CN106491561A - Preparation method of PAMAM-based nano delivery system jointly carrying adriamycin and drug resistance reversal agent - Google Patents
Preparation method of PAMAM-based nano delivery system jointly carrying adriamycin and drug resistance reversal agent Download PDFInfo
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- CN106491561A CN106491561A CN201610988454.3A CN201610988454A CN106491561A CN 106491561 A CN106491561 A CN 106491561A CN 201610988454 A CN201610988454 A CN 201610988454A CN 106491561 A CN106491561 A CN 106491561A
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- pamam
- drug resistance
- reversal agent
- amycin
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- 206010059866 Drug resistance Diseases 0.000 title claims abstract description 34
- 239000012313 reversal agent Substances 0.000 title claims abstract description 29
- 229920000962 poly(amidoamine) Polymers 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 title abstract description 72
- 229940009456 adriamycin Drugs 0.000 title abstract 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 72
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 24
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- 239000006228 supernatant Substances 0.000 claims abstract description 7
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 claims abstract description 4
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- HPZOOQSXPMEJBV-ODCFVKFUSA-N Tirilazad mesylate Chemical compound CS(O)(=O)=O.O=C([C@@H]1[C@@]2(C)CC=C3[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)CN(CC1)CCN1C(N=1)=CC(N2CCCC2)=NC=1N1CCCC1 HPZOOQSXPMEJBV-ODCFVKFUSA-N 0.000 description 3
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- 102000003886 Glycoproteins Human genes 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
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- 229920001427 mPEG Polymers 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- 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
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- 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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- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
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- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a PAMAM-based nano delivery system jointly carrying adriamycin and a drug resistance reversal agent, which comprises the following steps: preparing a methanol solution of the PAMAM targeting drug delivery carrier; preparing methanol solution of doxorubicin hydrochloride, adding triethylamine to neutralize hydrochloric acid, and dissociating doxorubicin to obtain methanol solution of doxorubicin; preparing a trichloromethane solution of the drug resistance reversal agent; mixing the methanol solution of the adriamycin, the trichloromethane solution of the drug resistance reversal agent and the methanol solution of the PAMAM targeting drug delivery carrier while stirring, and carrying out oil bath under the protection of nitrogen; removing the organic solvent; dissolving with distilled water; centrifuging and taking supernatant. The acting site of the drug resistance reversal agent of the invention is P glycoprotein on the cell membrane, which can increase the amount of adriamycin entering cells and can not be pumped out. The invention improves the defect of poor water solubility of the drug resistance reversal agent, and the bioavailability of the drug resistance reversal agent, namely the ecaprat, can be improved by embedding the drug resistance reversal agent in the PAMAM.
Description
Technical field
The invention belongs to biomedicine technical field, is related to the preparation method that a kind of targeting joins drug-carrying nanometer particle, specifically relates to
And a kind of preparation method for combining the nano-delivery system for carrying amycin and reversal agent of drug resistance based on PAMAM.
Background technology
China's tumor incidence and mortality rate persistently rise for many years, it has also become a public health that must pay much attention to is asked
Topic or even social problem.At present, chemotherapy is one of Main Means for the treatment of cancer, and in clinical practice, single medicine is not only
Effective antitumour effect can not be played, but also along with serious toxic and side effects.Additionally, the abuse of chemotherapeutics can draw again
The multidrug resistance of tumor is played, is that the treatment of tumor increases difficulty.Therefore, Development of Novel delivery system, the effective administering mode of exploration
Extremely urgent.There is the new delivery system for carrying medicine high efficiency, conditional response and passive targeting to have become to work as
Very powerful and exceedingly arrogant field in front treatment of cancer, new delivery system will bring glad tidings for cancer patient.
The appearance of the multidrug resistance (multidrug resistance, MDR) of tumor ultimately results in malignant tumor chemotherapy
Failure.Find effective reversal agent of drug resistance and reversionmethods overcome MDR, it has also become study hotspot both domestic and external.Wherein, joint is used
Medicine all has a good application prospect to the reverse of MDR and the treatment of malignant tumor.
P- glycoproteins (P-glycoprotein, P glycoprotein) are a member in ATP-binding cassette superfamily, are a kind of efflux proteins,
It is most commonly seen one of the reason for cause MDR.P glycoproteins are the transmembrane glycoproteins that a kind of relative molecular weight is 170000.P sugar eggs
In vain by two identical structure compositions, while having ATP-binding site, can pass through to hydrolyze two molecule ATP offer energy, realize two
Secondary P glycoproteins conformational change, pumps out intracellular medicine and weakens medicine effect.The high expression of tumor cell P glycoproteins is that its generation is resistance to
The key factor of the property of medicine.
The chemotherapy of tumors of single medicine is easily caused chemotherapy and fails and produce MDR, but the different medicine connection of multiple model of action
With chemotherapy success rate can be effectively improved.Trace it to its cause, the single medicine mechanism of action is single, and multi-medicament can press down from multiple approach
Tumour growth processed.Therefore, different medication combined of model of action has become current research focus for reversion MDR.Joint is used
Medicine mainly has three kinds of forms：1. two kinds of different chemotherapy drugs in combination of model of action are used.Clinically, Treated with Chemotherapeutic Drugs Internet of Things is closed
Using the generation for contributing to effectively preventing multidrug resistance while antitumor action is played.2. chemotherapeutics and gene class
Drug combination.
Gene supports the essential structure of life and performance.Therefore tumor can be directed to occur and distinctive gene in development,
The generation of MDR is reduced from source, improves the curative effect of chemotherapeutics.3. chemotherapeutics are used in combination with MDR reversal agents.MDR is inverse
Turn the outer row that medicine often can be directly contained in agent, so as to improve medicine valid density in the cell.
Content of the invention
It is an object of the invention to provide a kind of based on PAMAM combine carry amycin and reversal agent of drug resistance nanometer delivering
The preparation method of system.
According to an aspect of the invention, there is provided a kind of carry amycin and reversal agent of drug resistance based on combining for PAMAM
Nano-delivery system preparation method, comprise the following steps：
(1) methanol solution of PAMAM targetable drug carriers is made；
(2) methanol solution of doxorubicin hydrochloride is made, and is added thereto in triethylamine and hydrochloric acid, make amycin dissociate
The methanol solution of amycin is obtained；
(3) chloroform soln of reversal agent of drug resistance is made；
(4) while stirring by the methanol solution of amycin, the chloroform soln of reversal agent of drug resistance and PAMAM target administrations
The methanol solution mixing of carrier oil bath under nitrogen protection；
(5) organic solvent is removed；
(6) with distillation water dissolution；
(7) after being centrifuged, the supernatant is taken.
In some embodiments, the formula of PAMAM targetable drug carriers is：
Wherein, n is 20-1000, and m is 1-4096.
In some embodiments, reversal agent of drug resistance is Yi Kelida.
In some embodiments, amycin is 20-5 with the mol ratio of Yi Kelida:1.
In some embodiments, the time of oil bath is 12-36h.
In some embodiments, organic solvent is removed by Rotary Evaporators.
Its advantage is：(1) amycin and reversal agent of drug resistance of the invention are embedded in PAMAM cavitys, amycin
Enter under conditions of being stirred continuously in PAMAM, drug-carrying nanometer particle is obtained.
(2) action site of reversal agent of drug resistance Yi Kelida of the present invention is the P glycoproteins on cell membrane, and entrance can be made thin
The amycin amount of born of the same parents increases, and is not pumped out.The present invention improves the defect of reversal agent of drug resistance Yi Kelida poorly water-solubles, and drug resistance is inverse
Turn agent Yi Kelida to be embedded in PAMAM, its bioavailability can be improved.
(3) Polyamidoamine Dendrimers (Polyamidoamine dendrimer, PAMAM) are used as a kind of cation
Polymer, surface are usually used in containing for gene with a large amount of positive charges.PAMAM can be in lysosome with " proton sponge effect "
Realize the quick release of medicine or gene.Additionally, PAMAM internal cavities have stronger hydrophobicity, can be used for hydrophobicity medicine
Thing is contained.The special tree of PAMAM makes it have certain pH sensitivity simultaneously, i.e., outer branch is received at low ph conditions
Contracting, kernel expose, and form " compact outer shell " structure, and form " fine and close kernel " structure under high ph conditions.
(4) there are the present invention PAMAM targetable drug carriers of pH and reduction-sensitive to be used for amycin and Yi Kelida
Deliver simultaneously.The carrier with itself there is acid-sensitive characteristic polyamide-amide as parent nucleus, Polyethylene Glycol is by reducing sensitive key
(disulfide bond) is modified to PAMAM, thus builds the carrier PAMAM-SS-PEG with doubling sensitivitym.By physics bag
Method is buried while amycin and Yi Kelida is wrapped in the hydrophobic cavity of carrier kernel PAMAM.Using lysosome in tumor cell
Acid environment and Cytoplasm in high reducing environment carry out the release of medicine, it is ensured that relatively low drug release in peripheral blood circulation
Amount, so that reduce the generation of toxic and side effects.Meanwhile, amycin and Yi Kelida combinations can achieve the inverse of breast carcinoma multidrug resistance
Turn, strengthen the chemotherapy efficiency of doxorubicin.Furthermore, connection carries drug resistance during nanoparticle can prevent or suppress chemotherapy of tumors to be changed, and holds back
Stress is arranged outside tumour medicine processed, reduces the difficulty of oncotherapy, with good potential applicability in clinical practice.
(5) PAMAM targetable drug carriers of the invention reduce sensitive disulfide bond by introducing between PAMAM and PEG,
Form PAMAM-SS-PEGmPolymer, the polymer can keep stable in blood circulation, and once reach in tumor cell,
Drug release in high GSH environment in lysosomal acid environment and Cytoplasm.Wherein Yi Kelida acts on P glycoproteins, suppression
The outer row of P glycoproteins processed, prevents the outer row of amycin, increases accumulation of the amycin in intracellular, especially endonuclear phase
To content, and then strengthen the effect of antitumor action and multi-medicine tolerant reversal.
(6) nanoparticle that the present invention carries amycin and Yi Kelida based on PAMAM targetable drug carriers effectively can be reversed
Breast carcinoma multidrug resistance, strengthens toxicity of the amycin to tumor cell, while effectively containing that general chemotherapy of tumors outlet has drug resistance
Change the drug efflux stress for causing, reduce the difficulty of oncotherapy, reduce the generation of toxic and side effects.
Description of the drawings
Fig. 1 is PAMAM, mPEG5000-SH and PAMAM-SS-PEG1151H-NMR collection of illustrative plates.
Fig. 2 is PAMAM, mPEG5000-SH and PAMAM-SS-PEG115FTIR collection of illustrative plates.
Fig. 3 compares drug-carrying nanometer particle PAMAM-SS-PEG for dispensing115The load medicine of DOX (A) and ELC (B) in/DOX/ELC
Amount, the impact block diagram of envelop rate；
Fig. 4 is PAMAM-SS-PEG obtained in embodiment 3115/ DOX/ELC release in vitro block diagrams；
Fig. 5 is PAMAM-SS-PEG115With free ELC anti tumor activity in vitro block diagram.
Fig. 6 is DOX, PAMAM-SS-PEG obtained in embodiment 4115/ DOX, PAMAM-SS-PEG obtained in embodiment 1115/
DOX/ELC, PAMAM-SS-PEG obtained in embodiment 2115/ DOX/ELC and PAMAM-SS-PEG obtained in embodiment 3115/DOX/
The anti tumor activity in vitro block diagram of ELC.
Specific embodiment
Polyamide-amide (PAMAM) dendrimer：End carries amino, and with ethylenediamine as core, 0-10.0 generations (are purchased from
Sigma-Aldrich)；N- butanimide 3- (2- pyridine dithio) propionic ester (SPD) falls in love with extra large chemical conversion industry purchased from ladder is uncommon
Development Co., Ltd；Mono methoxy polyethylene glycol (mPEG115- SH) it is purchased from Jiankai Science and Technology Co., Ltd., Beijing；Yi Kelida
(ELC) Shanghai Han Xiang biotechnologies company is purchased from；Doxorubicin hydrochloride (DOX HCl) has purchased from Beijing Hua Fenglianbo science and technology
Limit company；Triethylamine, methanol, chloroform etc. are purchased from Chemical Reagent Co., Ltd., Sinopharm Group；Water is distilled water.
With Unity Inova 400MHz nuclear magnetic resonance analyser (1H-NMR) to PAMAM-SS-PEG115Carry out structural identification；With
ProStarLC240 infrared spectrometers (FTIR) are to PAMAM-SS-PEG115Characterized.
PAMAM-SS-PEG115's1H-NMR and FTIR is characterized
Using Unity Inova 400MHz nuclear magnetic resonance analyser, with heavy water (D2O) for solvent respectively to PAMAM,
MPEG5000-SH and PAMAM-SS-PEG115Carry out1H-NMR is analyzed, by PAMAM-SS-PEG after purification115Carry out1H-NMR cores
Magnetic analysis, characterization result are as shown in Figure 1.A small amount of PAMAM, mPEG are weighed respectively5000-SH、PAMAM-SS-PEG115With
ProStarLC240 infrared spectrometers carry out FTIR analysis (sweep limitss 600-4000cm-1), characterization result is as shown in Figure 2.
Embodiment 1
Weigh 3mg lyophilizing carrier PAMAM-SS-PEG115It is dissolved in 1mL methanol；The DOX HCl for weighing 1mg are dissolved in methanol
1mL, adds in 30 μ L of triethylamine and hydrochloric acid, makes DOX separate outs, with PAMAM-SS-PEG115Solution mixes；Weigh 1mg's again
ELC is dissolved in chloroform 1mL.With DOX and ELC mol ratios 20:The ELC of 1 DOX for measuring 30 μ L and 30 μ L puts into above-mentioned reaction
In bottle, nitrogen is protected, 30 DEG C of oil bath 24h.Revolving removes organic solvent, is dissolved with distilled water 2mL, is centrifuged (3600g) 10min.
Take supernatant to store for future use after centrifugation, the mol ratio of DOX and ELC is 20:1.
Embodiment 2
Weigh 3mg lyophilizing carrier PAMAM-SS-PEG115It is dissolved in 1mL methanol；The DOX HCl for weighing 1mg are dissolved in methanol
1mL, adds in 30 μ L of triethylamine and hydrochloric acid, makes DOX separate outs, with PAMAM-SS-PEG115Solution mixes；Weigh 1mg's again
ELC is dissolved in chloroform 1mL.With DOX and ELC mol ratios 10:The ELC of 1 DOX for measuring 30 μ L and 30 μ L puts into above-mentioned reaction
In bottle, nitrogen is protected, 30 DEG C of oil bath 24h.Revolving removes organic solvent, is dissolved with distilled water 2mL, is centrifuged (3600g) 10min.
Take supernatant to store for future use after centrifugation, the mol ratio of DOX and ELC is 10:1.
Embodiment 3
Weigh 3mg lyophilizing carrier PAMAM-SS-PEG115It is dissolved in 1mL methanol；The DOX HCl for weighing 1mg are dissolved in methanol
1mL, adds in 30 μ L of triethylamine and hydrochloric acid, makes DOX separate outs, with PAMAM-SS-PEG115Solution mixes；Weigh 1mg's again
ELC is dissolved in chloroform 1mL.With DOX and ELC mol ratios 5:The ELC of 1 DOX for measuring 30 μ L and 30 μ L puts into above-mentioned reaction
In bottle, nitrogen is protected, 30 DEG C of oil bath 24h.Revolving removes organic solvent, is dissolved with distilled water 2mL, is centrifuged (3600g) 10min.
Take supernatant to store for future use after centrifugation, the mol ratio of DOX and ELC is 5:1.
Embodiment 4
Weigh 3mg lyophilizing carrier PAMAM-SS-PEG115It is dissolved in 1mL methanol；The DOX HCl for weighing 1mg are dissolved in methanol
1mL, adds in 30 μ L of triethylamine and hydrochloric acid, makes DOX separate outs, with PAMAM-SS-PEG115Solution mixes；Weigh 1mg's again
ELC is dissolved in chloroform 1mL.With DOX and ELC mol ratios 1:The ELC of 0 DOX for measuring 30 μ L and 30 μ L puts into above-mentioned reaction
In bottle, nitrogen is protected, 30 DEG C of oil bath 24h.Revolving removes organic solvent, is dissolved with distilled water 2mL, is centrifuged (3600g) 10min.
Take supernatant to store for future use after centrifugation, the mol ratio of DOX and ELC is 1:0.
Dispensing compares drug-carrying nanometer particle PAMAM-SS-PEG115The shadow of DOX and ELC drug loading, envelop rate in/DOX/ELC
Ring
In embodiment 1,2,3, DOX and ELC drug loading and envelop rate are utilized respectively and ultraviolet divided photometry and HPLC to be surveyed
Fixed.The drug loading and envelop rate that DOX and ELC is calculated using indirect method, that is, calculate unentrapped and enter PAMAM-SS-PEG115Trip
Amount from DOX and ELC.By taking ELC as an example, the free ELC for failing to contain mainly has two kinds of sources：PAMAM-SS-PEG first115/
DOX/ELC water redissolves, and is centrifuged the free ELCa that unentrapped in the precipitation for producing enters carrier, mensuration absorbance after dissolving.So
Precision measures 500 μ L of nanoparticle solution afterwards, puts in ultra-filtration centrifuge tube (Mw 3500), is centrifuged (6700g) 30min, and filtrate is dissolving
In water, unentrapped enters the free ELCb of carrier, the content of the ELCa and ELCb that dissociates in ultraviolet determination filtrate.Two parts dissociate
The content of ELC is added as total free dose, calculates drug loading and envelop rate by following formula.DOX adopts same procedure meter
Calculate envelop rate, drug loading.
The computing formula of drug loading is：
The computing formula of envelop rate is：
As shown in figure 3, ELC and DOX drug loading and envelop rate are higher, by calculating, dispensing mol ratio is 20:1
When, real income mol ratio is followed successively by 13.8:1；Dispensing mol ratio is 10:1, real income mol ratio is followed successively by 9.4:1；Dispensing
Mol ratio is 5:When 1, real income mol ratio is followed successively by 4.9:1.
DOX and ELC is wrapped into simultaneously by carrier by the method for physically trapping, DOX is prepared:The connection of ELC different mol ratios is carried
Nanoparticle.For the nanoparticle of three kinds of mol ratios, the drug loading and envelop rate of two kinds of medicines is higher.But carrier carries medical instrument one
Fixed saturability, two medicines combine carry show drug loading shifting the characteristics of, if improve drug-supplying system in DOX contents,
Can cause that ELC concentration is too low to be unable to reversion MDR；If conversely, reducing the content of DOX in drug-supplying system, although can realize low dense
Degree MDR is reversed, but can reduce the overall antitumor efficiency of drug-loading system.
Drug-carrying nanometer particle PAMAM-SS-PEG115/ DOX/ELC release in vitro is investigated
In embodiment 3, nanoparticle is investigated by three kinds of release conditions, respectively：(1) (0.1M, pH are 7.4) for PBS；
(2) (0.1M, pH are 7.4) for the PBS of glutathion containing 10mM (GSH)；(3) acetate buffer (pH 5.0) containing 10mMGSH.Tool
Gymnastics conduct：Investigated using dynamic dialysis method.Solution 2ml prepared by accurate extraction embodiment 3, puts bag filter (Mw
3500) in, immediately in the input different release medium of 20mL, 37 DEG C put, be incubated in 100r/min shaking tables.Respectively at 0.5,1,2,
4th, 6,8,10,12 and 24h sampling 3ml (while supplementing the fresh dissolution medium of equality of temperature equivalent), 0.22 μm of membrane filtration, subsequent filtrate
Middle DOX determined by ultraviolet spectrophotometry contents, ELC Syrups by HPLC contents, are calculated respectively according to below equation
The accumulative release rate of DOX, ELC.10mM GSH are for simulating the reducing environment in tumor cell.
In formula：Accumulative release rates of the Er for DOX or ELC；Displaced volumes of the Ve for PBS；V0 is release medium
Cumulative volume；M is the content of DOX in nanoparticle；Ci is that i ＆ lt replaces the drug level discharged during sampling.
Knowable to Fig. 4 results, DOX, ELC simultaneously discharge and significantly do not interfere, and individually contain and discharge phase
Reduction, pH sensitivity are shown than its release behavior.In the medium of pH 7.4, DOX, ELC release is slow and not prominent
Release, 24h preparations ELC is less than 10%, and the release of DOX is relatively fast.Medium in the pH 7.4 containing 10mM GSH
In two kinds of drug releases slightly improve, respectively 46.35%, 19.20%.Medium in the pH 5.0 containing 10mM GSH
In, DOX releases are rapid, and 24h preparations are 64.45%, then relatively low for ELC, are 51.32%.Above knot
Fruit shows that the PSSP/DOX/ELC of structure has obvious pH and reduction-sensitive.DOX, ELC molecular weight is close simultaneously, both
Carrier kernel is entered simultaneously by way of physically trapping, and its release behavior is not significantly interfered.Both are giving birth to simultaneously
Under the conditions of reason, release rate is relatively low, and delivery system shows good stability.And once reach tumor locus, two medicines can be
Simultaneously rapid under intracellular reduction, pH environmental stimuluses discharge.Make as ELC be able to can be played under the low consistency conditions of 20nM
With, and act on hold time longer, so two medicines is contained suppress P while discharge and being more beneficial for just reaching at the initial stage for discharging simultaneously
Outer row's effect of glycoprotein, increases the intracellular accumulation of DOX.
PAMAM-SS-PEG115/ DOX/ELC anti tumor activity in vitro
Weigh a certain amount of empty vectors PAMAM-SS-PEG115, it is dissolved in culture medium and is made into 1mg/mL mother solutions, then with newly
Fresh culture medium is diluted to final concentration of 50,100,200,400,600,800 μ g/mL.A certain amount of free ELC is weighed, is dissolved in
1mg/mL mother solutions are made in DMSO, then are diluted to final concentration of 0.1,1,2.5,5,10,15 μM with fresh culture.Take the logarithm life
Long-term MCF-7 and MCF-7/ADR cells, are inoculated in 96 orifice plates with the density in 1 × 104/hole, cultivate 24h at 37 DEG C.So
Afterwards, old culture medium being discarded, the 100 μ L of above-mentioned solution of variable concentrations being added per hole, each concentration group arranges 4 multiple holes, while in
Same plate arranges blank control group, continues incubation 48h under same culture conditions.After incubation terminates, pastille culture medium is sucked,
Again with PBS twice, each 100 μ L of the MTT solution of addition 0.5mg/mL per hole.Continue incubation 4h, suck MTT solution, per hole
100 μ L DMSO solutions are added, is vibrated to crystallization dissolving, with microplate reader record per absorbance (OD) of the hole at 492nm.
Cell survival rate, Resistance index (RI) are calculated respectively using below equation and reverses the factor (RF), formula is as follows：
Cell survival rate=experimental group OD values/matched group OD values × 100%RI=IC50(MCF-7/ADR)/IC50(MCF-
7)
RF=IC50(DOX)/IC50(Nanoparticles)
Wherein median lethal dose(LD 50) IC50Statistics software SPSS can be utilized to calculate obtain.
Take DOX and examples of implementation 1,2,3,4 are diluted to series concentration (final concentration of 0.1,1,2.5,10,25 and of DOX respectively
50 μM), according to the method described above, cytotoxicity and the reverse effect to MDR that connection carries nanoparticle is investigated, while investigate difference rubbing
You compare the impact of reversing effect.
As can be drawn from Figure 5:Blank PAMAM-SS-PEG115And ELC is substantially acellular in the range of experimental concentration (PSSP)
Toxicity, with good safety.Embodiment 1 is calculated to embodiment 4, independent DOX to MCF-7 and MCF-7/ADR from Fig. 6 data
The IC of cell50Value is as follows：
As can be seen from the above table, the cytotoxicity of nanoparticle is constituted and proportioning and cell type by dosage, nanoparticle
Impact.For MCF-7 and MCF-7/ADR cells, the IC of DOX50Value is respectively (1.72 ± 0.19) and (59.62 ± 3.48) μ
M, drug resistance multiple (RI) 34.66, MCF-7/ADR cells shows go out stronger drug resistance.And after DOX and ELC combinations, MCF-7/
The survival rate of ADR cells is decreased obviously, PAMAM-SS-PEG115DOX in/DOX/ELC nanoparticles:ELC mol ratios are respectively 20:
1、10:1、5:When 1, the IC50 values of DOX are followed successively by (1.50 ± 0.16), (1.01 ± 0.08) and (0.82 ± 0.04) μM, accordingly
The reverse factor (RF) value be 39.75,59.03 and 72.71, i.e., with the increase of ELC ratios in drug ratio, drug resistance inversion journey
Degree increases.For nanoparticle prepared by embodiment 3, its RI value is only the antitumous effect of 1.34, the i.e. nanoparticle and trip
Close from DOX.And under identical DOX concentration, for MCF-7/ADR cells, prepared by embodiment 4, nanoparticle is compared with free DOX
Cell survival rate is decreased obviously, but it is relatively low to compare anti-tumor activity with connection load nanoparticle.The main cause for producing this phenomenon can
Can be that nanoparticle prepared by embodiment 4 enters cell by way of Active transport, free DOX is mainly entered by the form for spreading
Enter cell, two kinds enter born of the same parents' approach and cause nanoparticle prepared by embodiment 4 and released the drug after can getting around P glycoproteins again, thus have one
Point DOX can enter nucleus and play antitumor action, and free DOX most of before nucleus are entered just by P glycoproteins outside
Row.
Above-described is only some embodiments of the present invention.For those of ordinary skill in the art, do not taking off
On the premise of conceiving from the invention, some deformations and improvement can also be made, these belong to the protection model of the present invention
Enclose.
Claims (6)
1. the preparation method for combining the nano-delivery system for carrying amycin and reversal agent of drug resistance based on PAMAM, its feature exist
In comprising the following steps：
(1) methanol solution of PAMAM targetable drug carriers is made；
(2) methanol solution of doxorubicin hydrochloride is made, and is added thereto in triethylamine and hydrochloric acid, make amycin separate out system
Obtain the methanol solution of amycin；
(3) chloroform soln of reversal agent of drug resistance is made；
(4) while stirring by the methanol solution of amycin, the chloroform soln of reversal agent of drug resistance and PAMAM targetable drug carriers
Methanol solution mixing and oil bath under nitrogen protection；
(5) organic solvent is removed；
(6) with distillation water dissolution；
(7) after being centrifuged, the supernatant is taken.
2. the nano-delivery system that carries amycin and reversal agent of drug resistance of combining based on PAMAM according to claim 1
Preparation method, it is characterised in that the formula of the PAMAM targetable drug carriers is：
Wherein, n is 20-1000, and m is 1-4096.
3. the nano-delivery system that carries amycin and reversal agent of drug resistance of combining based on PAMAM according to claim 1
Preparation method, it is characterised in that the reversal agent of drug resistance be Yi Kelida.
4. the nano-delivery system that carries amycin and reversal agent of drug resistance of combining based on PAMAM according to claim 3
Preparation method, it is characterised in that the mol ratio of the amycin and Yi Kelida is 20-5:1.
5. the nano-delivery system that carries amycin and reversal agent of drug resistance of combining based on PAMAM according to claim 1
Preparation method, it is characterised in that the time of the oil bath be 12-36h.
6. the nano-delivery system that carries amycin and reversal agent of drug resistance of combining based on PAMAM according to claim 1
Preparation method, it is characterised in that the organic solvent is removed by Rotary Evaporators.
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| CN114606190A (en) * | 2022-03-08 | 2022-06-10 | 东南大学 | Nano reagent for killing and foaming cells, cell micro-vesicle and preparation method and application thereof |
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| CN107281161A (en) * | 2017-05-16 | 2017-10-24 | 浙江大学 | A kind of medicament nano-preparation and preparation method thereof |
| CN107281161B (en) * | 2017-05-16 | 2020-02-21 | 浙江大学 | A nanometer medicinal preparation and its preparation method |
| CN114606190A (en) * | 2022-03-08 | 2022-06-10 | 东南大学 | Nano reagent for killing and foaming cells, cell micro-vesicle and preparation method and application thereof |
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