CN102302782A - Preparation method of hepatoma carcinoma cell-targeted polyamido-amine dendrimer support - Google Patents
Preparation method of hepatoma carcinoma cell-targeted polyamido-amine dendrimer support Download PDFInfo
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Abstract
The invention relates to a preparation method of a hepatoma carcinoma cell-targeted polyamido-amine dendrimer support, which comprises the following steps of: (1) modifying a polyamido-amine dendrimer by using fluorescein isothiocyanate to obtain G5.NH2-FI; (2) partially acetylizing the G5.NH2-FI to obtain a product of G5-FI-Ac-NH2 in which an amino-group on the surface of the dendrimer is partially acetylized; (3) modifying the G5-FI-Ac-NH2 by using lactobionic acid to obtain G5-FI-Ac-La with functions of targeting a hepatoma carcinoma cell and tracing by fluorescent. The preparation method provided by the invention is simple and has moderate reaction conditions. Furthermore, a used polymer is an environmental-friendly high polymer material and has a prospect of being industrialized. The functional dendrimer material prepared by the invention is good in biocompatibility and can combine a specific target with the hepatoma carcinoma cell, so that the support can be used in load and targeting delivery of medicines, genes or molecule diagnosing probes.
Description
Technical field
The invention belongs to the preparation field of macromolecule targeted nano carrier, particularly relate to a kind of method for preparing of polyamide-amine dendrimer carrier of HCC targeting.
Background technology
Chemotherapy is shown great attention to as one of important means of treatment of cancer for a long time always.Yet problem such as the existing clinical efficacy of many antitumor drug is low, toxic and side effects is big has become the bottleneck in the cancer drug treatment.Especially in liver cancer treatment,, will cause patient's normal structure and organ to receive unnecessary damages, even threaten patient's life because uncontrollable antitumor drug concentrates on the lesions position of liver.In recent years, develop a kind of liver-targeted nanometer carrier, realize that drug specificity is transported to the diseased region of liver, alleviate injury when improving therapeutic effect, become the focus and the emphasis of research other internal organs.It is the liver-targeted nanometer preparation of drug carriers method of targeted molecular with the enoxolone that at present existing multinomial patent discloses, and is the patent of CN101549158, CN101254308, CN101249266, CN101642573 like publication number.
(asialoglycoprotein receptor ASGPR) can specificity identification molecular end have the glycoprotein of galactose residue and combination with it to the asialoglycoprotein receptor that the liver plasma membrane surface specific is expressed.Research shows: the surface of galactose residue being modified nano-carrier; Not only can guide combining of nano-carrier and liver cancer cell specificity; Also be expected to the medicine that connects on the nano-carrier, enzyme, gene or tracer molecule are oriented to hepatocyte through receptor-mediated endocytosis process; Thereby reduce toxic and side effects, improve therapeutic effect, and possibly realize the early diagnosis of hepatocarcinoma other internal organs.Chinese patent CN101129342 has synthesized the vinyl acetate monomer that has galactose residue, and has obtained liver targeting polyelectrolyte with unsaturated cation or anionic monomer copolymerization.The synthetic method of this targeting material is comparatively complicated, and can only be used for the load and the conveying of antitumor drug through the method for self assembly layer by layer, therefore in using and promoting, still has certain limitation.
Retrieval both at home and abroad document and the patent results of relevant HCC targeting vector shows: with lactobionic acid polyamide-amine dendrimer is carried out functional modification, and diagnose or relevant report is not seen in the research of the targeting vector of treating as HCC.
Summary of the invention
Technical problem to be solved by this invention provides a kind of method for preparing of polyamide-amine dendrimer carrier of HCC targeting, and this method for preparing is simple, and reaction condition is gentle, easy operating, raw material environmental protection; The functional dendritic macromolecular material of gained has excellent biological compatibility, and targeting is attached on the HCC specifically.
The method for preparing of the polyamide-amine dendrimer carrier of a kind of HCC targeting of the present invention comprises:
(1) Fluorescein isothiocyanate of polyamide-amine dendrimer (FITC) is modified:
Contain the 15-25mg end group at 8-12mL and be the 5th amino generation polyamide-amine dendrimer G5.NH
2Anhydrous DMSO solution in dropwise add the DMSO solution that 5-15mL has Fluorescein isothiocyanate FITC, stirred under the room temperature 24 hours, then through the dialysis purification, last lyophilization obtains G5.NH
2-FI;
(2) partial acetylation of polyamide-amine dendrimer is modified:
With above-mentioned G5.NH
2-FI is dissolved in the DMSO solution of 8-13mL; After adding the triethylamine mix homogeneously; Dropwise add 3-8mL and contain the DMSO solution of acetic anhydride, stirring reaction 24 hours obtains the product G5-FI-Ac-NH of dendrimer surface amino groups partial acetylation then through dialysis purification and lyophilization
2
(3) lactobionic acid of polyamide-amine dendrimer (La) is modified:
Lactobionic acid (La), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxy-succinamide (NHS) are dissolved in the 3-8mL PBS, and stirring at room reaction 2-5 hour is added drop-wise to above-mentioned G5-FI-Ac-NH then
2The 10-15mL aqueous solution in, stirring at room 2-5 days, after obtain G5-FI-Ac-La after dialysis purification and the lyophilization.
Fluorescein isothiocyanate FITC described in the step (1) and dendrimer G5.NH
2Mol ratio be 3: 1～10: 1.
The mol ratio of acetic anhydride described in the step (2) and triethylamine is 1: 1～1: 12.
Acetic anhydride described in the step (2) and dendrimer G5.NH
2Mol ratio be 80: 1～100: 1.
Lactobionic acid and dendrimer G5.NH described in the step (3)
2Mol ratio be 3: 1～20: 1.
The mol ratio of lactobionic acid described in the step (3) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride 1: 3～1: 10; The mol ratio of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxy-succinamide is 2: 1～1: 1.
The pH value of the PBS described in the step (3) is 6.0.
Dialysis described in step (1)～(3) is the dialysis 3 days in PBS buffer solution 4L * 3 and ultra-pure water 4L * 3 one by one of 10000 cellulose dialyzer for using molecular cut off.
Daiamid (PAMAM) dendrimer is a kind of highly branched single macromole that disperses, and it has good dimensional controllability and water solublity, under using dosage, does not have cytotoxicity and immunogenicity, has therefore received extensive concern.It has regular meticulous structure: inside is the hydrophobicity cavity, can the place be provided for the load of hydrophobic drug and inorganic probe molecule; There are a large amount of controllable function groups on the surface, can connect or adsorb some targeting groups, antibody or drug molecule etc. by chemistry.
Lactobionic acid (La) is a kind of micromolecule that contains galactose residue, and the surface that can be modified at nano-carrier or macromolecular material is to improve it to the hepatocyte binding ability.Therefore,, then be expected to prepare a kind of nano-carrier, realize the load and the targeted of medicine, gene or diagnosis molecular probe with HCC target function if lactobionic acid is modified at the dendrimer surface.
The present invention is that the 5th amino generation daiamid (PAMAM) dendrimer is a raw material with the end group; Give carrier fluorescent tracing function at 5 Fluorescein isothiocyanates of its surface grafting (FITC) molecule; The part end amino that dendrimer is surperficial carries out acetylization reaction makes its surface charge be neutral to improve biocompatibility; Again 10 lactobionic acid molecules are connected the dendrimer surface, have finally obtained having the G5-FI-Ac-La nano-carrier of HCC target function.
The present invention uses the method for nuclear magnetic resoance spectrum (NMR) and the auxiliary laser desorption ionizing of medium flight time mass spectrum (MALDI-TOF MS) to characterize the dendrimer carrier of the HCC targeting of preparation, and to come the carrier of checking functionization with mtt assay, flow cytometry and laser confocal microscope be the toxicity and the specificity combination of HepG2 cell to human hepatoma cell.The result shows that the dendrimer carrier according to the present invention's preparation does not have cytotoxicity to HCC when concentration reaches 2000 nM; And specific bond HCC significantly; The dendrimer that does not contain lactobionic acid of contrast does not then show the specific bond to HCC, so the dendrimer of the modification lactobionic acid of the present invention's preparation can be used for the targeted to chemotherapeutics, gene and the contrast agent etc. of HCC as carrier.
Beneficial effect
(1) method for preparing of the present invention is simple, easy operating, reaction condition is gentle, to equipment require lowly, and used polymer is eco-friendly macromolecular material, has industrialization application prospect;
(2) the functional dendritic macromolecular material of the present invention's preparation has excellent biological compatibility, and targeting is attached on the HCC specifically, can be used for the load and the targeted of medicine, gene or diagnosis molecular probe.
Description of drawings
Fig. 1 is the G5-FI-Ac (a) of Comparative Examples 1 gained and the nmr spectrum of the G5-FI-Ac-La (b) of embodiment 1 gained;
Fig. 2 is the MALDI-TOF spectrogram of G5-FI-Ac-La of G5-FI-Ac and embodiment 1 gained of Comparative Examples 1 gained;
The HepG2 cell that Fig. 3 tests for mtt assay passes through the G5-FI-Ac of Comparative Examples 1 gained and the G5-FI-Ac-La (concentration range is at 0-2000nM) of embodiment 1 gained handles the cell viability after 24 hours respectively;
Fig. 4 be two kinds of materials of G5-FI-Ac-La of G5-FI-Ac and embodiment 1 gained of Comparative Examples 1 gained under variable concentrations with HepG2 co-culture of cells 2h after flow cytometry result;
Fig. 5 for through the PBS buffer (a, d), the G5-FI-Ac of Comparative Examples 1 gained (b, e) (c f) handles HepG2 cell and the laser confocal microscope picture of MCF-7 cell behind the 2h with the G5-FI-Ac-La of embodiment 1 gained;
Fig. 6 is a reaction equation of the present invention.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.Should be understood that in addition those skilled in the art can do various changes or modification to the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
(1) the Fluorescein isothiocyanate FITC of polyamide-amine dendrimer modifies:
Containing the 5th generation polyamide-amine dendrimer G5.NH of 20mg end group for amino
210mL anhydrous dimethyl sulfoxide (DMSO) solution in dropwise add the 10mL DMSO solution contain 1.5mg FITC; Strong magnetic agitation is 24 hours under the room temperature; Subsequently product being used molecular cut off is the dialysis 3 days in PBS buffer solution 4L * 3 and ultra-pure water 4L * 3 one by one of 10000 cellulose dialyzer, after lyophilization obtains product G5.NH
2-FI.
(2) partial acetylation of polyamide-amine dendrimer is modified:
With G5.NH
2-FI is dissolved in the DMSO solution of 10mL; After 9.6 μ L triethylamines fully mix; Dropwise add the DMSO solution 5mL that contains the 7.1mg acetic anhydride, reaction is 24 hours under the strong magnetic agitation, obtains the product G5-FI-Ac-NH of dendrimer surface amino groups partial acetylation through dialyse purification and lyophilization
2
(3) lactobionic acid of polyamide-amine dendrimer (La) is modified:
2.76mg lactobionic acid (La); 5.9mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) is dissolved in (pH6.0) in the 5mL PBS with 3.6mg N-hydroxy-succinamide (NHS); Room temperature condition lower magnetic force stirring reaction 3 hours is added drop-wise to G5-FI-Ac-NH gradually with reacted solution
2Aqueous solution in, strong magnetic agitation is 3 days under the room temperature condition.Product obtains G5-FI-Ac-La after dialysis purification and lyophilization.
The product G 5-FI-Ac-La that obtains is carried out nuclear-magnetism characterize, the result sees accompanying drawing 1b: a tangible proton peak is arranged at 1.87ppm place, correspondence the characteristic peak of methyl on the acetyl group; Belong to the characteristic peak on the phenyl ring among the fluorescence molecule FITC of dendrimer finishing in the proton peak at 6.47-7.07ppm place; Proton peak at the 3.40-4.10ppm place is corresponding to the characteristic peak on the lactobionic acid molecule.Each peak is carried out integral and calculating can be known: the dendrimer carrier surface has been modified 5 FITC molecules, 90 acetyl group and 7.7 lactobionic acid molecules.Therefore, successfully prepared the dendrimer G5-FI-Ac-La that designs synthetic functionalization.
Embodiment 2
According to synthetic two kinds of material G5-FI-Ac-La of the method for embodiment 1 and Comparative Examples 1 and G5-FI-Ac, carry out the auxiliary laser desorption ionizing of medium flight time mass spectrum (MALDI-TOF MS) test, the result is shown in accompanying drawing 2.The result shows: the molecular weight of having modified the chemical compound G5-FI-Ac-La of lactobionic acid has remarkable increase than the molecular weight of the chemical compound G5-FI-Ac of unmodified lactobionic acid.Find that through calculating the G5-FI-Ac-La finishing has 4 lactobionic acid molecules.Though this test result and NMR result have certain difference; But the test result of considering MALDI-TOF MS can not reflect the mean molecule quantity of material; Can only provide a wide in range range of molecular weight distributions; Therefore this result can prove well that still lactobionic acid successfully is modified at the dendrimer surface, has prepared the G5-FI-Ac-La nano-carrier.
Embodiment 3
With human liver cancer cell HepG2 is the cytotoxicity that model cell is checked embodiment 1 and Comparative Examples 1 synthetic two kinds of material G5-FI-Ac-La and G5-FI-Ac.Cultivation is after 24 hours in the culture fluid that contains G5-FI-Ac-La, G5-FI-Ac of variable concentrations respectively with model cell, and with the survival that mtt assay comes the test model cell, the result sees accompanying drawing 3.Interpretation of result shows; Concentration range is when 0-2000nM; The HepG2 cell is after G5-FI-Ac-La and G5-FI-Ac handle 24 hours; The survival rate of the cell of mtt assay test still is higher than more than 95%, proves according to the synthetic carrier material of the present invention to have excellent biological compatibility, in the finite concentration scope, does not have vitro cytotoxicity.
Embodiment 4
With the human liver cancer cell HepG2 with strong ASGPR expression is that model cell is checked embodiment 1 and Comparative Examples 1 synthetic two kinds of material G5-FI-Ac-La and the G5-FI-Ac targeting effect to HCC.Cultivation is after 2 hours in the culture fluid of G5-FI-Ac-La that contains variable concentrations and G5-FI-Ac respectively with model cell, and with the fluorescence intensity of flow cytometry rating model cell, the result sees accompanying drawing 4.Test result shows: in selected concentration range, the HepG2 cell of cultivating altogether with G5-FI-Ac-La all has than being total to the stronger fluorescence signal of cultured cells with G5-FI-Ac.When 500nM concentration; The fluorescence intensity of the HepG2 cell of cultivating altogether with G5-FI-Ac-La is and G5-FI-Ac more than 5 times of cultured cells altogether; This shows that G5-FI-Ac-La can combine with the HepG2 cell specifically, and the dendrimer of unmodified lactobionic acid does not combine or only exist a spot of non-specific adsorption to the HepG2 cell.
Embodiment 5
Be model cell to have respectively than the human liver cancer cell HepG2 of strong ASGPR expression and the human breast cancer cell MCF-7 of low ASGPR expression; Use concentration respectively to carry out laser confocal microscope after 2 hours as the G5-FI-Ac material processed of the G5-FI-Ac-La of embodiment 1 gained of 500nM and Comparative Examples 1 gained and observe, the result sees accompanying drawing 5.For having the HepG2 cell that strong ASGPR expresses, after the material G5-FI-Ac-La that modifies with lactobionic acid cultivated altogether, cell had stronger fluorescence signal; And after cultivating with the material G5-FI-Ac of unmodified lactobionic acid, cell does not almost have fluorescence signal, and is similar with PBS buffer matched group.This result proves: the G5-FI-Ac-La that has only lactobionic acid to modify has specific targeting and combination to HCC, and the material of unmodified does not have the targeting effect to HCC.The human breast cancer cell MCF-7 that expresses for low ASGPR, similar with cell after G5-FI-Ac-La cultivates altogether and G5-FI-Ac, PBS matched group all almost do not have fluorescence signal.This G5-FI-Ac-La that has proved that also lactobionic acid is modified only has specific targeting effect to the HCC with high ASGPR expression, and other cell is not had the targeting effect.
Comparative Examples 1
(1) the Fluorescein isothiocyanate FITC of polyamide-amine dendrimer modifies:
Containing 20mg polyamide-amine dendrimer G5.NH
2The DMSO solution of 10mL in dropwise add the 10mL DMSO solution that contains 1.5mg FITC; Strong magnetic agitation is 24 hours under the room temperature; Subsequently product being used molecular cut off is the dialysis 3 days in PBS buffer solution 4L * 3 and ultra-pure water 4L * 3 one by one of 10000 cellulose dialyzer, after lyophilization obtains product G5.NH
2-FI.
(2) the complete acetylation of polyamide-amine dendrimer is handled:
With G5.NH
2-FI is dissolved in the DMSO solution of 10mL; After 12.8 μ L triethylamines fully mix; Dropwise add the DMSO solution 5mL that contains the 9.5mg acetic anhydride, reaction is 24 hours under the strong magnetic agitation, obtains the complete acetylizad product G5-FI-Ac of dendrimer surface amino groups through dialysis purification and lyophilization.
The product G 5-FI-Ac that obtains is carried out nuclear-magnetism characterize, the result sees accompanying drawing 1a.The nuclear-magnetism result has shown the finishing of G5-FI-Ac dendrimer 5 FITC molecules, all acetylations of the amino quilt of residue.
Claims (8)
1. the method for preparing of the polyamide-amine dendrimer carrier of a HCC targeting comprises:
(1) contains the 15-25mg end group at 8-12mL and be the 5th amino generation polyamide-amine dendrimer G5.NH
2Anhydrous DMSO solution in dropwise add the DMSO solution of 5-15mL Fluorescein isothiocyanate FITC, stirred 24 hours under the room temperature, then through the dialysis purification, last lyophilization obtains G5.NH
2-FI;
(2) with above-mentioned G5.NH
2-FI is dissolved in the DMSO solution of 8-13mL; After adding the triethylamine mix homogeneously; Dropwise add 3-8mL and contain the DMSO solution of acetic anhydride, stirring reaction 24 hours obtains the product G5-FI-Ac-NH of dendrimer surface amino groups partial acetylation then through dialysis purification and lyophilization
2
(3) lactobionic acid, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and N-hydroxy-succinamide are dissolved in the 3-8mL PBS, stirring at room reaction 2-5 hour is added drop-wise to above-mentioned G5-FI-Ac-NH then
2The 10-15mL aqueous solution in, stirring at room 2-5 days, after obtain G5-FI-Ac-La after dialysis purification and the lyophilization.
2. the method for preparing of the polyamide-amine dendrimer carrier of a kind of HCC targeting according to claim 1 is characterized in that: Fluorescein isothiocyanate FITC described in the step (1) and dendrimer G5.NH
2Mol ratio be 3: 1～10: 1.
3. the method for preparing of the polyamide-amine dendrimer carrier of a kind of HCC targeting according to claim 1 is characterized in that: the mol ratio of acetic anhydride described in the step (2) and triethylamine is 1: 1～1: 1.2.
4. the method for preparing of the polyamide-amine dendrimer carrier of a kind of HCC targeting according to claim 1 is characterized in that: acetic anhydride described in the step (2) and dendrimer G5.NH
2Mol ratio be 80: 1～100: 1.
5. the method for preparing of the polyamide-amine dendrimer carrier of a kind of HCC targeting according to claim 1 is characterized in that: lactobionic acid and dendrimer G5.NH described in the step (3)
2Mol ratio be 3: 1～20: 1.
6. the method for preparing of the polyamide-amine dendrimer carrier of a kind of HCC targeting according to claim 1 is characterized in that: the mol ratio of lactobionic acid described in the step (3) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride 1: 3～1: 10; The mol ratio of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxy-succinamide is 2: 1～1: 1.
7. the method for preparing of the polyamide-amine dendrimer carrier of a kind of HCC targeting according to claim 1 is characterized in that: the pH value of the PBS described in the step (3) is 6.0.
8. the method for preparing of the polyamide-amine dendrimer carrier of a kind of HCC targeting according to claim 1 is characterized in that: step (1)～(3) described dialysis is the dialysis 3 days in PBS buffer solution 4L * 3 and ultra-pure water 4L * 3 one by one of 10000 cellulose dialyzer for using molecular cut off.
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| CN104587488A (en) * | 2015-02-02 | 2015-05-06 | 哈尔滨工业大学 | Preparation method of mesoporous apatite nano-drug carrier with pH responsiveness and cellular targeting property for hepatoma cell |
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| CN105963718A (en) * | 2016-04-28 | 2016-09-28 | 东华大学 | Preparation method of gadolinium-based chelate MR contrast agent modified by maltose |
| CN106632748A (en) * | 2016-09-21 | 2017-05-10 | 武汉理工大学 | Lactose-based intelligent polymer and application thereof |
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| CN110614089A (en) * | 2019-10-23 | 2019-12-27 | 鲁东大学 | Preparation method of functionalized polyamide-amine dendrimer adsorbent |
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