CN104109248B - Aggregate based on bridged biscyclodextrin subject and object induced aggregation construction and application thereof - Google Patents
Aggregate based on bridged biscyclodextrin subject and object induced aggregation construction and application thereof Download PDFInfo
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- CN104109248B CN104109248B CN201410278214.5A CN201410278214A CN104109248B CN 104109248 B CN104109248 B CN 104109248B CN 201410278214 A CN201410278214 A CN 201410278214A CN 104109248 B CN104109248 B CN 104109248B
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Abstract
An aggregate based on bridged biscyclodextrin subject and object induced aggregation construction. The construction unit uses cystine bridged double beta-cyclodextrin as the subject and adamantane polyethylenimine as the object; the subject and object induced aggregation constructs a binary supramolecular aggregate and can effectively condense plasmid DNA; when the N / P ratio of the aggregate and plasmid DNA reaches 20, the formed nanoparticle has particle diameter of 83 nm; and the aggregate can be used as a gene transport vector for loading plasmid DNA and transfect green fluorescin plasmid DNA into 293T cells The invention has the advantages that the aggregate can effectively form a complex with the negatively charged plasmid DNA through electrostatic interaction, so as to reach high transfection efficiency; due to the existence of the disulfide bond, the aggregate degrades under the effect of high-concentration glutathione after entering the cells, so as to reduce the toxic and side effects; the preparation technology of the aggregate is simple, easy for implementation and low in material cost; therefore the aggregate has wide application prospect in the field of gene transfer.
Description
Technical field
The present invention relates to biological gene treatment technology, particularly one kind are based on bridged dicyclic dextrin Subjective and Objective induced aggregation structure
The aggregation built and its application.
Background technology
The carrier being applied to gene therapy at present is broadly divided into two classes, i.e. viral vector and non-viral vector.Virus
Although class carrier has efficient transfection efficiency, its safety is low, immunogenicity is high and it is complicated to prepare.With viral vector phase
Than, non-viral gene vector due to its low immunogenicity, good biocompatibility and gratifying gene load capacity,
Widely studied in recent years.Polyethyleneimine (pei) is a kind of conventional cationic polymer non-viral gene vector, it
It is by monomer (- ch2-ch2- nh-) water-soluble polymer with primary amine, secondary amine and tertiary amine group that constitutes.Every 3 in pei monomer
Individual atom contains 1 amido, and the pka value of these amidos has nothing in common with each other, make polyethyleneimine (pei) almost under the conditions of any ph all
There is the possibility being protonated, so that it is rich in positive charge, combination dna that can be stronger and adherent cell are as gene delivery
Carrier.Especially molecular weight is the branched chain type polyethyleneimine of 25 kda often by the golden standard as non-viral gene vector.
The transfection efficiency of polyethyleneimine is affected by its molecular weight, although the polyethyleneimine of high molecular has efficient transfection effect
Rate, but the presence due to its own a large amount of positive charge and its non-biodegradable are so as to have higher cytotoxicity.Mesh
Before, one of most efficient method is exactly to be coupled together the polyethyleneimine of low-molecular-weight using the covalent bond of degradable, so
Not only its toxicity can have been reduced but also it can be kept to have efficient transfection efficiency.Compared with covalent bond, supermolecule non-covalent bond phase
Interaction has the advantages that convenient synthetic method, controlled molecular recognition, suitable binding constants and easy self aggregation.Ring
Dextrin biological neck because its gratifying water solublity, good biocompatibility and non-immunogenic are widely used in
Domain.Additionally, the induced aggregation of cyclodextrin and guest molecule is to build efficient genophore to provide one kind simply and easily side
Method.Therefore, Subjective and Objective induced aggregation is applied to, on the structure of non-viral genoid carrier, there is good application prospect.
Content of the invention
The purpose of the present invention is for above-mentioned technical Analysis and existing problems, provides one kind to be based on bridged dicyclic dextrin host and guest
Aggregation and its application that body induced aggregation is constructed, this aggregation is based on bridged dicyclic dextrin and diamantane (obsolete) polyethyleneimine host and guest
Body induced aggregation is constructed, and can effectively condense and load dna, and the presence due to disulfide bond in aggregation, enters thin
Can degrade under the Glutathione effect of high concentration after born of the same parents and transfection efficiency is high, toxic and side effects are low, preparation method is simple, yield
Higher, it is suitable to amplify synthesis and production application.
Technical scheme:
A kind of aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation, its construction unit is with cystine bridge-type
Double beta-schardinger dextrin -s are main body (lcd), with diamantane (obsolete) polyethyleneimine as object (pei-ada), by Subjective and Objective induced aggregation structure
The binary supramolecular aggregation built simultaneously can effectively condense plasmid dna, wherein the chemical molecular of the double beta-schardinger dextrin-of cystine bridge-type
Formula is c48h84n2o22s2, the average macromolecular chain of diamantane (obsolete) polyethyleneimine is modified 13.7 adamantane units, this gathering
The structure of body construction unit is as follows:
.
, during for 20, the size of formed nanoparticle is 83 nm, surface for described aggregation and plasmid dna nitrogen/phosphorus ratio
Potential is 27.2 mv, can effectively pass through electrostatic interaction and form complex with electronegative plasmid dna.
A kind of preparation method of the described aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation, including following
Step:
1) under nitrogen atmosphere, adamantane acetic acid is dissolved in dehydrated alcohol and obtains adamantane acetic acid-ethanol solution, then
To add dissolved with the ethanol solution of 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and n- N-Hydroxysuccinimide
To in above-mentioned adamantane acetic acid-ethanol solution, stirring reaction 30 min, obtain reactant liquor；
2) polyethyleneimine that molecular weight is 10000 is dissolved in dehydrated alcohol, is added in above-mentioned reactant liquor, at 25 DEG C
Under the conditions of stir 24 hours, be then charged into retaining continuous dialysis 5 days in the bag filter that scope is 8000-14000, gained dialysed
Diamantane (obsolete) modifying polyethyleneimine (pei-ada) is can be prepared by after liquid lyophilizing；
3) will be soluble in water for above-mentioned diamantane (obsolete) modifying polyethyleneimine, it is subsequently adding the double beta-schardinger dextrin-of cystine bridge-type and mix
Close uniformly, you can the aggregation based on Subjective and Objective induced aggregation constructed is obtained.
In described adamantane acetic acid-ethanol solution, adamantane acetic acid and the amount ratio of ethanol are 0.058 mol/l；In 1- second
In base-(3- dimethylaminopropyl) carbodiimide hydrochloride-n- N-Hydroxysuccinimide-ethanol solution, 1- ethyl-(3- bis-
Dimethylaminopropyl) carbodiimide hydrochloride and n- N-Hydroxysuccinimide be 0.151 mol/l with the amount ratio of ethanol；Instead
Answer adamantane acetic acid in liquid, 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and n- N-Hydroxysuccinimide
Mol ratio is 0.58: 0.754: 0.754.
Amount ratio 0.001 mol/l of described polyethyleneimine and ethanol, adamantane acetic acid and polyethyleneimine mole
Than for 0.58: 0.01.
Described diamantane (obsolete) modifying polyethyleneimine is 0.397 mmol/l with the amount ratio of water, and diamantane (obsolete) modifies polyethyleneimine
Amine is 0.397: 0.121 with the mol ratio of the double beta-schardinger dextrin-of cystine bridge-type.
A kind of application of the described aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation, for loading plasmid
Green fluorescent protein plasmid dna as the carrier of gene delivery and is transfected and enters 293t cell by dna, load plasmid dna poly-
The preparation method of polymer solution is as follows:
By the aggregation being obtained with plasmid dna is soluble in water respectively obtains the gathering liquid solution that concentration is 0.397 mmol/l
With the plasmid dna solution for 0.1mg/ μ l for the concentration, 20 μ l are assembled liquid solution and mixes with 20 μ l plasmid dna solution, in mixed liquor
Nitrogen/phosphorus ratio for 20, after vibrating 5 seconds, under room temperature, stand 30 min, you can the polymer solution that loaded plasmid dna is obtained.
The invention has the advantage that it is mutual should effectively to pass through electrostatic based on the aggregation that Subjective and Objective induced aggregation is constructed
Effect forms complex with electronegative plasmid dna, and keeps the original proton sponge effect of polyethyleneimine so as to from molten
Escape inside enzyme body, it is to avoid dna degrades, and has higher transfection efficiency；Due to the presence of disulfide bond, enter after cell
Can degrade under the Glutathione effect of high concentration, reduce its toxic and side effects；The preparation process is simple of this aggregation, it is easy to real
Apply and the cost of material is low, have broad application prospects in gene delivery field.
[brief description]
Fig. 1 is the synthetic route chart of diamantane (obsolete) polyethyleneimine and aggregation.
Fig. 2 is to act on schematic diagram based on the aggregation that Subjective and Objective induced aggregation is constructed with plasmid dna.
Fig. 3 is the atomic force microscope that the aggregation constructed based on Subjective and Objective induced aggregation and plasmid dna form complex
Figure.
Fig. 4 is the cytotoxicity experiment result of 293t cell.
Fig. 5 is the fluorogram after 293t cell transfecting green fluorescent protein plasmid.
Fig. 6 is the flow cytometry analysis result after 293t cell transfecting green fluorescent protein plasmid.
[specific embodiment]
Below by example, the present invention is described further:
Embodiment:
A kind of aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation, its construction unit is with cystine bridge-type
Double beta-schardinger dextrin -s are main body (lcd), with diamantane (obsolete) polyethyleneimine as object (pei-ada), by Subjective and Objective induced aggregation structure
The binary supramolecular aggregation built simultaneously can effectively condense plasmid dna, wherein the chemical molecular of the double beta-schardinger dextrin-of cystine bridge-type
Formula is c48h84n2o22s2, the average macromolecular chain of diamantane (obsolete) polyethyleneimine is modified 13.7 adamantane units, this gathering
The structure of body construction unit is as follows:
；
, during for 20, the size of formed nanoparticle is 83 nm, surface for described aggregation and plasmid dna nitrogen/phosphorus ratio
Potential is 27.2 mv, can effectively pass through electrostatic interaction and form complex with electronegative plasmid dna.
A kind of preparation method of the described aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation, step is such as
Under:
1) under nitrogen atmosphere, by 112.68 mg(0.58 mmol) adamantane acetic acid is dissolved in 10 ml dehydrated alcohol must
To adamantane acetic acid-ethanol solution, then will be dissolved with 144.54 mg (0.754 mmol) 1- ethyl-(3- dimethylamino third
Base) 5 ml ethanol solution of carbodiimide hydrochloride and 86.78 mg (0.754 mmol) n- N-Hydroxysuccinimide are added to
In above-mentioned adamantane acetic acid-ethanol solution, stirring reaction 30 min, obtain reactant liquor；
2) by 100 mg(0.01 mmol) molecular weight is that 10000 polyethyleneimine is dissolved in 10 ml dehydrated alcohol, plus
Enter in above-mentioned reactant liquor, stir 24 hours under the conditions of 25 DEG C, be then charged into retaining the bag filter that scope is 8000-14000
In continuous dialysis 5 days, can be prepared by diamantane (obsolete) modifying polyethyleneimine (pei-ada) by after gained dialysis solution lyophilizing；
The nuclear-magnetism of the diamantane (obsolete) modifying polyethyleneimine of detection display preparation is characterized as below:1h nmr (400 mhz, d2o,
tms, ppm): δ 1.61 (m, 12h, h of -ch2of ada), 1.95 (m, 5h, h of -ch of ada),
2.48-3.40 (m, 68h, h of -ch2of pei and h of nh of -conhch2)；By amassing to nuclear magnetic spectrogram
Divide calculating can obtain modifying 13.7 adamantane units on the average macromolecular chain of diamantane (obsolete) polyethyleneimine.
3) above-mentioned 24.65 mg diamantane (obsolete) modifying polyethyleneimines are dissolved in 5 ml water that (solution concentration is 0.397
Mmol/l), it is subsequently adding the double beta-schardinger dextrin-of 0.15 mg cystine bridge-type mix homogeneously, you can be obtained based on Subjective and Objective induction
Assemble the aggregation constructed.
Fig. 1 is the synthetic route chart of diamantane (obsolete) polyethyleneimine and aggregation.
A kind of application of the prepared aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation, for loading
Plasmid dna as gene delivery carrier and by green fluorescent protein plasmid dna transfect enter 293t cell, load plasmid dna
Polymer solution preparation method as follows:
By the aggregation being obtained with plasmid dna is soluble in water respectively obtains the gathering liquid solution that concentration is 0.397 mmol/l
With the plasmid dna solution for 0.1mg/ μ l for the concentration, 20 μ l are assembled liquid solution and mixes with 20 μ l plasmid dna solution, in mixed liquor
Nitrogen/phosphorus ratio for 20, after vibrating 5 seconds, under room temperature, stand 30 min, you can be obtained loaded plasmid dna polymer molten
Liquid.
Fig. 2 is that this aggregation acts on schematic diagram with plasmid dna.
Fig. 3 is the atomic force microscopy diagram that aggregation and plasmid dna form complex, in figure: the atom of (a) plasmid dna
Force microscope figure, (b) diamantane (obsolete) polyethyleneimine and plasmid dna form the atomic force microscopy diagram of complex, (c) aggregation with
Plasmid dna forms the atomic force microscopy diagram of complex, and in figure shows: aggregation can effectively pass through electrostatic interaction with
Electronegative plasmid dna forms the complex with uniform particle size.
Concrete application effect:
293t cell (people's renal epithelial cell) is layered on culture in 96 orifice plates of the dmem culture medium containing 10% hyclone
24 hours, it is separately added into variable concentrations 25 kda pei, pei-ada, pei-ada-lcd, continuous culture 24 hours, use mtt
Method measures the cells survival rate under each experiment condition.
Fig. 4 is the cytotoxicity experiment result of 293t cell, and in figure shows: in the range of 24 hours, pei-ada-lcd pair
The toxicity of 293t cell be much smaller than 25kda pei it was demonstrated that the aggregation of the present invention show under the same conditions than 25 kda gather
The lower cytotoxicity of aziridine.
293t cell (people's renal epithelial cell) is covered with culture in 6 orifice plates of the dmem culture medium containing 10% hyclone
24 hours, it is separately added into the polymer solution (n/p=20) that 20 μ l contain 2 μ g green fluorescent protein plasmids, continuously cultivate 48
Hour, use fluorescence microscope egfp expression.Fig. 5 is glimmering after 293t cell transfecting green fluorescent protein plasmid
Light figure, in figure shows: aggregation can effectively mediate green fluorescent protein plasmid transfection 293t cell.
With the quantitative analysis egfp expression amount of flow cytometer, Fig. 6 is 293t cell transfecting green fluorescence egg
Flow cytometry analysis result after white matter grain, in figure shows: 25 kda pei transfection efficiencies are 30%, and aggregation (pei-
Ada-lcd) when n/p is 20, transfection efficiency can reach 41% hence it is evident that being higher than 25 kda polyethyleneimine.
Claims (7)
1. a kind of aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation it is characterised in that: construction unit is with Guang
The double beta-schardinger dextrin-of propylhomoserin bridge-type is main body (lcd), with diamantane (obsolete) polyethyleneimine as object (pei-ada), is lured by Subjective and Objective
Lead and assemble the binary supramolecular aggregation constructed and can effectively condense plasmid dna, wherein cystine bridge-type double beta-schardinger dextrin-
Chemical molecular formula is c48h84n2o22s2, the average macromolecular chain of diamantane (obsolete) polyethyleneimine is modified 13.7 diamantane (obsolete) lists
Unit, the structure of this aggregation construction unit is as follows:
2. the aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation according to claim 1 it is characterised in that:
When the mol ratio of the nitrogen of described aggregation and the P elements of plasmid dna is 20, the size of formed nanoparticle is
83nm, surface potential is 27.2mv, can effectively pass through electrostatic interaction and form complex with electronegative plasmid dna.
3. a kind of preparation side of the aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation as claimed in claim 1
Method is it is characterised in that comprise the following steps:
1) under nitrogen atmosphere, adamantane acetic acid is dissolved in dehydrated alcohol and obtains adamantane acetic acid-ethanol solution, then will be molten
1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and the ethanol solution of n- N-Hydroxysuccinimide is had to be added to
State in adamantane acetic acid-ethanol solution, stirring reaction 30min, obtain reactant liquor；
2) the branched chain type polyethyleneimine that molecular weight is 10000 dalton is dissolved in dehydrated alcohol, is added to above-mentioned reactant liquor
In, stir 24 hours under the conditions of 25 DEG C, be then charged in the bag filter that molecular cut off scope is 8000-14000 dalton
Continuous dialysis 5 days, can be prepared by diamantane (obsolete) polyethyleneimine (pei-ada) by after gained dialysis solution lyophilizing；
3) will be soluble in water for above-mentioned diamantane (obsolete) polyethyleneimine, it is subsequently adding the double beta-schardinger dextrin-of cystine bridge-type mix homogeneously,
Can be prepared by the aggregation constructed based on Subjective and Objective induced aggregation.
4. the preparation method of the aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation according to claim 3,
It is characterized in that: in described adamantane acetic acid-ethanol solution, adamantane acetic acid and the amount ratio of ethanol are 0.058mol/l；In 1-
In ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride-n- N-Hydroxysuccinimide-ethanol solution, 1- ethyl-(3-
Dimethylaminopropyl) carbodiimide hydrochloride and n- N-Hydroxysuccinimide be 0.151mol/l with the amount ratio of ethanol；
Adamantane acetic acid, 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and n- N-Hydroxysuccinimide in reactant liquor
Mol ratio be 0.58:0.754:0.754.
5. the preparation method of the aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation according to claim 3,
It is characterized in that: the amount ratio 0.001mol/l of described polyethyleneimine and ethanol, adamantane acetic acid is rubbed with polyethyleneimine
That ratio is 0.58:0.01.
6. the preparation method of the aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation according to claim 3,
It is characterized in that: described diamantane (obsolete) modifying polyethyleneimine is 0.397mmol/l with the amount ratio of water, and diamantane (obsolete) modifies polyethylene
Imines is 0.397:0.121 with the mol ratio of the double beta-schardinger dextrin-of cystine bridge-type.
7. a kind of application of the aggregation constructed based on bridged dicyclic dextrin Subjective and Objective induced aggregation as claimed in claim 1, its
It is characterised by transfecting entrance 293t for loading plasmid dna as the carrier of gene delivery and by green fluorescent protein plasmid dna
Cell, the preparation method of the polymer solution of load plasmid dna is as follows:
By the aggregation being obtained and plasmid dna, the concentration that obtains soluble in water is the gathering liquid solution of 0.397mmol/l and dense respectively
Spend the plasmid dna solution for 0.1mg/ μ l, 20 μ l are assembled liquid solution and mixes with 20 μ l plasmid dna solution, the nitrogen in mixed liquor/
Phosphorus ratio for 20, after vibrating 5 seconds, stands 30min, you can the polymer solution that loaded plasmid dna is obtained under room temperature.
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