CN105497911A - Preparation method of CdTe quantum dot nanometer medicine carrying system carrying daunorubicin and gambogic acid - Google Patents
Preparation method of CdTe quantum dot nanometer medicine carrying system carrying daunorubicin and gambogic acid Download PDFInfo
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- CN105497911A CN105497911A CN201610010573.1A CN201610010573A CN105497911A CN 105497911 A CN105497911 A CN 105497911A CN 201610010573 A CN201610010573 A CN 201610010573A CN 105497911 A CN105497911 A CN 105497911A
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- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 title claims abstract description 71
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 title claims abstract description 71
- 229960000975 daunorubicin Drugs 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 title abstract description 38
- 239000002096 quantum dot Substances 0.000 title abstract description 8
- GEZHEQNLKAOMCA-RRZNCOCZSA-N (-)-gambogic acid Chemical compound C([C@@H]1[C@]2([C@@](C3=O)(C\C=C(\C)C(O)=O)OC1(C)C)O1)[C@H]3C=C2C(=O)C2=C1C(CC=C(C)C)=C1O[C@@](CCC=C(C)C)(C)C=CC1=C2O GEZHEQNLKAOMCA-RRZNCOCZSA-N 0.000 title abstract 5
- 229910004613 CdTe Inorganic materials 0.000 title abstract 5
- GEZHEQNLKAOMCA-UHFFFAOYSA-N epiisogambogic acid Natural products O1C2(C(C3=O)(CC=C(C)C(O)=O)OC4(C)C)C4CC3C=C2C(=O)C2=C1C(CC=C(C)C)=C1OC(CCC=C(C)C)(C)C=CC1=C2O GEZHEQNLKAOMCA-UHFFFAOYSA-N 0.000 title abstract 5
- GEZHEQNLKAOMCA-GXSDCXQCSA-N gambogic acid Natural products C([C@@H]1[C@]2([C@@](C3=O)(C\C=C(/C)C(O)=O)OC1(C)C)O1)[C@H]3C=C2C(=O)C2=C1C(CC=C(C)C)=C1O[C@@](CCC=C(C)C)(C)C=CC1=C2O GEZHEQNLKAOMCA-GXSDCXQCSA-N 0.000 title abstract 5
- QALPNMQDVCOSMJ-UHFFFAOYSA-N isogambogic acid Natural products CC(=CCc1c2OC(C)(CC=C(C)C)C=Cc2c(O)c3C(=O)C4=CC5CC6C(C)(C)OC(CC=C(C)/C(=O)O)(C5=O)C46Oc13)C QALPNMQDVCOSMJ-UHFFFAOYSA-N 0.000 title abstract 5
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 31
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 238000003756 stirring Methods 0.000 claims abstract description 18
- 229920000642 polymer Polymers 0.000 claims abstract description 14
- 230000004048 modification Effects 0.000 claims abstract description 10
- 238000012986 modification Methods 0.000 claims abstract description 10
- 238000000746 purification Methods 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000001556 precipitation Methods 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 3
- MARUHZGHZWCEQU-UHFFFAOYSA-N 5-phenyl-2h-tetrazole Chemical compound C1=CC=CC=C1C1=NNN=N1 MARUHZGHZWCEQU-UHFFFAOYSA-N 0.000 claims description 83
- 239000002253 acid Substances 0.000 claims description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 claims description 7
- 229940097265 cysteamine hydrochloride Drugs 0.000 claims description 7
- 238000010266 Sephadex chromatography Methods 0.000 claims description 5
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 claims description 5
- 238000005374 membrane filtration Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 230000010355 oscillation Effects 0.000 claims description 5
- 230000004044 response Effects 0.000 claims description 4
- 229910020366 ClO 4 Inorganic materials 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 18
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- -1 carbamyl maleimide Chemical compound 0.000 abstract 1
- 238000005119 centrifugation Methods 0.000 abstract 1
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- 239000002539 nanocarrier Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
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- 238000002626 targeted therapy Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 241000598860 Garcinia hanburyi Species 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 238000004847 absorption spectroscopy Methods 0.000 description 1
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
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- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
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- 230000034994 death Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 229940117709 gamboge Drugs 0.000 description 1
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Classifications
-
- 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
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
Abstract
The invention discloses a preparation method of a CdTe quantum dot nanometer medicine carrying system carrying daunorubicin and gambogic acid, and relates to a preparation technology of a nanometer medicine carrying system carrying antitumor drugs and tumor multidrug resistance reversal drugs. The method comprises the steps that functional modification is conducted on CdTe through high-molecular polymer polyethylene glycol; BMPH is dropwise added in a DMF solution for dissolving daunorubicin, a stirring reaction is conducted at room temperature, and DNR carbamyl maleimide is obtained; a modified CdTe solution is added for conducting oscillating incubation, filtration and purification are conducted, and a PH sensitive novel medicine carrying system CdTe-DNR is obtained; a CdTe-DNR solution and a gambogic acid (GA) solution are mixed according to a certain proportion, after a reaction in a dark place is conducted, centrifugation is conducted, precipitation is washed through water, and the CdTe quantum dot nanometer medicine carrying system carrying daunorubicin and gambogic acid is obtained.
Description
Technical field
The invention belongs to pharmaceutical field, particularly relate to a kind of preparation method of carrying daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether.
Background technology
Tumor is a large disease of serious threat human health, and current Therapeutic Method mainly comprises operative treatment, chemotherapy, radiotherapy and targeted therapy.Malignant tumor patient perioperatively is aided with chemotherapy more, and the infeasible operative treatment of part patients with terminal, therefore, current chemotherapy still has considerable status in oncotherapy.But according to the display of American Cancer Society statistics, the cause of the death of the cancer patient of more than 90% is relevant with tumor multi-medicine drug-resistant, and multidrug resistance is the major reason causing chemotherapy failure, therefore prevention and reversing clinical tumor multi-medicine drug-resistant, and to improving, chemotherapeutic efficacy is very important.
Daunorubicin, as a kind of anthracycline antibiotics, has good antitumor action, but there are some researches show, its energy inducing tumor cell overexpression mdr-1mRNA, strengthens the outer row effect of tumor cell to medicine, thus causes drug resistance of tumor cell.Studies have found that, and our previous work is also verified, the main active gamlogic acid of Chinese medicine gamboge can be worked in coordination with daunorubicin and be suppressed drug-resistant cell strain K562/A02 cell proliferation, promotes apoptosis, and persister mdr-1mRNA can be lowered express, thus the multidrug resistance of reverse both strain.Therefore, collaborative daunorubicin and the gamlogic acid of using effectively can improve chemotherapeutic efficacy.
But in chemotherapy process, while chemotherapeutics killing tumor cell, often also normal tissue and organ cause irreversible infringement, make chemotherapy fall flat.As daunorubicin simultaneously can produce obvious toxic and side effects at antineoplastic, comprise bone marrow depression, cardiac toxicity, digestive tract reaction, hypoimmunity etc., have a strong impact on its application clinically.Therefore, antitumor drug can be carried to inside tumor cells or around be of great significance with the pharmaceutical carrier tool reducing drug side effect by exploitation.
Current pharmaceutical carrier mainly comprises nano-carrier, liposome vectors, particulate carrier, bio-carrier etc., but is not reported by the medicine that daunorubicin, gamlogic acid and pharmaceutical carrier combine.
Summary of the invention
In order to overcome the deficiencies in the prior art, a kind of realization is the object of the present invention is to provide to integrate the multiple advantage such as reverse multiple drug resistance of tumor medicine and chemotherapeutics synergism, nano drug-carrying controllable sustained-release, the responsive target tumor of PH, thus reduce chemotherapeutics use amount, reduce chemical therapy toxic side effect, strengthen chemotherapeutic efficacy, play a kind of preparation method of carrying daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether of better antitumor action.
For achieving the above object, the present invention is achieved by the following technical solutions.
Carry the preparation method of daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether, it is characterized in that, comprise the following steps:
(1) with high molecular polymer Polyethylene Glycol (PEG) functional modification cadmium telluride (CdTe): by Cd (ClO
4)
2h
2o is dissolved in water, adds cysteamine hydrochloride (Cys), adjust pH to 5.9, then passes into Ar gas, add H under stirring under stirring
2te, mixture back flow reaction 10min to 9h, finally add high molecular polymer Polyethylene Glycol (PEG) and react 24h;
(2) daunorubicin (DNR) is dropwise added 1H-pyrroles-1-propanoic acid with after dimethyl formamide (DMF) solubilize, 2,5-dihydro-2,5-dioxy-hydrazides (BMPH), DNR-carbamyl maleimide is obtained at temperature 10 ~ 30 DEG C of stirring reactions, cadmium telluride (CdTe) the solution collective oscillation adding step (1) modified again hatches 180-300min, and filtration, purification, obtain nanometer medicine-carried system CdTe-DNR afterwards;
(3) by CdTe-DNR water dissolution prepared by step (2), at 10-30 DEG C by CdTe-DNR solution and the mixing of gamlogic acid (GA) solution, stirring reaction, centrifugal, wash precipitation with water, obtain and carry daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system (CdTe-DNR/GA) altogether.
Cd (ClO in described step (1) further
4)
2h
2o, cysteamine hydrochloride (Cys), H
2the mol ratio of Te, high molecular polymer Polyethylene Glycol (PEG) is 1:2.4:0.2:1.6.
H in described step (1) further
2te is Al
2te
3with H
2sO
4reaction produces.
In described step (2), the response time of preparation DNR-carbamyl maleimide is 1 ~ 3 hour further.
The membrane filtration of employing 0.2 μm is filtered further in described step (2).
In described step (2), purification adopts sephadex chromatography analytical column (PDG-25) purification further.
In described step (2), step (3), DNR concentration is 10-50mg/mL, CdTe-DNR solution concentration 10-15nmol/L further, and gamlogic acid (GA) solution concentration is 5-10mg/mL.
The ratio that in described step (3), CdTe-DNR solution and gamlogic acid (GA) solution are 1 ~ 2:2 ~ 3 by volume further mixes.
The speed stirred in described step (3) is further 100 ~ 150rpm, 4 ~ 8 hours response time; Centrifugal with 10000 ~ 15000rpm speed centrifugal 10 ~ 30 minutes.
Operation further in described step (2) and step (3) should be carried out under lucifuge condition.
Nano-carrier mainly has the following advantages: (1) has higher drug encapsulation ability, and it is comparatively wide to wrap the medicine scope of carrying, and can be hydrophobic drug also can be hydrophilic medicament, and no matter folk prescription medicine or compound medicines all can wrap and carry; (2) can water-wet side be formed by modification, thus prevent the absorption of protein, hide the seizure of reticuloendothelial system; (3) the little and narrowly distributing of particle diameter, easily by physiologic barrier, has unique distribution characteristics in vivo.Nanoparticle distribution in vivo depends primarily on size and the configuration of surface of particle diameter, little with the pharmaceutical properties relation of wrapping up in core; (4) slow releasing function is had, can action time of prolong drug; (5) by connecting target body, initiatively targeting moiety can be reached, as tumor tissues etc.; (6) under the prerequisite ensureing drug effect, dosage can be reduced, thus alleviates or avoid toxic and side effects.The CdTe Nanoparticle Size of functional modification is about about 3nm, has good using value as a kind of nano-carrier in the controlled release of medicine and the spike of disease etc.
.polyethylene Glycol because having amphipathic, good biocompatibility, safe, nontoxic, reduced immunogenicity, farthest can avoid albumen and cell non-specific adsorption, range of molecular weight distributions is wide, choice is large etc., and multiple advantage becomes modifies carrier at present, makes it avoid one of the most frequently used high molecular polymer engulfed by endothelium reticular system.Experiment shows, polyethyleneglycol modified CdTe has good dispersibility and good crystal structure.Daunorubicin can be connected by hydrazone key (C=N-N) with modified CdTe quantum, and hydrazone key is a kind of chemical bond of pH sensitive, is introduced into medicine-carried system, the characteristic of its acid labile can be utilized, i.e. sour environment, as in lymphoma cell, pH=6.0, its drug release rate is accelerated; Neutral environment, as normal structure, blood, pH=7.4, it slows down or shields non-specific release, thus gives the controllability of pharmaceutical carrier release, and this is very important with reduction general toxicity for minimizing drug loss.Experiment shows that the CdTe nanoparticle of functional modification and gamlogic acid can form novel Nano medication complex, the Nano medication complex of the type has higher carrying drug ratio and entrapment efficiency, significantly can strengthen the concentration of medicine in tumor cell, the particularly intracellular concentration of persister, for improving the drug effect of medicine and utilization rate, the targeting of raising medicine has important effect.
beneficial effect: compared with prior art, the invention has the advantages that:
1) the present invention adopts the CdTe quantum of functional modification as medicine carrying granule, can prevent the absorption of protein, hide engulfing of endothelium reticular system, and has good dispersibility, higher envelop rate and bag year rate.
2) the nanometer medicine-carried system particle diameter prepared of the present invention is less, easily by various physiologic barrier, can form unique distribution characteristics in vivo.
3) this nanometer medicine-carried system carries chemotherapeutics and reverse multiple drug resistance of tumor medicine altogether, makes two kinds of medicines play synergism, than single year chemotherapy medicine antitumor better effects if.
4) this nanometer medicine-carried system has sustained releasing character, can in the concentration of lesions position, extend chemotherapeutics in intracellular action time, strengthen antitumor action by stable maintenance chemotherapeutics in a long time.
5) nanometer medicine-carried system of the present invention has pH sensitivity characteristic, has certain targeting to the sour environment of tumor, can reduce dosage, can reduce the infringement of normal tissue, cell, thus alleviate toxic and side effects, improves chemotherapy effect.If connect tumour-specific target body, targeted therapy more accurately can be realized, therefore have broad application prospects.
Accompanying drawing explanation
Fig. 1 is that scanning electron microscope characterizes intuitively to through polyethyleneglycol modified CdTe quantum.Its mean diameter is about 10nm, and spacing of lattice is about 0.23nm, shows that this quantum dot has good dispersibility and good crystal structure.
Fig. 2 is ultraviolet absorption spectroscopy, the CdTe quantum that in figure, QD representative is modified through PEG, DNR represents daunorubicin, and GA represents gamlogic acid, QD-DNR-GA representative carries daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system, characteristic peak respective as seen in figure altogether.
Fig. 3 is infrared absorption spectrum analysis, the CdTe quantum that in figure, QD representative is modified through PEG, DNR represents daunorubicin, GA represents gamlogic acid, QD+DNR represents the CdTe quantum of single year daunorubicin, QD+DNR+GA representative carries daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system, characteristic peak respective as seen in figure altogether.
Fig. 4 is that CdTe quantum is to the release profiles of GA under different pH, illustrate that the drug release of CdTe bag year GA nanometer medicine-carried system has good sustained releasing character, and present pH sensitivity, under sour environment, (pH6.0) is faster than the rate of release of the physiological environment (pH7.4) of human normal and preparation is many.
Fig. 5 is the hydration kinetics radius measuring single year DNRCdTe quantum dot with nano particle size and electrokinetic potential analyzer.Its average hydration radius is 94nm, and polydispersity coefficient is 0.132.
Fig. 6 measures with nano particle size and electrokinetic potential analyzer the hydration kinetics radius carrying DNR and GACdTe quantum dot altogether.Its average hydration radius is 135nm, and polydispersity coefficient is 0.185.
Fig. 7 is the In-vitro release curves carrying DNR and GACdTe quantum dot altogether, illustrates that this nanometer medicine-carried system has drug slow release function.
Detailed description of the invention
Below in conjunction with example, the present invention is described in further detail.
Embodiment 1
Carry a preparation method for daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether, it is characterized in that the method comprises the following steps:
(1) with high molecular polymer Polyethylene Glycol (PEG) functional modification cadmium telluride (CdTe): with the Al of 0.23mmol
2te
3with the H of 15mL0.5M
2sO
4reaction produces H
2te is for subsequent use; By the Cd (ClO of 2.3mmol
4)
2h
2o is dissolved in 125mL ultra-pure water, under the condition stirred, drips the cysteamine hydrochloride (Cys) of 5.5mmol, subsequently pH value is adjusted to 5.9, then passes into Ar gas 30min, then drip obtained H
2te, mixture back flow reaction 10min to 9h, to control the growth of CdTe quantum, finally add the high molecular polymer Polyethylene Glycol (PEG) of rear 1.84mmol, and reaction 24h obtains cadmium telluride (CdTe) solution of modified;
(2) be dropwise add 1H-pyrroles-1-propanoic acid after 10mg/mL daunorubicin (DNR) dimethyl formamide (DMF) solubilize by concentration, 2,5-dihydro-2,5-dioxy-hydrazides (BMPH), in 20 DEG C, lucifuge stirring reaction 1 hour, obtain DNR-carbamyl maleimide, cadmium telluride (CdTe) the solution collective oscillation adding step (1) modified again hatches 240min, afterwards with membrane filtration, use sephadex chromatography analytical column (PDG-25) purification of 0.2 μm, obtain nanometer medicine-carried system CdTe-DNR;
(3) CdTe-DNR ultra-pure water prepared by step (2) is dissolved, ultrasonic disperse is even, making concentration is the solution containing CdTe-DNR12.5nmol/L, be containing gamlogic acid (GA) solution of GA5mg/mL by volume for the ratio of 1:2 mixes by this CdTe-DNR solution and concentration at 20 DEG C, lucifuge, at the uniform velocity stirring reaction 6 hours, stir speed (S.S.) is 100rpm, with 10000rpm speed centrifugal 20 minutes, by deionized water wash precipitation, obtain and carry daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system (CdTe-DNR/GA) altogether.
Embodiment 2
Carry a preparation method for daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether, it is characterized in that the method comprises the following steps:
(1) with high molecular polymer Polyethylene Glycol (PEG) functional modification cadmium telluride (CdTe): with the Al of 0.23mmol
2te
3with the H of 15mL0.5M
2sO
4reaction produces H
2te is for subsequent use; By the Cd (ClO of 2.3mmol
4)
2h
2o is dissolved in 125mL ultra-pure water, under the condition stirred, drips the cysteamine hydrochloride (Cys) of 5.5mmol, subsequently pH value is adjusted to 5.9, then passes into Ar gas 30min, then drip obtained H
2te, mixture back flow reaction 10min to 9h, to control the growth of CdTe quantum, finally add the high molecular polymer Polyethylene Glycol (PEG) of rear 1.84mmol, and reaction 24h obtains cadmium telluride (CdTe) solution of modified;
(2) be dropwise add 1H-pyrroles-1-propanoic acid after 50mg/mL daunorubicin (DNR) dimethyl formamide (DMF) solubilize by concentration, 2,5-dihydro-2,5-dioxy-hydrazides (BMPH), in 10 DEG C, lucifuge stirring reaction 3 hours, obtain DNR-carbamyl maleimide, cadmium telluride (CdTe) the solution collective oscillation adding step (1) modified again hatches 300min, afterwards with membrane filtration, use sephadex chromatography analytical column (PDG-25) purification of 0.2 μm, obtain nanometer medicine-carried system CdTe-DNR;
(3) CdTe-DNR ultra-pure water prepared by step (2) is dissolved, ultrasonic disperse is even, making concentration is the solution containing CdTe-DNR15nmol/L, be containing gamlogic acid (GA) solution of GA5mg/mL by volume for the ratio of 1:3 mixes by this CdTe-DNR solution and concentration at 10 DEG C, lucifuge, at the uniform velocity stirring reaction 4 hours, stir speed (S.S.) is 150rpm, with 15000rpm speed centrifugal 10 minutes, by deionized water wash precipitation, obtain and carry daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system (CdTe-DNR/GA) altogether.
Embodiment 3
Carry a preparation method for daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether, it is characterized in that the method comprises the following steps:
(1) with high molecular polymer Polyethylene Glycol (PEG) functional modification cadmium telluride (CdTe): with the Al of 0.23mmol
2te
3with the H of 15mL0.5M
2sO
4reaction produces H
2te is for subsequent use; By the Cd (ClO of 2.3mmol
4)
2h
2o is dissolved in 125mL ultra-pure water, under the condition stirred, drips the cysteamine hydrochloride (Cys) of 5.5mmol, subsequently pH value is adjusted to 5.9, then passes into Ar gas 30min, then drip obtained H
2te, mixture back flow reaction 10min to 9h, to control the growth of CdTe quantum, finally add the high molecular polymer Polyethylene Glycol (PEG) of rear 1.84mmol, and reaction 24h obtains cadmium telluride (CdTe) solution of modified;
(2) be dropwise add 1H-pyrroles-1-propanoic acid after 30mg/mL daunorubicin (DNR) dimethyl formamide (DMF) solubilize by concentration, 2,5-dihydro-2,5-dioxy-hydrazides (BMPH), in 30 DEG C, lucifuge stirring reaction 2 hours, obtain DNR-carbamyl maleimide, cadmium telluride (CdTe) the solution collective oscillation adding step (1) modified again hatches 180min, afterwards with membrane filtration, use sephadex chromatography analytical column (PDG-25) purification of 0.2 μm, obtain nanometer medicine-carried system CdTe-DNR;
(3) CdTe-DNR ultra-pure water prepared by step (2) is dissolved, ultrasonic disperse is even, making concentration is the solution containing CdTe-DNR10nmol/L, be containing gamlogic acid (GA) solution of GA5mg/mL by volume for the ratio of 2:3 mixes by this CdTe-DNR solution and concentration at 30 DEG C, lucifuge, at the uniform velocity stirring reaction 8 hours, stir speed (S.S.) is 120rpm, with 12000rpm speed centrifugal 30 minutes, by deionized water wash precipitation, obtain and carry daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system (CdTe-DNR/GA) altogether.
Adopt scanning electron microscope to characterize intuitively through polyethyleneglycol modified CdTe quantum, recording its mean diameter is about 10nm, and spacing of lattice is about 0.23nm, shows that this quantum dot has good dispersibility and good crystal structure, sees Fig. 1.
Adopt ultra-violet absorption spectrum to carry out to CdTe quantum, DNR, GA and the characteristic absorption peak of CdTe quantum that carries DNR and GA altogether analysiss to contrast, CdTe quantum has obvious absworption peak at 525nm place, DNR has obvious absworption peak at 484nm place, and the CdTe quantum of carrying DOX and GA altogether at 484nm and 525nm place all visible significantly absworption peak, indicate CdTe quantum successfully to wrap and carried DNR, see Fig. 2.
Adopt infrared absorption spectroscopy to CdTe quantum, DNR, GA, the absworption peak wrapping the CdTe quantum of carrying DNR and the CdTe quantum of carrying DNR and GA altogether carries out analysis contrast, CdTe quantum is at 1577cm-1, there is characteristic absorption peak at 1404cm-1 place, DNR is at 1284cm-1, there is characteristic absorption peak at 1207cm-1 place, GA is at 1670cm-1, 1256cm-1, there is characteristic absorption peak at 804cm-1 place, and bag carries the visible CdTe quantum of CdTe quantum infrared absorption spectroscopy of DNR and the characteristic absorption peak of DNR, carry in the infrared absorption spectroscopy of the CdTe quantum of DNR and GA altogether, CdTe quantum, DNR, the characteristic absorption peak of GA is all visible, indicate CdTe quantum and successfully can wrap year DNR and GA, see Fig. 3.
By the release profiles under different pH, illustrate that the drug release of CdTe bag year GA nanometer medicine-carried system has good sustained releasing character, and present pH sensitivity, under sour environment, (pH6.0) is faster than the rate of release of the physiological environment (pH7.4) of human normal and preparation is many, sees Fig. 4.
Nano particle size and electrokinetic potential analyzer is adopted to measure hydration radius and the polydispersity coefficient of the CdTe quantum of wrapping and carrying DNR and the CdTe quantum of carrying DNR and GA altogether respectively, two kinds of all visible hydration radius distribution width of nano-particle are narrower, show that these two kinds of nano-particle sizes are homogeneous.See Fig. 5, Fig. 6.
By measuring the In-vitro release curves of the CdTe quantum of carrying DNR and GA altogether, illustrating that this nanometer medicine-carried system has drug slow release function, seeing Fig. 7.
The present invention is illustrated according to above-described embodiment, should be appreciated that above-described embodiment does not limit the present invention in any form, and all employings are equal to replacement or the technical scheme that obtains of equivalent transformation mode, all drop within protection scope of the present invention.
Claims (10)
1. carry the preparation method of daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether, it is characterized in that, comprise the following steps:
(1) with high molecular polymer Polyethylene Glycol (PEG) functional modification cadmium telluride (CdTe): by Cd (ClO
4)
2h
2o is dissolved in water, adds cysteamine hydrochloride (Cys), adjust pH to 5.9, then passes into Ar gas, add H under stirring under stirring
2te, mixture back flow reaction 10min to 9h, finally add high molecular polymer Polyethylene Glycol (PEG) and react 24h;
(2) daunorubicin (DNR) is dropwise added 1H-pyrroles-1-propanoic acid with after dimethyl formamide (DMF) solubilize, 2,5-dihydro-2,5-dioxy-hydrazides (BMPH), DNR-carbamyl maleimide is obtained at temperature 10 ~ 30 DEG C of stirring reactions, cadmium telluride (CdTe) the solution collective oscillation adding step (1) modified again hatches 180-300min, and filtration, purification, obtain nanometer medicine-carried system CdTe-DNR afterwards;
(3) by CdTe-DNR water dissolution prepared by step (2), at 10-30 DEG C by CdTe-DNR solution and the mixing of gamlogic acid (GA) solution, stirring reaction, centrifugal, wash precipitation with water, obtain and carry daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system (CdTe-DNR/GA) altogether.
2. preparation method of carrying daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether according to claim 1, is characterized in that, Cd (ClO in described step (1)
4)
2h
2o, cysteamine hydrochloride (Cys), H
2the mol ratio of Te, high molecular polymer Polyethylene Glycol (PEG) is 1:2.4:0.2:1.6.
3. preparation method of carrying daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether according to claim 1, is characterized in that, H in described step (1)
2te is Al
2te
3with H
2sO
4reaction produces.
4. preparation method of carrying daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether according to claim 1, is characterized in that, in described step (2), the response time of preparation DNR-carbamyl maleimide is 1 ~ 3 hour.
5. preparation method of carrying daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether according to claim 1, is characterized in that, filters the membrane filtration of employing 0.2 μm in described step (2).
6. preparation method of carrying daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether according to claim 1, is characterized in that, in described step (2), purification adopts sephadex chromatography analytical column (PDG-25) purification.
7. preparation method of carrying daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether according to claim 1, it is characterized in that, in described step (2), step (3), DNR concentration is 10-50mg/mL, CdTe-DNR solution concentration is 10-15nmol/L, and gamlogic acid (GA) solution concentration is 5-10mg/mL.
8. preparation method of carrying daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether according to claim 1, is characterized in that, the ratio that in described step (3), CdTe-DNR solution and gamlogic acid (GA) solution are 1 ~ 2:2 ~ 3 by volume mixes.
9. preparation method of carrying daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether according to claim 1, is characterized in that, the speed stirred in described step (3) is 100 ~ 150rpm, 4 ~ 8 hours response time; Centrifugal with 10000 ~ 15000rpm speed centrifugal 10 ~ 30 minutes.
10. preparation method of carrying daunorubicin and gamlogic acid CdTe quantum nanometer medicine-carried system altogether according to claim 1, is characterized in that, the operation in described step (2) and step (3) should be carried out under lucifuge condition.
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