogen protection after stirring reaction 24 h, 24 h are reacted again at 18-25 DEG C, insoluble matter in reaction solution is crossed after filtering, solvent is removed in filtrate distilling under reduced pressure under vacuum is 0.1Pa and obtains solid a, gained solid a is dissolved in chloroform, three times are extracted again with water, collect organic facies with after anhydrous sodium sulfate drying, concentrated by distilling under reduced pressure under being 0.1Pa in vacuum, then be the petroleum ether of 100:1 and the mixed liquor of chloroform with volume ratio be developing solvent, be separated with 200-300 order silicagel column and can obtain N-adamantyl thioctamide,
2) synthesis of the golden nanometer particle of N-adamantyl thioctamide modification
Under nitrogen atmosphere, four hydration gold chlorides are dissolved in dry N, in dinethylformamide, add the N of the drying being dissolved with sodium borohydride and N-adamantyl thioctamide more fast, dinethylformamide solution, reactant liquor becomes dark brown by light yellow, continue nitrogen protection stirring reaction 24 h at 18-25 DEG C, then acetonitrile precipitation product is added, the black solid b that collected by centrifugation obtains, be first acetonitrile and the N of 1:1 by volume ratio, dinethylformamide mixed solution washs, use washing with alcohol again, collected by centrifugation solid b under vacuum is 0.1Pa after drying, obtain the golden nanometer particle that N-adamantyl thioctamide is modified,
3) preparation of polysaccharide-golden nanometer particle super-molecule assembling body
Solution is obtained by soluble in water for HACD, the amount ratio of HACD and water is 0.05 mmol/L, the golden nanometer particle that N-adamantyl thioctamide is modified is added in above-mentioned solution super molten, the polysaccharide-golden nanometer particle super-molecule assembling body of the multiple cancer therapy drug of targeted delivery can be obtained.
2. the preparation method of polysaccharide-golden nanometer particle super-molecule assembling body according to claim 1, it is characterized in that: described thioctic acid and N, the amount ratio of dinethylformamide is 0.1 mol/L, 1-amantadine and N, N-dicyclohexyl phosphinylidyne diimine and N, the amount ratio of dinethylformamide is respectively 0.12 mol/L and 0.1 mol/L, and the amount ratio of solid a and chloroform is 3mg/mL.
3. the preparation method of polysaccharide-golden nanometer particle super-molecule assembling body according to claim 1, it is characterized in that: described four hydration gold chloride and N, the amount ratio of dinethylformamide is 7.4 mmol/L, sodium borohydride and N-adamantyl thioctamide and N, the amount ratio of dinethylformamide is respectively 10 mmol/L and 0.81 mmol/L, and the consumption volume ratio of acetonitrile and reactant liquor is 1:1.
4. an application for the polysaccharide prepared by claim 1-golden nanometer particle super-molecule assembling body, is characterized in that: for load cancer therapy drug, and the preparation method of the aqueous solution of the golden nanometer particle super-molecule assembling body of load cancer therapy drug is as follows:
In obtained polysaccharide-golden nanometer particle super-molecule assembling body, the aqueous solution of slow dropping cancer therapy drug, at 18-25 DEG C, lucifuge stirs collected by centrifugation solid after 24 h, the solids washed with water obtained 3-5 time, collected by centrifugation solid, and the aqueous solution obtaining the golden nanometer particle super-molecule assembling body of load cancer therapy drug under vacuum is 0.1Pa after drying.
5. the preparation method of the aqueous solution of the golden nanometer particle super-molecule assembling body of load cancer therapy drug according to claim 4, it is characterized in that: the solution of described cancer therapy drug is doxorubicin hydrochloride aqueous solution, irinotecan hydrochloride aqueous solution, topotecan hydrochloride aqueous solution, camptothecine N, dinethylformamide solution or paclitaxel DMF solution; The concentration of the solution of cancer therapy drug is 3mg/mL.
6. the preparation method of the aqueous solution of the golden nanometer particle super-molecule assembling body of load cancer therapy drug according to claim 4, is characterized in that: the mass ratio of described polysaccharide-golden nanometer particle super-molecule assembling body and cancer therapy drug is 9.26:1.
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