CN109806252A - Tri compound nanometer system and its preparation method and application - Google Patents
Tri compound nanometer system and its preparation method and application Download PDFInfo
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- CN109806252A CN109806252A CN201910084885.0A CN201910084885A CN109806252A CN 109806252 A CN109806252 A CN 109806252A CN 201910084885 A CN201910084885 A CN 201910084885A CN 109806252 A CN109806252 A CN 109806252A
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Abstract
The invention discloses tri compound nanometer system and its preparation method and application, the system includes iron compound, small molecule, anti-tumor reactive compound and polyphenol compound containing phenyl ring, and the weight ratio of three is 1-4:2-10:5-20.Compared with the existing technology, the present invention only assembles means by physics and different small molecule compound or drug can be carried out to stablize assembling, it is formed by the antineoplastic treatment function of composite Nano drug not only small molecule, anti-tumor reactive compound, the iron death therapy effect also mediated with iron compound and polyphenol compound based on Fenton's reaction intracellular, furthermore, the novel composite nano drug that the present invention is formed also has photo-thermal effect outstanding, chemotherapy can be integrated, iron death therapy is integrated with photo-thermal therapy, three's synergistic effect, it is mutually improved, reach the joint antineoplaston effect of many integration.
Description
Technical field
The invention belongs to art of pharmacy, are related to a kind of new type antineoplastic medicine preparation, are specially contained based on iron compound-
It small molecule, anti-tumor reactive compound-polyphenol compound tri compound nanometer system of phenyl ring and preparation method thereof and answers
With.
Background technique
Cancer is current one of the principal disease for threatening human health, and classic chemotherapy drug is as current clinical cancer therapy
Main body, usually can not obtain satisfied therapeutic effect since bioavilability is low, is also easy to produce the drawbacks such as multidrug resistance, face
Frequently with drug combination mode on bed.Chemotherapy drugs in combination use can generate synergistic effect, improve therapeutic effect；And due to
Chemotherapeutics mechanism of action is different, can prevent the generation of multidrug resistance to a certain extent.But chemotherapy combined treatment can not solve
The certainly intrinsic defect of classic chemotherapy medicine, such as poor specificity, unexpected pharmacokinetics and bio distribution, these lead to chemotherapeutic
Object normal tissue when killing tumour cell also results in serious damage；And combination therapy often has the toxic side effect of enhancing,
Patient's compliance and poor resistance greatly limit the application of combined chemotherapy clinically.
" iron is dead " (ferroptosis) is a kind of novel cell death way that Dxion in 2012 is proposed, can be passed through
Lipid peroxide intracellular (LPO) is mediated to be accumulate to ferritin Death Level and final inducing cell death, essence is a kind of
Novel cellular oxidation death pathways (Dixon S, LembergK, Lamprecht M, et al.Ferroptosis:An
Iron-Dependent Form ofNonapoptotic Cell Death[J].Cell,2012(5),149.).It is dead using iron
Dying mediate tumor cell death can bypass apoptosis of tumor cells access, thus avoid other oncotherapy modes such as chemotherapy, photo-thermal
Treatment etc. is through drug resistance (V.S.Viswanathan, M.J.Ryan, H.D.Dhruv, et caused by apoptosis pathway mediating cell death
al.Dependency of a therapy-resistant state of cancer cells on a lipid
Peroxidase pathway [J] .Nature, 2017 (7664): 453-457.).Iron death therapy and other oncotherapy sides
Formula such as chemotherapy, photo-thermal therapy, optical dynamic therapy use in conjunction also can be relieved the limitation such as treatment resistance that monotherapy is easy to cause
Property.By taking iron death inducing agents Erastin as an example, Erastin can inhibit cystine/glutamic acid reverse transport protein intake cystine
To inhibit the synthesis of glutathione intracellular (GSH), and then glutathione peroxidase (GPXs) intracellular is reduced, makes cell
Oxidation resistance reduces.The sustainable oxidation of polyunsaturated fatty acid (PUFAs) intracellular simultaneously, and generated in a manner of stereospecificity
LPO.In the presence of iron, LPO is further formed toxic lipid free radical, such as alkoxy radical, final to induce iron dead
It dies.In addition, these lipid free radicals generated can also shift the proton of neighbouring PUFAs, the lipid oxidation of a subsequent start-up new round
Oxidative damage is reacted and further transmitted, cell killing effect (Stockwell B R, the Jos é of circulation amplification is generated
Pedro,Angeli F,et al.Ferroptosis:A Regulated Cell Death Nexus Linking
Metabolism,Redox Biology,and Disease[J].Cell,2017(2):273-285.).In addition, iron compound
Also it can generate a large amount of active oxygens (Reactive oxygen species, abbreviation ROS) by participating in Fenton's reaction intracellular and insert
Enter adipose membrane and form LPO, to efficiently mediate iron death (Hofmans S, Berghe T V, Devisscher L, et
al.Novel ferroptosis inhibitors with improved potency and ADME properties[J]
.Journal of Medicinal Chemistry,2015(5):2041-53).However, iron compound is used for oncotherapy institute
Need dosage big, toxic side effect risk is high, therefore its use is restricted.
Small molecule, anti-tumor reactive compound containing phenyl ring often has serious toxic side effect, in addition, other inorganic are received
Rice optothermal material has the drawbacks of can not degrading, to bring unpredictable genotoxic potential.
Summary of the invention
The technical issues of solution: for overcome the deficiencies in the prior art, it is single to solve anti-tumor activity small molecule compound
The defect of easy inducible resistance is treated, the technical bottleneck that iron compound is applied in tumor therapeutic agent is improved, the present invention provides
Small molecule, anti-tumor reactive compound-polyphenol compound tri compound nanometer system based on iron compound-containing phenyl ring and
Preparation method and application.Specific purposes are as follows:
Purpose 1: a kind of small molecule, anti-tumor reactive compound-Polyphenols chemical combination based on iron compound-containing phenyl ring is obtained
Tri compound nanometer system of object and preparation method thereof.
Purpose 2: providing above-mentioned tri compound nanometer system application in preparation of anti-tumor drugs, realizes that iron death is controlled
It treats, the combination therapy of photo-thermal therapy and chemotherapy or optical dynamic therapy.
Purpose 3: the treatment of the small molecule, anti-tumor reactive compound in above-mentioned tri compound nanometer system containing phenyl ring is widened
Window.
Purpose 4: it abolishes the small molecule, anti-tumor reactive compound drug resistance in above-mentioned tri compound nanometer system containing phenyl ring, resist
The barriers such as the deep layer delivering of tumour Nano medication.
Purpose 5: based on above-mentioned tri compound nanometer system, a kind of improvement iron death therapy-photo-thermal therapy-change is provided
The strategy for the treatment of or the triple combination therapy toxic side effects of optical dynamic therapy.Small molecule, anti-tumor designed by the present invention containing phenyl ring is living
It is existing that property compound-polyphenol compound-iron compound tri compound nanometer system can reduce these by following mechanism
Or potential toxic side effect: 1. improving the cancer target distribution of each active component, its non-selective whole body distribution is reduced, to reduce
System toxicity；2. each assembling unit of the nanometer system is degradable and metabolizable active constituent, Jenner's grain of rice is avoided
It can not degrade bring toxic side effect etc. inorganic optothermal material；3. polyphenol compound and iron ion are logical in Fenton's reaction intracellular
The generation for promoting ROS and LPO intracellular is crossed, the reaction efficiency for the iron death that simple iron ion mediates can be greatly improved, to mention
The utilization rate of high chalybeate reduces its dosage, achievees the effect that attenuation.
Technical solution: tri compound nanometer system, the system include iron compound, the small molecule, anti-tumor work containing phenyl ring
Property compound and polyphenol compound, the weight ratio of three is 1-4:2-10:5-20.
The tri compound nanometer system partial size is 10-1000nm.
Preferably, the iron compound is ferric citrate, ironic citrate, ferrous sulfate, Ferric Ammonium Citrate, fumaric acid Asia
At least one of iron, frerrous chloride and ferric chloride hexahydrate.
Preferably, the small molecule, anti-tumor reactive compound containing phenyl ring is doxorubicin hydrochloride, hydrochloric acid darubicin, salt
Sour daunorubicin, doxorubicin hydrochloride, aclarubicin hydrochloride, epirubicin hydrochloride, mitoxantrone hydrochloride, mitoxantrone methanesulfonic acid
At least one of salt, melphalan, Ondansetron, indocyanine green, methotrexate (MTX), irinotecan hydrochloride and taxol.
Preferably, the polyphenol compound is tannic acid, catechin, epicatechin, pyrogallol catechin, epi-nutgall
At least one of phenol catechin, tea polyphenols, apple polyphenol, eriodictyol, vine polyphenol and resveratrol.
The preparation method of any description above tri compound nanometer system, the method are iron compound, containing the small of phenyl ring
Molecule active compound for anti tumor and polyphenol compound are self-assembly of tri compound nanometer system in solution environmental.
Preferably, the method be iron compound and polyphenol compound pass through first Coordinative Chemistry assemble to be formed it is pre-assembled
Primitive, and then tri compound nanometer system is formed by π-πconjugation with the small molecule, anti-tumor reactive compound containing phenyl ring.
Further, specific step is as follows for the method:
(1) iron compound, small molecule, anti-tumor reactive compound and polyphenol compound containing phenyl ring are weighed respectively, and are matched
Aqueous solution is made；
(2) iron compound and polyphenol compound solution are mixed, organic solvent is added in mixed process；
(3) the small molecule, anti-tumor active compounds solution containing phenyl ring is added into the mixed solution of step (2), after mixing
Precipitation solvent is added, centrifugation redissolves, collects product after ultrasound.
Preferably, the organic solvent in step (2) is ethyl alcohol, in ethanol water, methanol, methanol-water, isopropanol, isopropanol water
At least one.
Preferably, the precipitation solvent in step (3) is ammonium hydroxide, sodium carbonate, urea, ammonium hydrogen carbonate, hexamethylenetetramine, second
At least one of edetate disodium, sodium hydroxide solution.
Preferably, organic solvent additional amount is iron compound and polyphenol compound aqueous solution in step (1) in step (2)
2-100 times of total volume, precipitation solvent additional amount is that iron compound and polyphenol compound are water-soluble in step (1) in step (3)
0.2-50 times of liquid total volume.
Any description above tri compound nanometer system application in preparation of anti-tumor drugs.
The principle of tri compound nanometer system of the present invention is: the tri compound nanometer system depolymerization in the cell
Afterwards, the free small molecule, anti-tumor reactive compound containing phenyl ring is acted in its corresponding chemotherapy of performance intracellular or optical dynamic therapy,
Inhibit the proliferation of tumour cell, while Fenton's reaction occurs in the cell and generates largely for free iron ion and polyphenol compound
ROS be piled up in adipose membrane, further induce LPO intracellular to generate, induction iron is dead.In addition, the nanoparticle complex system also has
Good photo-thermal effect not only can further promote ROS intracellular to generate, may additionally facilitate deep of the nanoparticle in tumour and pass
It send, abolishes the delivering obstacle to Nano medication of interstitial, it is final to realize that iron death therapy, photo-thermal therapy and chemotherapy or light power are controlled
The combination therapy for the treatment of.The tri compound nanometer system is in the small molecule, anti-tumor reactive compound low concentration containing phenyl ring
Higher tumor cytotoxicity activity can be kept, significantly improves the small molecule, anti-tumor reactive compound therapeutic effect containing phenyl ring to medicine
The height accordance with tolerance of object concentration.In addition, improving storage of the small molecule, anti-tumor reactive compound in tumour cell containing phenyl ring
Product and delay, make the small molecule, anti-tumor reactive compound containing phenyl ring keep effective cell to kill in wider concentration fluctuation area
Hurt ability, the therapeutic effect fluctuation due to caused by drug concentration change is unfavorable in significant counteracting cellular material equilibrium process
It influences, the small molecule, anti-tumor of therapeutic effect, reduction containing phenyl ring for improving the small molecule, anti-tumor reactive compound containing phenyl ring is living
Property toxicity of compound, effectively widens the therapeutic window of the small molecule, anti-tumor reactive compound containing phenyl ring.
The utility model has the advantages that small molecule, anti-tumor reactive compound-polyphenol compound-containing phenyl ring that (1) present invention constructs
The tri compound nanometer system of iron compound need to only be assembled by physics, not change pharmaceutical chemistry structure, be different from chemical modification
The change for the structure-activity relationship that means may cause；Breach polymeric prodrugs micella, tree constructed by tradition conjugation modification means
Shape macromolecular prodrug nanoparticle etc. is because synthesis technology complexity, Medicine small molecule chemical structure change because of chemical modification, structure
Effect relationship can not clearly wait development and application caused by factors to limit.
(2) small molecule, anti-tumor reactive compound-polyphenol compound-iron compound containing phenyl ring that the present invention constructs
Tri compound nanometer system preparation method is simple, and preparation condition is mild, avoids mass uniformity caused by complicated preparation method
The problems such as poor, favorable reproducibility, industry transformation technology are simple.
(3) small molecule, anti-tumor reactive compound-polyphenol compound-iron compound containing phenyl ring that the present invention constructs
Tri compound nanometer system is also a kind of degradable photo-thermal composite nano materials.
(4) small molecule, anti-tumor reactive compound-polyphenol compound-iron compound containing phenyl ring that the present invention constructs
The multidigit one for realizing iron death therapy, photo-thermal therapy and chemotherapy or photodynamic therapy of tri compound nanometer system convenient and efficient
Body combination therapy, treats functional high Collaboration, and genotoxic potential is dissolved mutually；Tri compound nanometer system provided by the invention is not
Only realize the combination therapy of tumour iron death therapy, photo-thermal therapy and chemotherapy or photodynamic therapy, and can also be swollen by improving
Tumor targets precision with the small molecule, anti-tumor activation of miss the target distribution and promotion formant component containing phenyl ring of less drug
The double means of intramicellar reaction for closing object, polyphenol compound and iron compound, the poison for reducing this polynary combined treatment are secondary
Effect improves the treatment practicability of this many integration joint system.
(5) small molecule, anti-tumor reactive compound-polyphenol compound-iron compound containing phenyl ring that the present invention constructs
Tri compound nanometer system can widen the therapeutic window of the small molecule, anti-tumor reactive compound containing phenyl ring.
(6) small molecule, anti-tumor reactive compound-polyphenol compound-iron compound three containing phenyl ring of invention building
First composite Nano system has also widened the application range that iron preparation is applied to therapeutic field of tumor, substantially increases its mediate tumor
The efficiency of cell iron death, specific aim solve that required dosage when iron preparation is applied to merely oncotherapy is big, toxicity is high answers
Use predicament.
(7) small molecule, anti-tumor reactive compound-polyphenol compound-iron compound containing phenyl ring that the present invention constructs
Tri compound nanometer system has outstanding tumor-targeting, and institute's supported active compound can be made selectively to be concentrated on tumour cell
To improve its Targeting distribution efficiency, and loaded compound can be protected not to be metabolized as activity reduction or inactivation in blood circulation
Compound, keep its stability.
Specific embodiment
Following embodiment further illustrates the contents of the present invention, but should not be construed as limiting the invention.Without departing substantially from
In the case where spirit of that invention and essence, to modification made by the method for the present invention, step or condition and replaces, belong to the present invention
Range.Unless otherwise specified, the conventional means that technological means used in embodiment is well known to those skilled in the art.
Embodiment 1: iron chloride/tannic acid/doxorubicin hydrochloride tri compound nanometer system preparation
Iron chloride, tannic acid, doxorubicin hydrochloride, which are weighed, according to the ratio precision of weight ratio 4:2:5 is dissolved in purifying respectively
Water is vortexed and mixes, and the ferric chloride solution of above-mentioned preparation and tannic acid solution are mixed, and injected slurry volume is chlorine under stirring condition
The dehydrated alcohol for changing iron and 5 times of tannic acid mixed solution total volume amounts, continues 1~60min of stirring.By doxorubicin hydrochloride solution
The system being added in above-mentioned stirring continues 1~60min of stirring, and it is that iron chloride and tannic acid mixed solution are overall that volume, which is then added,
The ammonium hydroxide of 0.2 times of amount of product, centrifugation, precipitating plus water redissolve, and tri compound nanometer system is made in 8~30min of Probe Ultrasonic Searching.
Embodiment 2: ironic citrate/tea polyphenols/daunorubicin hydrochloride tri compound nanometer system preparation
Ironic citrate, tea polyphenols, daunorubicin hydrochloride, which are weighed, according to the ratio precision of weight ratio 4:6:9 is dissolved in purifying respectively
Water is vortexed and mixes, and the citric acid solution of above-mentioned preparation and tea polyphenols solution are mixed, and injects stirring bar under stirring condition
Under part injected slurry volume be ironic citrate and 10 times of tea polyphenols mixed solution total volume amount anhydrous methanols, continue stirring 1~
60min.The system in above-mentioned stirring is added in daunorubicin hydrochloride solution, continues 1~60min of stirring, volume, which is then added, is
The urea of ironic citrate and 2 times of tea polyphenols mixed solution total volume amounts, centrifugation, precipitating plus water redissolve, 8~30min of water bath sonicator,
Tri compound nanometer system is made.
Embodiment 3: ironic citrate/tea polyphenols/doxorubicin hydrochloride tri compound nanometer system preparation
Ironic citrate, tea polyphenols, doxorubicin hydrochloride, which are weighed, according to the ratio precision of weight ratio 4:6:9 is dissolved in purifying respectively
Water is vortexed and mixes, and the citric acid solution of above-mentioned preparation and tea polyphenols solution are mixed, and injected slurry volume is under stirring condition
The anhydrous isopropyl alcohol of ironic citrate and 30 times of tea polyphenols mixed solution total volume amounts, continues 1~60min of stirring.Hydrochloric acid is how soft
The system in above-mentioned stirring is added than star solution, continues 1~60min of stirring, it is ironic citrate and tea polyphenols that volume, which is then added,
The urea of 0.4 times of mixed solution total volume amount, centrifugation, precipitating plus water redissolve, and 8~30min of Probe Ultrasonic Searching, obtained tri compound is received
Rice system.
Embodiment 4: ferrous sulfate/catechin/epirubicin hydrochloride tri compound nanometer system preparation
Ferrous sulfate, catechin, epirubicin hydrochloride, which are weighed, according to the ratio precision of weight ratio 2:4:6 is dissolved in purifying respectively
Water is vortexed and mixes, and the ferrous sulfate solution of above-mentioned preparation and catechin solution are mixed, and injected slurry volume is under stirring condition
The ethanol water mixture of ferrous sulfate and 20 times of catechin mixed solution total volume amounts, continues 1~60min of stirring.By hydrochloric acid table
The soft system being added in above-mentioned stirring than star solution, continues 1~60min of stirring, and it is ferrous sulfate and catechu that volume, which is then added,
The sodium bicarbonate of 50 times of plain mixed solution total volume amounts, centrifugation, precipitating plus water redissolve, and ternary is made in 8~30min of Probe Ultrasonic Searching
Composite Nano system.
Embodiment 5: ferrous sulfate/epicatechin/epirubicin hydrochloride tri compound nanometer system preparation
According to the ratio precision of weight ratio 2:4:6 weigh ferrous sulfate, epicatechin, epirubicin hydrochloride be dissolved in respectively it is pure
Change water, be vortexed and mix, the ferrous sulfate solution of above-mentioned preparation and epicatechin solution are mixed, injects body under stirring condition
Product is the methanol water mix-ture of ferrous sulfate and 40 times of epicatechin mixed solution total volume amounts, continues 1~60min of stirring.It will
The system in above-mentioned stirring is added in epirubicin hydrochloride solution, continues 1~60min of stirring, and it is ferrous sulfate that volume, which is then added,
The sodium bicarbonate measured with 42 times of epicatechin mixed solution total volume, centrifugation, precipitating plus water redissolve, 8~30min of water bath sonicator,
Tri compound nanometer system is made.
Embodiment 6: ferric citrate/resveratrol/mitoxantrone hydrochloride tri compound nanometer system preparation
It is molten that ferric citrate, resveratrol, mitoxantrone hydrochloride difference are weighed according to the ratio precision of weight ratio 1:5:10
It in purified water, is vortexed and mixes, the ironic citrate ammonium salt solution of above-mentioned preparation and resveratrol solution are mixed, under stirring condition
Volume is the injection isopropanol-water mixture of ferric citrate and 60 times of resveratrol mixed solution total volume amounts, continues stirring 1
~60min.The system in above-mentioned stirring is added in mitoxantrone hydrochloride solution, continues 1~60min of stirring, volume is then added
For ferric citrate and 34 times of the resveratrol mixed solution total volume hexamethylenetetramines measured, centrifugation, precipitating plus water redissolve, and visit
Head 8~30min of ultrasound, is made tri compound nanometer system.
Embodiment 7: ferric citrate/resveratrol/epirubicin hydrochloride tri compound nanometer system preparation
It is molten that ferric citrate, resveratrol, epirubicin hydrochloride difference are weighed according to the ratio precision of weight ratio 1:5:10
It in purified water, is vortexed and mixes, the ironic citrate ammonium salt solution of above-mentioned preparation and resveratrol solution are mixed, under stirring condition
Injected slurry volume be ferric citrate and 50 times of resveratrol mixed solution total volume amount anhydrous methanols, continue stirring 1~
60min.The system in above-mentioned stirring is added in epirubicin hydrochloride solution, continues 1~60min of stirring, volume, which is then added, is
The hexamethylenetetramine of ferric citrate and 26 times of resveratrol mixed solution total volume amounts, centrifugation, precipitating plus water redissolve, probe
Tri compound nanometer system is made in 8~30min of ultrasound.
Embodiment 8: ferrous fumarate/apple polyphenol/hydrochloric acid darubicin tri compound nanometer system preparation
Ferrous fumarate, apple polyphenol, hydrochloric acid darubicin is weighed according to the ratio precision of weight ratio 2:6:5 to be dissolved in respectively
Purified water is vortexed and mixes, and the ferrous fumarate solution of above-mentioned preparation and apple polyphenol solution are mixed, stirring condition bet
Enter the dehydrated alcohol that volume is ferrous fumarate and 60 times of apple polyphenol mixed solution total volume amounts, continues 1~60min of stirring.
The system in above-mentioned stirring is added in hydrochloric acid darubicin solution, continues 1~60min of stirring, it is fumaric acid that volume, which is then added,
Ferrous and 36 times of apple polyphenol mixed solution total volume amounts ammonium hydrogen carbonate, centrifugation, precipitating plus water redissolve, and water bath sonicator 8~
Tri compound nanometer system is made in 30min.
Embodiment 9: ferrous fumarate/apple polyphenol/aclarubicin hydrochloride tri compound nanometer system preparation
Ferrous fumarate, apple polyphenol, aclarubicin hydrochloride is weighed according to the ratio precision of weight ratio 2:6:5 to be dissolved in respectively
Purified water is vortexed and mixes, and the ferrous fumarate solution of above-mentioned preparation and apple polyphenol solution are mixed, stirring condition bet
Enter volume be ferrous fumarate and 80 times of apple polyphenol mixed solution total volume amount ethanol water mixtures, continue stirring 1~
60min.The system in above-mentioned stirring is added in aclarubicin hydrochloride solution, continues 1~60min of stirring, volume, which is then added, is
The ammonium hydrogen carbonate of ferrous fumarate and 50 times of apple polyphenol mixed solution total volume amounts, centrifugation, precipitating plus water redissolve, Probe Ultrasonic Searching
Tri compound nanometer system is made in 8~30min.
Embodiment 10: frerrous chloride/tannic acid/indocyanine green tri compound nanometer system preparation
Chlorine Asia iron, tannic acid, indocyanine green, which are weighed, according to the ratio precision of weight ratio 1:5:4 is dissolved in purified water, whirlpool respectively
Rotation mixes, and the chlorine Asia ferrous solution and tan-liquor of above-mentioned preparation are mixed, and injected slurry volume is protochloride under stirring condition
The anhydrous isopropyl alcohol of iron and 40 times of tannic acid mixed solution total volume amounts, continues 1~60min of stirring.Indocyanine green solution is added
System in above-mentioned stirring continues 1~60min of stirring, and it is frerrous chloride and tannic acid mixed solution total volume that volume, which is then added,
The disodium ethylene diamine tetraacetate of 34 times of amounts, centrifugation, precipitating plus water redissolve, and tri compound nanometer is made in 8~30min of Probe Ultrasonic Searching
System.
Embodiment 11: frerrous chloride/eriodictyol/taxol tri compound nanometer system preparation
Chlorine Asia iron, eriodictyol, taxol, which are weighed, according to the ratio precision of weight ratio 1:5:10 is dissolved in purified water, whirlpool respectively
Rotation mixes, and the chlorine Asia ferrous solution of above-mentioned preparation and mountain balsam phenol solution are mixed, and injected slurry volume is that chlorine is sub- under stirring condition
Change 50 times of amount anhydrous methanols of iron and eriodictyol mixed solution total volume, continues 1~60min of stirring.Paclitaxel solution is added
The system in stirring is stated, 1~60min of stirring is continued, it is chlorine Asia iron and eriodictyol mixed solution total volume that volume, which is then added,
15 times of amount ammonium hydroxide, centrifugation, precipitating plus water redissolve, and tri compound nanometer system is made in 8~30min of Probe Ultrasonic Searching.
Embodiment 12: frerrous chloride/eriodictyol/methotrexate (MTX) tri compound nanometer system preparation
Chlorine Asia iron, eriodictyol, methotrexate (MTX), which are weighed, according to the ratio precision of weight ratio 1:5:10 is dissolved in purified water respectively,
It is vortexed and mixes, the chlorine Asia ferrous solution of above-mentioned preparation and mountain balsam phenol solution are mixed, injected slurry volume is chlorine under stirring condition
70 times of amount isopropanol-water mixtures of Asiaization iron and eriodictyol mixed solution total volume, continue 1~60min of stirring.By methotrexate (MTX)
The system in above-mentioned stirring is added in solution, continues 1~60min of stirring, and it is that chlorine Asia iron and eriodictyol mix that volume, which is then added,
18 times of amount ammonium hydroxide of overall solution volume, centrifugation, precipitating plus water redissolve, and tri compound nanometer system is made in 8~30min of water bath sonicator.
Embodiment 13: iron chloride/pyrogallol catechin/melphalan tri compound nanometer system preparation
Iron chloride, pyrogallol catechin, melphalan, which are weighed, according to the ratio precision of weight ratio 3:6:9 is dissolved in purifying respectively
Water is vortexed and mixes, and the ferric chloride solution of above-mentioned preparation and pyrogallol catechin solution are mixed, and injects under stirring condition
Volume is 30 times of amount dehydrated alcohols of iron chloride and pyrogallol catechin mixed solution total volume, continues 1~60min of stirring.It will
The system in above-mentioned stirring is added in melphalan solution, continues 1~60min of stirring, and it is iron chloride and galla turcica that volume, which is then added,
17 times of amount ammonium hydroxide of phenol catechin mixed solution total volume, centrifugation, precipitating plus water redissolve, and ternary is made in 8~30min of Probe Ultrasonic Searching
Composite Nano system.
Embodiment 14: iron chloride/epi-nutgall phenol catechin/melphalan tri compound nanometer system preparation
According to the ratio precision of weight ratio 3:6:9 weigh iron chloride, epi-nutgall phenol catechin, melphalan be dissolved in respectively it is pure
Change water, be vortexed and mix, the ferric chloride solution of above-mentioned preparation and epi-nutgall phenol catechin solution are mixed, under stirring condition
Injected slurry volume be 45 times of amount anhydrous methanols of iron chloride and epi-nutgall phenol catechin mixed solution total volume, continue stirring 1~
60min.The system in above-mentioned stirring is added in melphalan solution, continues 1~60min of stirring, it is iron chloride that volume, which is then added,
With 24 times of amount ammonium hydroxide of epi-nutgall phenol catechin mixed solution total volume, centrifugation, precipitating plus water redissolve, and Probe Ultrasonic Searching 8~
Tri compound nanometer system is made in 30min.
Embodiment 15: iron chloride/vine polyphenol/Ondansetron tri compound nanometer system preparation
Iron chloride, vine polyphenol, Ondansetron, which are weighed, according to the ratio precision of weight ratio 5:6:8 is dissolved in purified water respectively,
It is vortexed and mixes, the ferric chloride solution of above-mentioned preparation and vine polyphenol solution are mixed, injected slurry volume is chlorine under stirring condition
Change 40 times of amount dehydrated alcohols of iron and vine polyphenol mixed solution total volume, continues 1~60min of stirring.Ondansetron solution is added
Enter the system in above-mentioned stirring, continue 1~60min of stirring, it is that iron chloride and vine polyphenol mixed solution are total that volume, which is then added,
27 times of amount ammonium hydroxide of volume, centrifugation, precipitating plus water redissolve, and tri compound nanometer system is made in 8~30min of Probe Ultrasonic Searching.
Embodiment 16: iron chloride/vine polyphenol/irinotecan hydrochloride tri compound nanometer system preparation
Iron chloride, vine polyphenol, irinotecan hydrochloride, which are weighed, according to the ratio precision of weight ratio 5:6:8 is dissolved in purifying respectively
Water is vortexed and mixes, and the ferric chloride solution of above-mentioned preparation and vine polyphenol solution are mixed, and injected slurry volume is under stirring condition
100 times of amount ethanol water mixtures of iron chloride and vine polyphenol mixed solution total volume, continue 1~60min of stirring.By hydrochloric acid Yi Li
The system in above-mentioned stirring is added for health solution, continues 1~60min of stirring, it is iron chloride and vine polyphenol that volume, which is then added,
48 times of amount ammonium hydroxide of mixed solution total volume, centrifugation, precipitating plus water redissolve, and tri compound nanometer is made in 8~30min of water bath sonicator
System.
Embodiment 17: tri compound nanometer system particle size determination
The tri compound nanometer system 1mL that Example 1-16 is prepared is diluted with water to 3mL, with particle size determination instrument
(Malvem Instruments, Malvern, UK) is measured, and the results are shown in Table 1.As seen from table, the tri compound being prepared
Nanometer system, nanometer system partial size reaches nanoscale, and particle diameter distribution is uniform.
The characterization of 1 tri compound nanometer system of table
Embodiment 18: the drugloading rate of tri compound nanometer system
Drugloading rate detection method: using UV absorptiometry, inhales to the therapeutic agent containing conjugated structure in its maximum
Receive the standard curve that peak area and concentration are drawn at wavelength.To the tri compound nanometer system after load medicine in above-mentioned maximum absorption wave
Strong point measures peak area, calculates concentration according still further to standard curve, and calculate drugloading rate with formula (1).Each system as shown in Table 2
Drugloading rate 6.5% or more, it was demonstrated that system drug-loading efficiency with higher, be conducive to improve drug in tumor locus
Selective aggregation improves the drugloading rate of drug, reduces side effects of pharmaceutical drugs.
Note: M1(mg) quality, M are put into for the small molecule, anti-tumor reactive compound containing phenyl ring2It (mg) is to contain benzene in supernatant
The quality of the small molecule, anti-tumor reactive compound of ring, M3It (mg) is the quality of iron compound investment, M4It (mg) is Polyphenols chemical combination
The investment quality of object.
The drugloading rate of 2 tri compound nanometer system of table
The mono- dye method of embodiment 19:PI detects different systems to the inhibiting effect of MCF7 cell
Take MCF7 cell with 5 × 105/ hole is inoculated in 6 orifice plates, and 37 DEG C are incubated for for 24 hours, is sucked culture solution, is separately added into
Free the small molecule, anti-tumor reactive compound containing phenyl ring, the small molecule, anti-tumor reactive compound-containing phenyl ring of 0.35 μ g/mL
After polyphenol compound-iron compound tri compound nano-solution 2mL, 37 DEG C of incubation 48h, 100 μ L PI are added, mix gently,
It is protected from light room temperature reaction 15 minutes or 4 DEG C and reacts 30 minutes.2mL is added and marks buffer, immediately upper machine (flow cytometer) detection.
The fluorescence intensity of each group is measured, and measures blank group fluorescence intensity and control group fluorescence intensity, n=6, record in the same way
PI (%) numerical value of flow cytometer.The cytotoxicity (PI%) of tri compound nanometer system group is significantly stronger than trip as shown in Table 3
From drug, and said preparation can also be combined photodynamic therapy, realize being used in combination for chemotherapeutics and photodynamic therapy, have good
Good antitumous effect.
The mono- dye method of 3 PI of table detects different systems to the inhibiting effect of MCF7 cell
Note: compared with free drug group**P < 0.01, compared with no laser irradiation tri compound nanometer system group##P<
0.01。
The mono- dye method of embodiment 20:PI detects different systems to human breast carcinoma multidrug resistance cell strain MCF-7/ADR cell
Inhibiting effect
Take MCF7/ADR cell with 5 × 105/ hole is inoculated in 6 orifice plates, 37 DEG C be incubated for for 24 hours, suck culture solution, respectively plus
Enter free the small molecule, anti-tumor reactive compound containing phenyl ring, the small molecule, anti-tumor active ingredient containing phenyl ring of 0.35 μ g/mL
After object-polyphenol compound-iron compound tri compound nano-solution 2mL, 37 DEG C of incubation 48h, 100 μ L PI are added, gently mix
It is even, it is protected from light room temperature reaction 15 minutes or 4 DEG C and reacts 30 minutes.2mL is added and marks buffer, immediately upper machine (flow cytometer) inspection
It surveys.The fluorescence intensity of each group is measured, and measures blank group fluorescence intensity and control group fluorescence intensity (n=6) in the same way,
Record PI (%) numerical value of flow cytometer.The controlling for drug-resistant cell strain of tri compound nanometer system group as shown in Table 4
Therapeutic effect (PI%) is significantly stronger than free drug, it was demonstrated that tumour cell of the tri compound nanometer system for generation drug resistance
With preferable therapeutic effect.
The mono- dye method of 4 PI of table detects different systems to the inhibiting effect of MCF7/ADR cell
Note: compared with free drug group**P < 0.01, compared with no laser irradiation tri compound nanometer system group##P<
0.01。
Embodiment 21: photo-thermal experiment
Using thermal infrared imager to small molecule, anti-tumor reactive compound-polyphenol compound-iron compound containing phenyl ring
The light thermal property of tri compound nano-solution is recorded, with monitoring temperature.By the nanoparticle (10 μ g/mL) containing various concentration
PBS dispersion be exposed to laser (808nm, 0.5W/cm2) under irradiate 10min, and record temperature change.Ternary as shown in Table 5
Nanometer system group has preferable photothermal conversion ability, it was demonstrated that tri compound nanometer system of the invention can be used for photo-thermal and control
It treats, develops a kind of novel optothermal material.
The temperature change of 5 tri compound nanometer system of table
Embodiment 22:ROS test experience
Take MCF7 cell with 5 × 105/ hole is inoculated in 6 orifice plates, and 37 DEG C are incubated for for 24 hours, is sucked culture solution, is separately added into
Free the small molecule, anti-tumor reactive compound containing phenyl ring, the small molecule, anti-tumor reactive compound-containing phenyl ring of 0.35 μ g/mL
After polyphenol compound-iron compound tri compound nano-solution 2mL, 37 DEG C of incubation 48h, DHE fluorescence probe is added, gently mixes
It is even, it is incubated for 30 minutes in incubator.It is washed three times after incubation with PBS, cell is resuspended in the ice-cold PBS of 1mL, immediately upper machine
(flow cytometer) detection.The fluorescence intensity of each group is measured, and measures blank group fluorescence intensity and control group in the same way
Fluorescence intensity is calculated the relative concentration of ROS by formula (2).Learn that tri compound nanometer system group can generate largely by table 6
ROS, is shown to be iron compound and the generation of Fenton's reaction induction ROS occurs in the cell for more classification compounds, and through laser
Combine photodynamic therapy when irradiation, co-induction generates a large amount of ROS, has better lethal effect to cell.
6 ROS test experience of table
Embodiment 23:LPO test experience
Take MCF7 cell with 5 × 105/ hole is inoculated in 6 orifice plates, and 37 DEG C are incubated for for 24 hours, is sucked culture solution, is separately added into
Free the small molecule, anti-tumor reactive compound containing phenyl ring, the small molecule, anti-tumor reactive compound-containing phenyl ring of 0.35 μ g/mL
After polyphenol compound-iron compound tri compound nano-solution 2mL, 37 DEG C of incubation 48h, washed 3 times with PBS, with 0.25%
Trypsin digestion cell, 1000r are centrifuged 5min, cell are resuspended to and are transferred to teat glass with the PBS of 0.5mL, into each pipe
Isometric Extract R saturation methanol is added and is vortexed, then to the cold chloroform of 1mL is added in each pipe, vortex is allowed to abundant
Mixing, and, with pasteur pipet or syringe needle, bottom chlorine is collected at 0 DEG C with 1,500 × g centrifugal mixture 5 minutes
Imitative layer.Chloroform layer is transferred in another test tube and is stored on ice, a certain amount of developing solution is added, is existed with microplate reader
Light absorption value is detected under 500nm wavelength.The fluorescence intensity of each group is measured, and measures blank group fluorescence intensity and right in the same way
According to a group fluorescence intensity, the relative concentration of LPO is calculated by formula (3).As shown in Table 7, tri compound nanometer system can induce LPO's
It is a large amount of to generate, there is difference between free preparation group, control group, and the facilitation to LPO of light group is more
Obviously, iron more can further be promoted when it is dead to show that ternary nano system group can produce LPO induction iron, and combining laser irradiation
Dead generation realizes being used in combination for phototherapy and iron death, and phototherapy has facilitation to iron death.
7 LPO of table detects different systems to the relative concentration of LPO in MCF7 cell
Embodiment 24: pharmacodynamic evaluation
Tumor-bearing mice is divided into 22 groups, every group 3 are respectively negative control group (Control), free adriamycin group, chlorination
Iron/tannic acid/doxorubicin hydrochloride group, iron chloride/tannic acid/doxorubicin hydrochloride+Laser group, free indocyanine green group, iron chloride/tan
Acid/indocyanine green group, iron chloride/tannic acid/indocyanine green+Laser group, free paclitaxel group, chlorine Asia iron/eriodictyol/Japanese yew
Alcohol group, chlorine Asia iron/eriodictyol/taxol+Laser group, free methotrexate (MTX) group, chlorine Asia iron/eriodictyol/methotrexate (MTX)
Group, chlorine Asia iron/eriodictyol/methotrexate (MTX)+Laser group, free melphalan group, iron chloride/pyrogallol catechin/melphalan
Group, iron chloride/pyrogallol catechin/melphalan+Laser group, free Ondansetron group, iron chloride/vine polyphenol/Ang Dansi
Fine jade group, iron chloride/vine polyphenol/Ondansetron+Laser group, free hydrochloric acid Irinotecan group, iron chloride/vine polyphenol/hydrochloric acid
Irinotecan group, iron chloride/vine polyphenol/irinotecan hydrochloride+Laser group, when the bulk grows to 100mm for the tumor of mouse3When,
Dissociated adriamycin (5mg/kg) by tail vein injection within 1,3,5th day, the iron chloride/tannic acid/doxorubicin hydrochloride group (agent of adriamycin
Amount be 2mg/kg), iron chloride/tannic acid/doxorubicin hydrochloride+Laser group (dosage of adriamycin is 2mg/kg), dissociate indocyanine green
Group (350 μ g/kg), iron chloride/tannic acid/indocyanine green group (140 μ g/kg of indocyanine green dosage), iron chloride/tannic acid/indoles cyanines
Green+Laser group ((140 μ g/kg of indocyanine green dosage), free paclitaxel group (10mg/kg), chlorine Asia iron/eriodictyol/Japanese yew
Alcohol group (dose of paclitaxel 4mg/kg), is dissociated at chlorine Asia iron/eriodictyol/taxol+Laser group (dose of paclitaxel 4mg/kg)
Methotrexate (MTX) group (3mg/kg), chlorine Asia iron/eriodictyol/methotrexate (MTX) group (methotrexate doses 1.2mg/kg), chlorine Asia iron/
Eriodictyol/methotrexate (MTX)+Laser group (methotrexate doses 1.2mg/kg), free melphalan group (7.5mg/kg), iron chloride/
Pyrogallol catechin/melphalan group (melphalan dosage 3mg/kg), iron chloride/pyrogallol catechin/melphalan+Laser
Group (melphalan dosage 3mg/kg), free Ondansetron group (8mg/kg), iron chloride/vine polyphenol/Ondansetron group (Ang Dansi
Fine jade dosage 3.2mg/kg), iron chloride/vine polyphenol/Ondansetron+Laser group (Ondansetron dosage 3.2mg/kg), free salt
Sour Irinotecan group (2mg/kg), iron chloride/vine polyphenol/irinotecan hydrochloride group (Irinotecan dosage 0.8mg/kg), chlorine
Change iron/vine polyphenol/irinotecan hydrochloride+Laser group (Irinotecan dosage 0.8mg/kg), for the reality of joint laser therapy
Group is tested, with 808nm laser with tumour 5 minutes of the irradiation mouse of 1W/cm 2.In experiment the 21st day, mouse is euthanized, is remembered daily
The weight of mouse and the size of amount tumor are recorded, for calculating the volume and weight of tumor and calculating tumor suppression efficiency.Ternary is multiple as shown in Table 8
Closing nanometer system group has preferable therapeutic effect for tumor-bearing mice, this is because the good nanometer particle size of preparation passes through EPR
Effect is assembled in tumor locus, improves the antitumous effect of free drug, and reduces free drug to the secondary work of the poison of mouse
With.
The pharmacodynamic evaluation of the different ternary complex preparations of table 8
Note: compared with Control group**P < 0.01, compared with free drug group##P < 0.01, with no laser preparation group phase
Than@@P<0.01
Embodiment 25: toxicity detection experiment
Tumor-bearing mice is divided into 22 groups, every group 3 are respectively negative control group (Control), free adriamycin group, chlorination
Iron/tannic acid/doxorubicin hydrochloride group, iron chloride/tannic acid/doxorubicin hydrochloride+Laser group, free indocyanine green group, iron chloride/tan
Acid/indocyanine green group, iron chloride/tannic acid/indocyanine green+Laser group, free paclitaxel group, chlorine Asia iron/eriodictyol/Japanese yew
Alcohol group, chlorine Asia iron/eriodictyol/taxol+Laser group, free methotrexate (MTX) group, chlorine Asia iron/eriodictyol/methotrexate (MTX)
Group, chlorine Asia iron/eriodictyol/methotrexate (MTX)+Laser group, free melphalan group, iron chloride/pyrogallol catechin/melphalan
Group, iron chloride/pyrogallol catechin/melphalan+Laser group, free Ondansetron group, iron chloride/vine polyphenol/Ang Dansi
Fine jade group, iron chloride/vine polyphenol/Ondansetron+Laser group, free hydrochloric acid Irinotecan group, iron chloride/vine polyphenol/hydrochloric acid
Irinotecan group, iron chloride/vine polyphenol/irinotecan hydrochloride+Laser group, when the bulk grows to 100mm for the tumor of mouse3When,
Dissociated adriamycin (5mg/kg) by tail vein injection within 1,3,5th day, the iron chloride/tannic acid/doxorubicin hydrochloride group (agent of adriamycin
Amount be 2mg/kg), iron chloride/tannic acid/doxorubicin hydrochloride+Laser group (dosage of adriamycin is 2mg/kg), dissociate indocyanine green
Group (350 μ g/kg), iron chloride/tannic acid/indocyanine green group (140 μ g/kg of indocyanine green dosage), iron chloride/tannic acid/indoles cyanines
Green+Laser group ((140 μ g/kg of indocyanine green dosage), free paclitaxel group (10mg/kg), chlorine Asia iron/eriodictyol/Japanese yew
Alcohol group (dose of paclitaxel 4mg/kg), is dissociated at chlorine Asia iron/eriodictyol/taxol+Laser group (dose of paclitaxel 4mg/kg)
Methotrexate (MTX) group (3mg/kg), chlorine Asia iron/eriodictyol/methotrexate (MTX) group (methotrexate doses 1.2mg/kg), chlorine Asia iron/
Eriodictyol/methotrexate (MTX)+Laser group (methotrexate doses 1.2mg/kg), free melphalan group (7.5mg/kg), iron chloride/
Pyrogallol catechin/melphalan group (melphalan dosage 3mg/kg), iron chloride/pyrogallol catechin/melphalan+Laser
Group (melphalan dosage 3mg/kg), free Ondansetron group (8mg/kg), iron chloride/vine polyphenol/Ondansetron group (Ang Dansi
Fine jade dosage 3.2mg/kg), iron chloride/vine polyphenol/Ondansetron+Laser group (Ondansetron dosage 3.2mg/kg), free salt
Sour Irinotecan group (2mg/kg), iron chloride/vine polyphenol/irinotecan hydrochloride group (Irinotecan dosage 0.8mg/kg), chlorine
Change iron/vine polyphenol/irinotecan hydrochloride+Laser group (Irinotecan dosage 0.8mg/kg), for the reality of joint laser therapy
Group is tested, with 808nm laser with 1W/cm2Irradiate tumour 5 minutes of mouse.In experiment the 21st day, mouse is euthanized, coring liver
Spleen and lung kidney prepares pathological section and carries out pathological examination analysis.Free drug has normal tissue higher as shown in Table 9
Toxic side effect, tri compound nanometer system can effectively improve its generation toxic side effect, this is because Polyphenols chemical combination
Object is a kind of good hydrogen donor, plays reduction in the cell, reduces the damage due to ROS for normal tissue.Show
Said preparation has preferable protective effect without with good antitumor action and for normal tissue, and having widely makes
With value.
9 toxicity assessment of table
Note: "-" is not damaged, "+" minor injury, " ++ " moderate lesion.
Claims (10)
1. tri compound nanometer system, which is characterized in that the system includes iron compound, the small molecule, anti-tumor work containing phenyl ring
Property compound and polyphenol compound, the weight ratio of three is 1-4:2-10:5-20.
2. tri compound nanometer system according to claim 1, which is characterized in that the iron compound is ironic citrate
At least one in ammonium, ironic citrate, ferrous sulfate, Ferric Ammonium Citrate, ferrous fumarate, frerrous chloride and ferric chloride hexahydrate
Kind.
3. tri compound nanometer system according to claim 1, which is characterized in that the small molecule, anti-tumor containing phenyl ring
Reactive compound is doxorubicin hydrochloride, hydrochloric acid darubicin, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, salt
Sour epirubicin, mitoxantrone hydrochloride, mitoxantrone mesylate, melphalan, Ondansetron, indocyanine green, methotrexate (MTX), salt
At least one of sour Irinotecan and taxol.
4. tri compound nanometer system according to claim 1, which is characterized in that the polyphenol compound be tannic acid,
Catechin, epicatechin, pyrogallol catechin, epi-nutgall phenol catechin, tea polyphenols, apple polyphenol, eriodictyol, grape are more
At least one of phenol and resveratrol.
5. the preparation method of any tri compound nanometer system of claim 1-4, which is characterized in that the method is iron
It is multiple that conjunction object, the small molecule, anti-tumor reactive compound containing phenyl ring and polyphenol compound are self-assembly of ternary in solution environmental
Close nanometer system.
6. the preparation method of tri compound nanometer system according to claim 5, which is characterized in that the method is iron
It closes object and polyphenol compound passes through Coordinative Chemistry first and assembles to form pre-assembled primitive, and then is anti-swollen with the small molecule containing phenyl ring
Tumor activity compound forms tri compound nanometer system by π-πconjugation.
7. the preparation method of tri compound nanometer system according to claim 6, which is characterized in that the method specifically walks
It is rapid as follows:
(1) iron compound, small molecule, anti-tumor reactive compound and polyphenol compound containing phenyl ring are weighed respectively, and are configured to
Aqueous solution；
(2) iron compound and polyphenol compound solution are mixed, organic solvent is added in mixed process；
(3) the small molecule, anti-tumor active compounds solution containing phenyl ring is added into the mixed solution of step (2), is added after mixing
Precipitation solvent, centrifugation redissolve, collect product after ultrasound.
8. the preparation method of tri compound nanometer system according to claim 7, which is characterized in that having in step (2)
Solvent is at least one of ethyl alcohol, ethanol water, methanol, methanol-water, isopropanol, isopropanol water.
9. the preparation method of tri compound nanometer system according to claim 7, which is characterized in that heavy in step (3)
Shallow lake solvent is ammonium hydroxide, sodium carbonate, urea, ammonium hydrogen carbonate, hexamethylenetetramine, disodium ethylene diamine tetraacetate, sodium hydroxide solution
At least one of.
10. any tri compound nanometer system application in preparation of anti-tumor drugs of claim 1-4.
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| CN110217877A (en) * | 2019-06-03 | 2019-09-10 | 燕山大学 | The method for handling organic wastewater as the class Fenton's reaction of oxidant using perborate |
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| CN114259474A (en) * | 2021-12-03 | 2022-04-01 | 浙江大学杭州国际科创中心 | Novel iron-based nano material and application thereof |
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| WO2020155673A1 (en) | 2020-08-06 |
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