CN107184990A - A kind of preparation method of antibody coupling medicine-carried nano particles - Google Patents
A kind of preparation method of antibody coupling medicine-carried nano particles Download PDFInfo
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- CN107184990A CN107184990A CN201710411521.XA CN201710411521A CN107184990A CN 107184990 A CN107184990 A CN 107184990A CN 201710411521 A CN201710411521 A CN 201710411521A CN 107184990 A CN107184990 A CN 107184990A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
- A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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Abstract
The present invention relates to a kind of preparation method of antibody coupling medicine-carried nano particles.The present invention comprises the following steps：Hydrophobic drug pterostilbene is connected chemically with hydrophilic polyglycol, synthesizing amphipathic polyethylene glycol pterostilbene conjugate；The conjugate by another dewatering medicament HCPT be encapsulated in be self-assembly of nano-particle, and insoluble drug release can be caused in response to environmental pH；In nanoparticle surface coupled antibody molecule, accurately targeted to tumour cell.It is characteristic of the invention that using antibody coupling medicine-carried nano particles, overcoming conventional antibodies coupling drug and carrying the not enough defect of medicine, and replace traditional inert material using hydrophobic cancer therapy drug, further improve drugloading rate.Advantages of the present invention：Drugloading rate is greatly improved using antibody coupling medicine-carried nano particles；Realize that medicine discharges to the targeting and intracellular pH sensitivities of tumour cell；Reduce the toxic side effect of normal tissue；Preparation technology is simple, it is easy to operate.
Description
Technical field
The present invention relates to a kind of preparation method of antibody coupling medicine-carried nano particles.
Background technology
Tumour has become the important diseases of harm human health, and its incidence of disease newly promotes 1,000 ten thousand, is used as treatment every year
The conventional means antibody therapy and chemical medicinal treatment of tumour, because respective limitation tends not to bring preferable effect.It is anti-swollen
The specific tumor cell of knurl antibody energy, but make its antitumous effect unobvious because of relatively low killing ability；Chemistry
Drug molecule can efficiently kill tumour cell, but because can not specific tumor cell and bring serious poison is secondary to make
With.Therefore, the therapeutic modality of targeting becomes focus of concern.Antibody and drug molecule are connected using chemical method,
Synthetic antibody drug conjugates, can specific tumor cell, tumour cell can be efficiently killed again, so as to reach height
Imitate the therapeutic purposes of low toxicity.
In recent years, the development of antibody drug conjugates had become one of study hotspot, up to the present more than 30 kinds
Antibody drug conjugates enter clinical research.But be the problem of drugloading rate antibody drug conjugates develop faced one it is huge
Big challenge, excessive load medicine can not only reduce the adhesion of antibody, and may influence pharmacokinetics.Therefore, in not shadow
Under the precursor for ringing antigen binding capacity, each antibody molecule is at most coupled 2 ~ 4 drug molecules, significantly limit it and controls curative effect
Really.
The developing into solve the above problems of nanometer medicine-carried system brings dawn.Compared with conventional antibodies drug conjugates,
Antibody molecule is coupled with nano medicament carrying system, can greatly increase its drugloading rate, so as to further improve its therapeutic effect.
In numerous nanometer medicine-carried systems, polymer nano-particle has the absorption of increase medicine, controlled release drug release, improves medicine target
Tropism and the significant advantage such as stability, reduction administration number of times and dosage, reduction toxic side effect, receive much concern in treatment of cancer.
In addition, the selection of nano carrier material is also extremely important.Under normal circumstances, carrier material is all inert material, their effect
It is merely possible to a kind of means of delivery.And in most Nano medication, these inert materials are its main ancestrals point, and medicine
Molecule only accounts for a ratio of very little.Therefore, in the treatment to reach preferable drug concentration, substantial amounts of carrier material is also made
With may result in serious system toxicity and increase the additional body burden of patient.Due to most drug molecule
It is hydrophobic, therefore we are substituted hydrophobic material using hydrophobic medicine and build amphipathic carrier material, farthest
The use of inert material is reduced, so as to substantially increase the drugloading rate of drug molecule.
Polymer nano-particle is easily recognized simultaneously because of its particle diameter factor in intravenously administrable by the phagocyte in immune system
Phagocytosis, therefore the histoorgan that can be enriched medicine passive target in phagocyte using this characteristic, such as liver, spleen, lung and pouring
Bar tissue, if particle diameter is sufficiently small to may further enter into myeloid tissue, so as to realize passive target.It is dissolved due to medicine, is encapsulated in and receives
In nanoparticle carrier, so can also keep the stability of medicine during body circulation, it is protected not broken before focus is reached
It is bad or swallow, make that stability is poor, facile hydrolysis medicine realizes oral administration.
With the development of antibody coupling medicament-carried nano system, its big advantage will be embodied in treatment of cancer and good
Potential applicability in clinical practice.
The content of the invention
The purpose of the present invention is to set up a kind of preparation method of antibody coupling medicine-carried nano particles：A kind of amphiphilic is synthesized first
Property macromolecule carrier polyethylene glycol-pterostilbene conjugate, internal self assembly shape is encapsulated in by hydrophobic drug 10-hydroxycamptothecine
Into medicine-carried nano particles, and in nanoparticle surface conjugated monoclonal antibodies, utilize body circulation and cell interior environmental pH
Difference, realizes intelligent medicine releasing.
Described amphipathy macromolecule carrier polyethylene glycol-pterostilbene conjugate is following structure：
Wherein：
Polyethylene glycol is the carboxy polyethylene glycol that maleic amide is modified；
Technical scheme：
(1) synthesis of amphipathy macromolecule carrier polyethylene glycol-pterostilbene conjugate
(2) preparation of medicine-carried nano particles
Precipitation method self assembly prepares nano-particle.Specific method：By the polyethylene glycol of synthesis-pterostilbene conjugate and hydrophobicity medicine
Thing 10-hydroxycamptothecine is dissolved in DMSO, is then added dropwise in the gentle agitation aqueous solution, PBS 3h；It is cold after filtering
Jelly is dried to obtain medicine-carried nano particles；
(3) antibody coupling nano-particle
Reducing agent handles monoclonal antibody, prepares the antibody molecule containing free sulfhydryl groups；Utilize antibody free sulfhydryl groups and nanoparticle
The maleic amide in sublist face is connected chemically, and obtains the targeted medicament carrying nano particle of antibody modification.
Advantages of the present invention：
(1) amphipathic high score is prepared instead of traditional hydrophobic inert material using hydrophobic small molecule anticancer drug pterostilbene
Subcarrier, improves drugloading rate, it is possible to therapeutic alliance is realized with other cancer therapy drugs, so as to improve therapeutic effect；
(2) using the thought of pH sensitiveness amphipathy macromolecule carriers, model drug 10- is encapsulated in the nanoparticle formed
HCPT, it is ensured that medicine realizes the intelligent control release of medicine in the cell while keeping stable in body circulation；
(3) a kind of drug delivery system thought of active targeting is devised, active targeting and passive target are organically combined
Come, the targeting of delivery system is improved to greatest extent；
(4) preparation technology is simple, it is easy to operate.
Brief description of the drawings
Fig. 1 is the TEM schematic diagrames of antibody coupling medicine-carried nano particles；
Fig. 2 is the cytotoxicity of pure medicine and nano-particle；
Fig. 3 is pure medicine and nano-particle pharmacokinetics.
Embodiment
The present invention is specifically described examples given below, but does not limit the present invention, and the scope of the present invention is by right
It is required that limiting.
Embodiment 1：
The synthesis of amphipathic ethylene glycol-pterostilbene conjugate：N is continually fed into the there-necked flask dried to 50 mL2；In N2's
By 0.013 g pterostilbenes under protection, 0.375 g polyethylene glycol (Mw 7,500) is dissolved in 10 mL DCM, adds 0.01 g
Then EDC, 0.012 g DMAP, 0 °C of lower stirring and dissolving, stirring reaction 1 hour be stirred at room temperature 24 h of reaction；Question response terminates
Afterwards, by the h of reaction solution PBS 6, freeze-drying obtains polyethylene glycol-pterostilbene conjugate of purity more than 95%；
The preparation of polyethylene glycol-pterostilbene/10-hydroxycamptothecine medicine-carried nano particles：0.2 g polyethylene glycol-pterostilbene combines
Thing and 0.05 g 10-hydroxycamptothecines are dissolved in 1 mL DMSO, in the aqueous solution for being added dropwise to 3.0 mL gentle agitations；So
Polyethylene glycol-pterostilbene/10-hydroxycamptothecine solution is moved into the h of PBS 3 in bag filter afterwards, after filtering, is freeze-dried
To medicine-carried nano particles；
The preparation of antibody coupling nano-particle：2 mL antibody-solutions (10 mg/mL) and reducing agent TCEP (40 μ L, 20 mM)
In 37 °C of lower h of hybrid reaction 2, the antibody molecule containing free sulfhydryl groups is obtained；Antibody-solutions are diluted to 2 mg/mL using PBS,
Then 1 mL antibody is added to polyethylene glycol-pterostilbene/10-hydroxycamptothecine nano-particle (4 mL, 5 mg/mL) PBS
2 h, the h of PBS 3 are reacted at room temperature in buffer solution, is freeze-dried, obtains the targeted nano-particle of antibody modification.
Embodiment 2：
The synthesis of amphipathic ethylene glycol-pterostilbene conjugate：N is continually fed into the there-necked flask dried to 50 mL2；In N2's
By 0.064 g pterostilbenes under protection, 0.375 g polyethylene glycol (Mw 7,500) is dissolved in 10 mL DCM, adds 0.05 g
Then EDC, 0.06 g DMAP, 0 °C of lower stirring and dissolving, stirring reaction 1 hour be stirred at room temperature 24 h of reaction；Question response terminates
Afterwards, by the h of reaction solution PBS 6, freeze-drying obtains polyethylene glycol-pterostilbene conjugate of purity more than 95%；
The preparation of polyethylene glycol-pterostilbene/10-hydroxycamptothecine medicine-carried nano particles：0.2 g polyethylene glycol-pterostilbene combines
Thing and 0.1 g 10-hydroxycamptothecines are dissolved in 1 mL DMSO, in the aqueous solution for being added dropwise to 3.0 mL gentle agitations；So
Polyethylene glycol-pterostilbene/10-hydroxycamptothecine solution is moved in bag filter after the h of PBS 3, membrane filtration afterwards, freezing is dry
It is dry to obtain medicine-carried nano particles；
The preparation of antibody coupling nano-particle：2 mL antibody-solutions (10 mg/mL) and reducing agent TCEP (40 μ L, 30 mM)
In 37 °C of lower h of hybrid reaction 2, the antibody molecule containing free sulfhydryl groups is obtained；Antibody-solutions are diluted to 4 mg/mL using PBS,
Then 1 mL antibody is added to polyethylene glycol-pterostilbene/10-hydroxycamptothecine nano-particle (4 mL, 5 mg/mL) buffering
2 h, the h of PBS 3 are reacted at room temperature in liquid, is freeze-dried, obtains the targeted nano-particle of antibody modification.
Embodiment 3：
The synthesis of amphipathic ethylene glycol-pterostilbene conjugate：N is continually fed into the there-necked flask dried to 50 mL2；In N2's
By 0.128 g pterostilbenes under protection, 0.375 g polyethylene glycol (Mw 7,500) is dissolved in 10 mL DMSO, adds 0.10 g
Then EDC, 0.12 g DMAP, 0 °C of lower stirring and dissolving, stirring reaction 1 hour be stirred at room temperature 24 h of reaction；Question response terminates
Afterwards, by the h of reaction solution PBS 6, freeze-drying obtains polyethylene glycol-pterostilbene conjugate of purity more than 95%；
The preparation of polyethylene glycol-pterostilbene/10-hydroxycamptothecine medicine-carried nano particles：0.2 g polyethylene glycol-pterostilbene with
0.15 g HCPTs are dissolved in 1 mL DMSO, in the aqueous solution for being added dropwise to 3.0 mL gentle agitations；Then by poly- second
Glycol-pterostilbene/10-hydroxycamptothecine solution moves to the h of PBS 3 in bag filter, after filtering, and freeze-drying obtains load medicine and received
Rice corpuscles；
The preparation of antibody coupling nano-particle：2 mL antibody-solutions (10 mg/mL) exist with reducing agent DTT (40 μ L, 20 mM)
37 °C of lower h of hybrid reaction 2, obtain the antibody molecule containing free sulfhydryl groups；Antibody-solutions are diluted to 2 mg/mL using PBS, so
1 mL antibody is added to polyethylene glycol-pterostilbene/10-hydroxycamptothecine nano-particle (4 mL, 5 mg/mL) buffer solution afterwards
Middle room temperature reaction 2 h, the h of PBS 3, freeze-drying, obtain the targeted nano-particle of antibody modification.
Embodiment 4：
The synthesis of amphipathic ethylene glycol-pterostilbene conjugate：N is continually fed into the there-necked flask dried to 50 mL2；In N2's
By 0.256 g pterostilbenes under protection, 0.375 g polyethylene glycol (Mw 7,500) is dissolved in 10 mL DMSO, adds 0.19 g
Then EDC, 0.24 g DMAP, 0 °C of lower stirring and dissolving, stirring reaction 1 hour be stirred at room temperature 24 h of reaction；Question response terminates
Afterwards, by the h of reaction solution PBS 6, freeze-drying obtains polyethylene glycol-pterostilbene conjugate of purity more than 95%；
The preparation of polyethylene glycol-pterostilbene/10-hydroxycamptothecine medicine-carried nano particles：0.2 g polyethylene glycol-pterostilbene and 0.2
G 10-hydroxycamptothecines are dissolved in 1 mL DMSO, in the aqueous solution for being added dropwise to 3.0 mL gentle agitations；Then by poly- second
Glycol-pterostilbene/10-hydroxycamptothecine solution is moved in bag filter after the h of PBS 3, membrane filtration, and freeze-drying is carried
Medicine nano-particle；
The preparation of antibody coupling nano-particle：2 mL antibody-solutions (10 mg/mL) exist with reducing agent DTT (40 μ L, 30 mM)
37 °C of lower h of hybrid reaction 2, obtain the antibody molecule containing free sulfhydryl groups；Antibody-solutions are diluted to 4 mg/mL using PBS, so
1 mL antibody is added to polyethylene glycol-pterostilbene/10-hydroxycamptothecine nano-particle (4 mL, 5 mg/mL) buffer solution afterwards
Middle room temperature reaction 2 h, the h of PBS 3, freeze-drying, obtain the targeted nano-particle of antibody modification.
Claims (9)
1. a kind of preparation method of antibody coupling medicine-carried nano particles, its architectural feature is：Described amphipathy macromolecule is carried
Body material is that the carboxy polyethylene glycol modified by hydrophilic maleic amide is combined with hydrophobic small molecules cancer therapy drug pterostilbene
Formed.
2. a kind of preparation method step of the antibody coupling medicine-carried nano particles prepared described in claim 1 is as follows：
(1) preparation of amphipathy macromolecule carrier material polyethylene glycol-pterostilbene conjugate：Using pterostilbene as raw material, in N2Protect
Under shield, pterostilbene, polyethylene glycol are dissolved in organic solvent, organic base is added under 0 °C as catalyst reaction 1 hour, then
Move to and react 24 h at room temperature；After question response terminates, phosphate buffered saline solution (PBS) 6 h of dialysis, filter freezing is dried, then
Obtain polyethylene glycol-pterostilbene conjugate of purity more than 95%；
(2) preparation of medicine-carried nano particles:Polyethylene glycol described in (1)-pterostilbene conjugate and 10-hydroxycamptothecine is molten
In dimethyl sulfoxide (DMSO) (DMSO), be self-assembly of in the aqueous solution for being then added dropwise to stirring polyethylene glycol-pterostilbene/
10-hydroxycamptothecine medicine-carried nano particles；After PBS 3h, membrane filtration, freeze-drying；
(3) disulfide bond between antibody molecule is opened using reducing agent, obtains the antibody molecule containing free sulfhydryl groups；
(4) antibody molecule containing free sulfhydryl groups is utilized with polyethylene glycol-pterostilbene/10-hydroxycamptothecine medicine-carried nano particles
Thioether bond is connected, and diafiltration obtains the targeted nano pharmaceutical carrier particle of antibody modification.
3. antibody coupling medicine-carried nano particles volume preparation method according to claim 2, it is characterised in that described is organic molten
Agent is one kind in dichloromethane (DCM), DMSO.
4. the preparation method of antibody coupling medicine-carried nano particles according to claim 2, it is characterised in that described poly- second two
Alcohol is the carboxy polyethylene glycol that maleic amide is modified, and molecular weight is 7500 dalton.
5. the preparation method of antibody coupling medicine-carried nano particles according to claim 2, it is characterised in that described organic base
For water-soluble carbodiimide (EDC) and DMAP (DMAP).
6. the preparation method of antibody coupling medicine-carried nano particles according to claim 2, it is characterised in that described organic base
The mol ratio of EDC and DMAP and pterostilbene is respectively 1:1 and 1:2.
7. the preparation method of antibody coupling medicine-carried nano particles according to claim 2, it is characterised in that described dialysis
Bag molecular cut off is 7,500 dalton.
8. the preparation method of antibody coupling medicine-carried nano particles according to claim 2, it is characterised in that described reduction
Agent is three (2- carboxyethyls) phosphines (TECP), one kind of dithiothreitol (DTT) (DTT).
9. the preparation method of antibody coupling medicine-carried nano particles according to claim 2, it is characterised in that described is amphipathic
Polymer carrier has nucleocapsid double-decker, and outer layer is hydrophilic polyethylene glycol, and internal layer wraps up for dewatering medicament molecule
Layer.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108524942A (en) * | 2018-04-17 | 2018-09-14 | 北京林业大学 | A kind of pH responsive type medicine-carried nano particles and preparation method thereof based on ganoderma lucidum polysaccharide-histidine conjugate |
| CN108635583A (en) * | 2018-05-15 | 2018-10-12 | 北京林业大学 | A kind of pH and reproducibility double-response type nano-medicament carrier and preparation method thereof |
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| CN108524942A (en) * | 2018-04-17 | 2018-09-14 | 北京林业大学 | A kind of pH responsive type medicine-carried nano particles and preparation method thereof based on ganoderma lucidum polysaccharide-histidine conjugate |
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Application publication date: 20170922 |