CN110755636A - Liver cancer targeted adriamycin coupled segmented copolymer nano micelle - Google Patents
Liver cancer targeted adriamycin coupled segmented copolymer nano micelle Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6907—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
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- 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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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/593—Polyesters, e.g. PLGA or polylactide-co-glycolide
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Abstract
The invention relates to a liver cancer targeted adriamycin coupled segmented copolymer nano micelle, which utilizes a liver cancer specific antibody HAb18F (ab')2And (3) mediating the adriamycin coupling segmented copolymer nano micelle to carry out targeted therapy. The DOX-PLGA-PEG nano micelle is prepared by covalently coupling Doxorubicine (DOX) and lactic acid-glycolic acid copolymer (PLGA-PEG) through a chemical method to synthesize DOX-PLGA-PEG and utilizing a dialysis method. By HAb18F (ab')2The DOX-PLGA-PEG nano micelle is modified by physical adsorption of the antibody to prepare the targeting micelle. The targeted micelle is satisfactory in characterization, can be phagocytized and taken up by tumor cells, and the bioactive medicine is released from the micelle. The anti-liver cancer effect of the drug-loaded nano micelle is more obvious than that of a drug monomer, namely the targetThe micelle is accumulated in the local tumor in a large amount by virtue of the dual functions of passive targeting and active targeting, so that the curative effect is most remarkable. The invention obtains a novel drug delivery system which has high efficiency, low toxicity and targeted killing of liver cancer cells, improves the treatment effect of liver cancer, develops a novel antitumor nano-drug with definite curative effect and has wide application prospect.
Description
[ technical field ] A method for producing a semiconductor device
The invention belongs to the improvement of biological pharmacy and medicament dosage forms, and relates to a liver cancer targeted adriamycin coupled segmented copolymer nano micelle.
[ background of the invention ]
Liver cancer is a common malignant tumor, surgical operation is the first choice for treatment, including partial hepatectomy and liver transplantation, and the liver cancer which can be survived for a long time after the operation, however, unresectable liver cancer still depends on drug therapy and the like, and the tumor belongs to a systemic disease, and has high probability of metastasis and recurrence, so the liver cancer has more important significance. Therefore, the development of new and more effective therapeutic strategies for liver cancer is an important and urgent task.
The drug-coupled segmented copolymer nano micelle is a research hotspot in the field of pharmacy, and can accurately and efficiently deliver a large dose of antitumor drugs to a designated part through passive targeting action and carry out controlled release drug delivery, so that the damage of the drugs to normal tissues is reduced, and the treatment effect is improved. The nano micelle can be further modified to combine with ligands such as antibodies and the like, so that the purpose of active targeting is achieved.
Use of liver cancer-specific antibody HAb18F (ab')2The mediated adriamycin coupled segmented copolymer nano micelle is used for guiding treatment, a novel drug delivery system which has high efficiency and low toxicity and can kill liver cancer cells in a targeted mode is obtained, the treatment effect of liver cancer is improved, a novel antitumor nano drug with a definite curative effect is developed, and the application prospect is wide.
[ summary of the invention ]
Aiming at the limitation of the treatment effect of the liver cancer drug, the liver cancer targeting adriamycin coupled segmented copolymer nano micelle can remarkably improve the treatment effect on liver cancer. The adriamycin is applied to clinic, and the loading of the adriamycin in the nano micelle for treating liver cancer is based on theory and has a prospect in clinical application. The DOX-PLGA-PEG nano micelle is prepared by covalently coupling Doxorubicine (DOX) and lactic acid-glycolic acid copolymer (PLGA-PEG) through a chemical method to synthesize DOX-PLGA-PEG and utilizing a dialysis method. By HAb18F (ab')2The DOX-PLGA-PEG nano micelle is modified by physical adsorption of the antibody to prepare the targeting micelle. The nano carrier material PLGA-PEG biodegrades in vivo into non-toxic water and carbon dioxide, which has been approved by the FDA in the United states as a pharmaceutical adjuvant for clinical use.
The preparation method comprises the following steps:
1. DOX-PLGA-PEG synthesis: 3g of PLGA-PEG diblock copolymer was dissolved in 30ml of ice-cold (0 ℃) methylene chloride, and then 80mg of p-nitrophenyl chloroformate and 63mg of pyridine were added dropwise and reacted at room temperature for 3 hours under a nitrogen blanket to activate the terminal hydroxyl groups of PLGA. The activated PLGA-PEG diblock copolymer was collected after ice-cold ether precipitation, the precipitate was filtered and dried at low pressure. Dissolving 0.25g of activated PLGA-PEG diblock copolymer in 7.5ml of dimethylformamide under the conditions of room temperature and nitrogen protection, adding 6.5mg of adriamycin and triethylamine which are 10mg, keeping away from light and continuously stirring for 24 h. The reaction solution was added to deionized water and dialyzed 3 times for 4 hours to purify the synthesized DOX-PLGA-PEG. After freeze drying, the DOX-PLGA-PEG dry powder is stored at-20 ℃ for later use.
2. Preparing nano micelle: DOX-PLGA-PEG dry powder 100mg was dissolved in 10ml acetone and then added to 100ml phosphate buffer solution (PBS, pH 7.4) overnight, micelles formed by self-assembly, and acetone and phosphate were removed by dialysis, as confirmed by observation of clear reddish solution and Tyndall phenomenon. After freeze drying, the micelle dry powder is stored at 4 ℃ for later use.
3. Antibody-modified micelles: HAb18F (ab')2The antibody was dissolved in 10mM PBS (pH 5.7) at a concentration of 2 mg/ml. The micelles were dispersed in deionized water at a concentration of 10 mg/ml. The volume ratio of the two solutions is 1: 1, mixed overnight at room temperature with moderate stirring to allow adsorption to occur. The mixed solution was collected by centrifugation at 4 ℃ for 10min at 20000rpm, and then washed 3 times with PBS (pH 7.4) to remove unbound antibody. The prepared targeting micelles were finally resuspended in 1.0ml PBS (pH 7.4).
Micelle characterization and biological activity:
the amido bond is connected with the primary amino of DOX and the terminal hydroxyl of PLGA to synthesize DOX-PLGA-PEG, and the infrared spectrum is observed to be 1575cm-1A peak appears at the position of the amide bond peak, DOX-PLGA-PEG1The H nuclear magnetic resonance spectrum can see the peak of DOX benzene ring at the position of 7.68ppm, and the results all prove that the connection is successful. The DOX-PLGA-PEG self-assembles in the water solution to form the nano micelle, and the phenomena of light red transparent suspension and Tyndall can be observed, which indicates that a colloid dispersion system is formed. The critical micelle concentration of the DOX-PLGA-PEG is 0.16mg/L, which is slightly lower than that of the PLGA-PEG, and the water solubility of the PLGA-PEG is increased after the DOX is combined. The particle sizes of DOX-PLGA-PEG micelle and targeting micelle are 54.97 +/-6.25 nm and 87.63 +/-9.34 nm respectively, and the polydispersity indexes are 0.098 and 0.142 respectively. The particle size increases by about 33nm due to the antibody coverage of the surface of the targeting micelle. Scanning electron microscopeAnd the transmission electron microscope observation shows that the nano micelle is spherical and has a smooth surface.
The drug loading rates of the DOX-PLGA-PEG micelle and the targeting micelle are respectively 2.36 +/-0.22% and 2.19 +/-1.9%, the encapsulation rates are respectively 91.69 +/-5.3% and 87.45 +/-4.8%, and the reduction of the drug loading rate and the encapsulation rate of the targeting micelle is also influenced by the existence of the modified antibody. The simulated in vitro drug release curves of the DOX-PLGA-PEG micelle and the targeting micelle are in a two-phase state, namely slow release is realized after burst release, the drug release amount in 5 days is about 30 percent, and the release amount in 3 hours accounts for 25 percent. The targeted micelle release was relatively slightly low due to the hindrance of surface antibodies.
Fluorescence, scanning and transmission electron microscopy results confirmed phagocytic uptake of micelles by Huh7 and HepG2 cells. The flow cytometry results indicate that the intracellular drug content of the targeted micelle group is higher than that of the DOX-PLGA-PEG micelle group, and the former is about 1.5 times of that of the latter. After the drug-loaded micelle is administrated, the drug with biological activity is released, the tumor cell morphology is subjected to destructive change, part of cells are dead, the clone forming capability is reduced, and the targeted micelle has an obvious effect compared with DOX-PLGA-PEG micelle. The 50% effective concentration of DOX-PLGA-PEG micelles and targeting micelles for Huh7 cells occurred at 2.4 and 5.5d post-administration, with DOX being released at concentrations of 1.15 and 1.24 μ g/ml, respectively. The 50% effective concentration of DOX-PLGA-PEG micelles and targeting micelles for HepG2 cells occurred at 3.3 and 7.4d post-dose, with DOX being released at concentrations of 1.20 and 1.31. mu.g/ml, respectively. After a nude mouse HepG2 transplanted tumor animal model is successfully established, targeted micelles are given, and after 2 hours, the micelles are mainly accumulated and distributed in tumor tissues and are few in brain, heart, lung, liver, kidney and spleen. The DOX, DOX-PLGA-PEG micelles and targeting micelles can all cause the tumor growth inhibition, and the tumor inhibition rates are 39.8, 50.2 and 63.9 percent respectively.
Claims (4)
1. A liver cancer targeted adriamycin coupled segmented copolymer nano micelle utilizes a liver cancer specific antibody HAb18F (ab') 2 to mediate the adriamycin coupled segmented copolymer nano micelle to carry out guided therapy, and is characterized in that: the preparation comprises adriamycin and polylactic acid-glycolic acid copolymer. Wherein the polylactic acid-glycolic acid copolymer is a high molecular biological carrier material. The DOX-PLGA-PEG nano micelle is prepared by covalently coupling Doxorubicine (DOX) and lactic acid-glycolic acid copolymer (PLGA-PEG) through a chemical method to synthesize DOX-PLGA-PEG and utilizing a dialysis method. The DOX-PLGA-PEG nano-micelle is modified by HAb18F (ab') 2 antibody physical adsorption to prepare the targeting micelle.
2. The liver cancer targeted adriamycin coupled segmented copolymer nano micelle has an obvious anti-tumor effect, can be administered by a vein way, can be controlled to release, has both passive targeting and active targeting, and can obviously improve the curative effect.
3. An anti-hepatoma nano preparation of adriamycin according to claim 1, wherein the adriamycin is biologically synthesized, and the polylactic acid-glycolic acid copolymer is artificially synthesized.
4. The preparation process according to claim 1:
① Synthesis of DOX-PLGA-PEG, dissolving 3g of PLGA-PEG diblock copolymer in 30ml of ice-cold (0 ℃) dichloromethane, then dropwise adding 80mg of p-nitrophenyl chloroformate and 63mg of pyridine, reacting for 3h under the condition of room temperature and nitrogen protection to activate the terminal hydroxyl group of PLGA, collecting the activated PLGA-PEG diblock copolymer after ice-cold ether precipitation, precipitating, filtering and drying at low pressure, dissolving 0.25g of the activated PLGA-PEG diblock copolymer in 7.5ml of dimethylformamide under the condition of room temperature and nitrogen protection, adding 10mg of adriamycin and 6.5mg of triethylamine, keeping the mixture in the dark and stirring for 24h, adding the reaction solution into deionized water, dialyzing for 3h for 4h to purify the synthesized DOX-PLGA-PEG, freeze-drying, and storing the DOX-PLGA-PEG dry powder at-20 ℃ for later use.
② preparation of nano micelle, dissolving DOX-PLGA-PEG dry powder 100mg in acetone 10ml, adding into phosphate buffer solution 100ml (PBS, pH 7.4) overnight, self-assembling micelle, dialyzing to remove acetone and phosphate, observing transparent light red solution and Tyndall phenomenon, and storing the micelle dry powder at 4 deg.C for use.
③ antibody-modified micelle HAb18F (ab')2AntibodiesDissolved in 10mM PBS (pH 5.7) at a concentration of 2 mg/ml. The micelles were dispersed in deionized water at a concentration of 10 mg/ml. The volume ratio of the two solutions is 1: 1, mixed overnight at room temperature with moderate stirring to allow adsorption to occur. The mixed solution was collected by centrifugation at 4 ℃ for 10min at 20000rpm, and then washed 3 times with PBS (pH 7.4) to remove unbound antibody. The prepared targeting micelles were finally resuspended in 1.0ml PBS (pH 7.4).
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| CN201811176514.7A CN110755636A (en) | 2018-10-15 | 2018-10-15 | Liver cancer targeted adriamycin coupled segmented copolymer nano micelle |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111467323A (en) * | 2020-04-08 | 2020-07-31 | 南方医科大学南方医院 | Synthesis method and application of VB12 combined nano-composite carrying miRNA |
| CN111514303A (en) * | 2020-05-11 | 2020-08-11 | 江苏省人民医院（南京医科大学第一附属医院） | Triple-negative breast cancer targeted drug carrier and preparation and application thereof |
| WO2024002385A1 (en) * | 2022-08-05 | 2024-01-04 | 成都华昊中天药业有限公司 | Echinomycin antibiotic micelle, preparation method therefor, and use |
-
2018
- 2018-10-15 CN CN201811176514.7A patent/CN110755636A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| JIN ET AL.: "Improved Therapeutic Effect of DOX-PLGA-PEG Micelles Decorated with Bivalent Fragment HAb18 F(ab’)2 for Hepatocellular Carcinoma", 《BIOMACROMOLECULES》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111467323A (en) * | 2020-04-08 | 2020-07-31 | 南方医科大学南方医院 | Synthesis method and application of VB12 combined nano-composite carrying miRNA |
| CN111467323B (en) * | 2020-04-08 | 2022-01-04 | 南方医科大学南方医院 | Synthesis method and application of VB12 combined nano-composite carrying miRNA |
| CN111514303A (en) * | 2020-05-11 | 2020-08-11 | 江苏省人民医院（南京医科大学第一附属医院） | Triple-negative breast cancer targeted drug carrier and preparation and application thereof |
| CN111514303B (en) * | 2020-05-11 | 2022-07-26 | 江苏省人民医院（南京医科大学第一附属医院） | Triple-negative breast cancer targeted drug carrier and preparation and application thereof |
| WO2024002385A1 (en) * | 2022-08-05 | 2024-01-04 | 成都华昊中天药业有限公司 | Echinomycin antibiotic micelle, preparation method therefor, and use |
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