CN106924220A - A kind of preparation of cancer target multi-arm polyethylene glycol triptolide Nano medication - Google Patents
A kind of preparation of cancer target multi-arm polyethylene glycol triptolide Nano medication Download PDFInfo
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- CN106924220A CN106924220A CN201710300421.XA CN201710300421A CN106924220A CN 106924220 A CN106924220 A CN 106924220A CN 201710300421 A CN201710300421 A CN 201710300421A CN 106924220 A CN106924220 A CN 106924220A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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Abstract
The invention discloses a kind of preparation of cancer target multi-arm polyethylene glycol triptolide Nano medication.Described self assembly targeting folic acid cancer therapy drug is to be coupled to form pro-drug by multi-arm polyethylene glycol and triptolide, folic acid is with ethylene diamine-modified into the reaction terminal groups with amino, it is coupled with prodrug, and multi-arm polyethylene glycol triptolide is prepared with another cancer therapy drug HCPT self assembly（HCPT）Nano medication.The double medicine systems of load prepared by the method solve the water-insoluble of triptolide and HCPT, targeting of the connection folic acid enhancing to tumor locus, the Nano medication has the carrying drug ratio of stabilization, the particle diameter distribution of envelop rate and stabilization, biological safety is high, preparation process is simple, low cost is adapted to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation of cancer target multi-arm polyethylene glycol-triptolide Nano medication, particularly
It is related to the reaction of a kind of utilization multi-arm polyethylene glycol and dewatering medicament, nano-particle is self-assembly of with another kind dewatering medicament
Method, target tumor position belongs to advanced nanometer technology and field of biological pharmacy.
Background technology
Triptolide（Triptolide, TP）It is Chinese herb triperygium wilfordii（Tripterygium wilfordii Hook.
f.）In the active highest epoxidation diterpenic lactone isolated, be one of principle active component of thunder godvine.Due to thunder
The physiologically active of public rattan is strong, with significant immunosupress, anti-inflammatory, antitumor and antifertility action.But it is very strong that it belongs to toxicity
Medicine, the occurrence frequency of clinical adverse is far above other medicines, occurs mainly in digestive system, urinary system, reproduction
System, cardiovascular system, marrow and hematological system.Wherein again it is most commonly seen with digestive system, be mainly shown as Nausea and vomiting,
Stomachache, diarrhoea and hemorrhage of digestive tract etc..Therefore, study new delivery system has highly important meaning to reduce its toxicity
Justice.
The content of the invention
It is an object of the invention to provide a kind of preparation of cancer target multi-arm polyethylene glycol-triptolide Nano medication,
The method has low cost, and nano-particle is homogeneous, folate-targeted tumour, suppresses tumour growth, promotes apoptosis.
Above-mentioned purpose of the invention is achieved through the following technical solutions：Described self assembly targeting folic acid cancer therapy drug be by
Multi-arm polyethylene glycol is coupled to form pro-drug with triptolide, and folic acid is with ethylene diamine-modified into the reaction end with amino
Base, is coupled, and prepare multi-arm polyethylene glycol-triptolide with another cancer therapy drug HCPT self assembly with prodrug
（HCPT）Nano medication.Comprise the following steps that：
（1）Folic acid is dissolved in dimethyl sulfoxide (DMSO), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides are added
（EDC）Activation 30 minutes, adds activator N-hydroxy-succinamide and ethylenediamine, and 5 milliliters of pyridine reacts 12 hours；
（2）To 3 times of ether of volume are added in above-mentioned solution, folic acid derivatives are precipitated, sediment is centrifuged, and added diethyl ether repeatedly
Washing, last sediment vacuum drying, obtains yellow powder；
（3）Multi-arm polyethylene glycol is scattered in pyridine, concentration is 0.01-5 mg/mls, magnetic agitation 10-30 minutes, is made
Its dissolving, adds EDC, activation carboxyl 30 minutes to add catalyst DMAP（DMAP）；
（4）Take appropriate triptolide and be dissolved in pyridine, and be transferred in multi-arm polyethylene glycol solution, 35 DEG C of reactions overnight, and connect
It is continuous to be passed through nitrogen, the water of removal esterification generation；
（5）To in reacted mixed liquor 1:3（Volume ratio）Ratio add absolute ether, there is flocculent deposit, 4000 leave
The heart 30 minutes, collects precipitation, and continuation is washed precipitation with ether twice, solids of sedimentation is collected by centrifugation, and is vacuum dried, and obtains multi-arm and gathers
Ethylene glycol-triptolide white powder；
（6）Take above-mentioned powder and be dissolved in pyridine in right amount, add folic acid derivatives, EDC and DMAP to react 48 hours, to reacted
1 in mixed liquor:3（Volume ratio）Ratio add absolute ether, 4000 leave the heart 30 minutes, collect precipitation, and continuation washed with ether
Wash precipitation twice, solids of sedimentation is collected by centrifugation；
（7）Above-mentioned gained solids of sedimentation is dissolved in deionized water, is dialysed 12 hours with PBS, and gentle agitation is saturating
The outer liquid of analysis, accelerates dialysis speed, and extracellular fluid dialysis were changed every 4 hours；
（8）By the subzero 80 DEG C of freeze overnights of above-mentioned dialysate, and freeze-drying 48 hours, obtain folic acid-multi-arm polyethylene glycol-thunder
Public rattan A prime yellow powder；
（9）Take above-mentioned powder and be dissolved in dimethyl sulfoxide (DMSO) jointly with HCPT in right amount, stir, be then slowly dropped into acutely
In the deionized water of stirring, self assembly obtains nano-particle, and solution 8000 is left into the heart 30 minutes, collects sediment, divides again
Dissipate in deionized water, dialyse 6 hours, the subzero 80 DEG C of freeze overnights of dialysate, and freeze-drying 48 hours, obtain yellow powder
End, as folate-targeted multi-arm polyethylene glycol-triptolide（HCPT）Nano medication.
Described multi-arm polyethylene glycol can be single armed, four arms or eight arm polyethylene glycol, can not contain different functional groups, and not
Reacted with water repellent medicine, and between molecular weight 2000 ~ 80000；
Described insoluble in water medicine triptolide is still applied to other water repellent medicines, such as black bearberry containing response function group
Acid, red sandalwood rises, dihydroartemisinine etc.；
Described packaging medicine HCPT can be substituted by the strong medicine of other hydrophobicitys, or nano level metal, nanometer
Level metal oxide；
Described pyridine tetrahydrofuran, dimethyl sulfoxide (DMSO), dichloromethane replacement, its coupling method stands good；
Described nano particle diameter is homogeneous, and in 10-100nm.
The present invention has advantages below：
1）Reaction mechanism of the invention is the hydroxyl of the carboxyl by macromolecular compound multi-arm polyethylene glycol and triptolide
Generation esterification, obtains multi-arm polyethylene glycol drug conjugates.
2）Multi-arm polyethylene glycol drug conjugates are connected by amido link with tumor targeted molecular folic acid, make the poly- second two of multi-arm
Alcohol has target function.
3）Self assembling process of the invention is made by the water repellent of the dewatering medicament group being reacted on multi-arm polyethylene glycol
With, hollow kernel is formed, the water-wet side of multi-arm polyethylene glycol is outer layer, and dewatering medicament HCPT is kernel core, from group
The amphiphilic nano particle for being formed is filled, nano-particle is homogeneous.
4）It is targeted molecular that the present invention uses folic acid, is connected with multi-arm polyethylene glycol, guides two kinds of dewatering medicaments to combine and kills
Dead tumour cell.
5）The present invention does not need the energy consumption equipments such as HTHP, does not also need complex appts, and chemical levels used are few,
Recyclable, process is simple reduces production cost.
Brief description of the drawings
Fig. 1 is the change curve of the drugloading rate with triptolide consumption of eight arms polyethylene glycol of the invention；
Fig. 2 prepares the arm polyethylene glycol of cancer target eight-triptolide Nano medication Flied emission Electronic Speculum shape appearance figure for the present invention；
Fig. 3 is the grain size distribution of the arm of folic acid-eight polyethylene glycol-triptolide Nano medication of the present invention；
Fig. 4 is the stability test figure of the arm of folic acid-eight polyethylene glycol-triptolide nano-particle of the present invention；
Fig. 5 is the pH response diagrams of the arm of folic acid-eight polyethylene glycol-triptolide Nano medication of the present invention.
Specific embodiment
Embodiment one
（1）Take 1 g folic acid to be dissolved in dimethyl sulfoxide (DMSO), add 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide hydrochlorides
Salt（EDC）Activation 30min, adds activator N-hydroxy-succinamide and ethylenediamine, and the mL of pyridine 5 reacts 12 h；
（2）To 3V ether is added in above-mentioned solution, folic acid derivatives are precipitated, sediment is centrifuged, and the repeatedly washing that adds diethyl ether, most
Sediment vacuum drying, obtains yellow powder afterwards；
（3）Multi-arm polyethylene glycol is scattered in pyridine, concentration is 0.01-5 mg/mL, magnetic agitation 10-30 min, makes its molten
Solution, adds EDC, activates the min of carboxyl 30, adds catalyst DMAP（DMAP）；
（4）Take 0.5 g triptolides and be dissolved in 5 mL pyridines, and be transferred in multi-arm polyethylene glycol solution, 35 DEG C are reacted overnight,
And continuously it is passed through nitrogen, the water of removal esterification generation；
（5）To in reacted mixed liquor 1:3（v/v）Ratio add absolute ether, there is flocculent deposit, 4000 rpm centrifugations
30 min, collect precipitation, and continuation is washed precipitation with ether twice, solids of sedimentation is collected by centrifugation, and is vacuum dried, and obtains the poly- second of multi-arm
Glycol-triptolide white powder；
（6）Take the g of above-mentioned powder 1 and be dissolved in 10 mL pyridines, add folic acid derivatives, EDC and DMAP 48 h to be reacted, after reaction
Mixed liquor in 1:3（v/v）Ratio add absolute ether, 4000 rpm that 30 min are centrifuged, collect precipitation, continuation washed with ether
Wash precipitation twice, solids of sedimentation is collected by centrifugation；
（7）Above-mentioned gained solids of sedimentation is dissolved in deionized water, is dialysed with PBS 12 h of dialysis, and gentle agitation
Outer liquid, accelerates dialysis speed, and extracellular fluid dialysis are changed every 4 h；
（8）By the subzero 80 DEG C of freeze overnights of above-mentioned dialysate, and the h of freeze-drying 48, folic acid-multi-arm polyethylene glycol-Thunder God is obtained
Rattan A prime yellow powder；
（9）Take above-mentioned powder and be dissolved in dimethyl sulfoxide (DMSO) jointly with HCPT in right amount, stir, be then slowly dropped into acutely
In the deionized water of stirring, self assembly obtains nano-particle, and the rpm of solution 8000 is centrifuged into 30 min, collects sediment, again
In deionized water, dialyse 6 h, the subzero 80 DEG C of freeze overnights of dialysate, and the h of freeze-drying 48, obtains yellow powder for dispersion,
As folate-targeted multi-arm polyethylene glycol-triptolide（HCPT）Nano medication.
Embodiment two
（1）Take 1 g folic acid to be dissolved in dimethyl sulfoxide (DMSO), add 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide hydrochlorides
Salt（EDC）Activation 30min, adds activator N-hydroxy-succinamide and ethylenediamine, and the mL of pyridine 5 reacts 12 h；
（2）To 3V ether is added in above-mentioned solution, folic acid derivatives are precipitated, sediment is centrifuged, and the repeatedly washing that adds diethyl ether, most
Sediment vacuum drying, obtains yellow powder afterwards；
（3）Multi-arm polyethylene glycol is scattered in pyridine, concentration is 0.01-5 mg/mL, magnetic agitation 10-30 min, makes its molten
Solution, adds EDC, activates the min of carboxyl 30, adds catalyst DMAP（DMAP）；
（4）Take 0.5 g triptolides and be dissolved in 5 mL pyridines, and be transferred in multi-arm polyethylene glycol solution, 35 DEG C are reacted overnight,
And continuously it is passed through nitrogen, the water of removal esterification generation；
（5）To in reacted mixed liquor 1:3（v/v）Ratio add absolute ether, there is flocculent deposit, 4000 rpm centrifugations
30 min, collect precipitation, and continuation is washed precipitation with ether twice, solids of sedimentation is collected by centrifugation, and is vacuum dried, and obtains the poly- second of multi-arm
Glycol-triptolide white powder；
（6）Take the g of above-mentioned powder 0.05 and be dissolved in pyridine, add folic acid derivatives 0.5 g, EDC and DMAP, 48 h are reacted, to reaction
1 in mixed liquor afterwards:3（v/v）Ratio add absolute ether, 4000 rpm be centrifuged 30 min, collect precipitation, continue to use ether
Washing precipitation twice, is collected by centrifugation solids of sedimentation；
（7）Above-mentioned gained solids of sedimentation is dissolved in deionized water, is dialysed with PBS 12 h of dialysis, and gentle agitation
Outer liquid, accelerates dialysis speed, and extracellular fluid dialysis are changed every 4 h；
（8）By the subzero 80 DEG C of freeze overnights of above-mentioned dialysate, and the h of freeze-drying 48, folic acid-multi-arm polyethylene glycol-Thunder God is obtained
Rattan A prime yellow powder；
（9）Take the g of above-mentioned powder 0.01 and 0.01 g HCPTs are dissolved in dimethyl sulfoxide (DMSO) jointly, stir, then slowly
In the deionized water that instillation is stirred vigorously, self assembly obtains nano-particle, and the rpm of solution 8000 is centrifuged into 30 min, collects precipitation
Thing, disperses in deionized water again, and dialyse 6 h, the subzero 80 DEG C of freeze overnights of dialysate, and the h of freeze-drying 48, obtains Huang
Color powder, as folate-targeted multi-arm polyethylene glycol-triptolide（HCPT）Nano medication.
Embodiment three
（1）Take 1 g folic acid to be dissolved in dimethyl sulfoxide (DMSO), add 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide hydrochlorides
Salt（EDC）Activation 30min, adds activator N-hydroxy-succinamide and ethylenediamine, and the mL of pyridine 5 reacts 12 h；
（2）To 3V ether is added in above-mentioned solution, folic acid derivatives are precipitated, sediment is centrifuged, and the repeatedly washing that adds diethyl ether, most
Sediment vacuum drying, obtains yellow powder afterwards；
（3）Multi-arm polyethylene glycol is scattered in pyridine, concentration is 0.01-5 mg/mL, magnetic agitation 10-30 min, makes its molten
Solution, adds EDC, activates the min of carboxyl 30, adds catalyst DMAP（DMAP）；
（4）Take 0.5 g triptolides and be dissolved in 5 mL pyridines, and be transferred in multi-arm polyethylene glycol solution, 35 DEG C are reacted overnight,
And continuously it is passed through nitrogen, the water of removal esterification generation；
（5）To in reacted mixed liquor 1:3（v/v）Ratio add absolute ether, there is flocculent deposit, 4000 rpm centrifugations
30 min, collect precipitation, and continuation is washed precipitation with ether twice, solids of sedimentation is collected by centrifugation, and is vacuum dried, and obtains the poly- second of multi-arm
Glycol-triptolide white powder；
（6）Take the g of above-mentioned powder 0.2 and be dissolved in pyridine, add folic acid derivatives, EDC and DMAP to react 48 h, to reacted mixed
Close 1 in liquid:3（v/v）Ratio add absolute ether, 4000 rpm be centrifuged 30 min, collect precipitation, continuation wash with ether sink
Form sediment twice, solids of sedimentation is collected by centrifugation；
（7）Above-mentioned gained solids of sedimentation is dissolved in deionized water, is dialysed with PBS 12 h of dialysis, and gentle agitation
Outer liquid, accelerates dialysis speed, and extracellular fluid dialysis are changed every 4 h；
（8）By the subzero 80 DEG C of freeze overnights of above-mentioned dialysate, and the h of freeze-drying 48, folic acid-multi-arm polyethylene glycol-Thunder God is obtained
Rattan A prime yellow powder；
（9）Take the g of the above-mentioned powder 0.2 and g of HCPT 0.1 and be dissolved in dimethyl sulfoxide (DMSO) jointly, stir, then slow drop
Enter in the deionized water being stirred vigorously, self assembly obtains nano-particle, the rpm of solution 8000 is centrifuged 30 min, collect precipitation
Thing, disperses in deionized water again, and dialyse 6 h, the subzero 80 DEG C of freeze overnights of dialysate, and the h of freeze-drying 48, obtains Huang
Color powder, as folate-targeted multi-arm polyethylene glycol-triptolide（HCPT）Nano medication.
Claims (7)
1. a kind of preparation of cancer target multi-arm polyethylene glycol-triptolide Nano medication, it is characterised in that：
Described self assembly targeting folic acid cancer therapy drug is to be coupled to form pro-drug by multi-arm polyethylene glycol and triptolide,
Folic acid with ethylene diamine-modified into the reaction terminal groups with amino, and prodrug coupling, and with another cancer therapy drug HCPT
Self assembly prepares multi-arm polyethylene glycol-triptolide（HCPT）Nano medication.
2. comprise the following steps that：
（1）Folic acid is dissolved in dimethyl sulfoxide (DMSO), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides are added
（EDC）Activation 30 minutes, adds activator N-hydroxy-succinamide and ethylenediamine, and 5 milliliters of pyridine reacts 12 hours；
（2）To 3 times of ether of volume are added in above-mentioned solution, folic acid derivatives are precipitated, sediment is centrifuged, and added diethyl ether repeatedly
Washing, last sediment vacuum drying, obtains yellow powder；
（3）Multi-arm polyethylene glycol is scattered in pyridine, concentration is 0.01-5 mg/mls, magnetic agitation 10-30 minutes, is made
Its dissolving, adds EDC, activation carboxyl 30 minutes to add catalyst DMAP（DMAP）；
（4）Take appropriate triptolide and be dissolved in pyridine, and be transferred in multi-arm polyethylene glycol solution, 35 DEG C of reactions overnight, and connect
It is continuous to be passed through nitrogen, the water of removal esterification generation；
（5）To in reacted mixed liquor 1:3（Volume ratio）Ratio add absolute ether, there is flocculent deposit, 4000 leave
The heart 30 minutes, collects precipitation, and continuation is washed precipitation with ether twice, solids of sedimentation is collected by centrifugation, and is vacuum dried, and obtains multi-arm and gathers
Ethylene glycol-triptolide white powder；
（6）Take above-mentioned powder and be dissolved in pyridine in right amount, add folic acid derivatives, EDC and DMAP to react 48 hours, to reacted
1 in mixed liquor:3（Volume ratio）Ratio add absolute ether, 4000 leave the heart 30 minutes, collect precipitation, and continuation washed with ether
Wash precipitation twice, solids of sedimentation is collected by centrifugation；
（7）Above-mentioned gained solids of sedimentation is dissolved in deionized water, is dialysed 12 hours with PBS, and gentle agitation is saturating
The outer liquid of analysis, accelerates dialysis speed, and extracellular fluid dialysis were changed every 4 hours；
（8）By the subzero 80 DEG C of freeze overnights of above-mentioned dialysate, and freeze-drying 48 hours, obtain folic acid-multi-arm polyethylene glycol-thunder
Public rattan A prime yellow powder；
（9）Take above-mentioned powder and be dissolved in dimethyl sulfoxide (DMSO) jointly with HCPT in right amount, stir, be then slowly dropped into acutely
In the deionized water of stirring, self assembly obtains nano-particle, and solution 8000 is left into the heart 30 minutes, collects sediment, divides again
Dissipate in deionized water, dialyse 6 hours, the subzero 80 DEG C of freeze overnights of dialysate, and freeze-drying 48 hours, obtain yellow powder
End, as folate-targeted multi-arm polyethylene glycol-triptolide（HCPT）Nano medication.
3. the preparation of a kind of cancer target multi-arm polyethylene glycol-triptolide Nano medication according to claim 1, its
It is characterised by：
The multi-arm polyethylene glycol can be single armed, four arms or eight arm polyethylene glycol, can contain different functional groups, from different water repellents
Medicine reacts, and between molecular weight 2000 ~ 80000.
4. the preparation of a kind of cancer target multi-arm polyethylene glycol-triptolide Nano medication according to claim 1, its
It is characterised by：
Described insoluble in water medicine triptolide is still applied to other water repellent medicines, such as black bearberry containing response function group
Acid.
5. the preparation of a kind of cancer target multi-arm polyethylene glycol-triptolide Nano medication according to claim 1, its
It is characterised by：
Described packaging medicine HCPT can be substituted by the strong medicine of other hydrophobicitys, or nano level metal, nanometer
Level metal oxide.
6. the preparation of a kind of cancer target multi-arm polyethylene glycol-triptolide Nano medication according to claim 1, its
It is characterised by：
Described pyridine tetrahydrofuran, dimethyl sulfoxide (DMSO) equal solvent replacement, its coupling method stands good.
7. the preparation of a kind of cancer target multi-arm polyethylene glycol-triptolide Nano medication according to claim 1, its
It is characterised by：
Described nano particle diameter is homogeneous, and less than 100nm.
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| CN107281165A (en) * | 2017-07-28 | 2017-10-24 | 上海中医药大学附属岳阳中西医结合医院 | A kind of triptolide folate-targeted Nano medication and its preparation method and application |
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| CN116284746A (en) * | 2023-03-23 | 2023-06-23 | 盘锦凯正医药科技有限公司 | Four-arm PEG artesunate and application thereof |
| CN116284746B (en) * | 2023-03-23 | 2024-04-30 | 盘锦凯正医药科技有限公司 | Four-arm PEG artesunate and application thereof |
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