CN105693544B - Small molecule material and preparation method and application for antineoplastic delivering - Google Patents
Small molecule material and preparation method and application for antineoplastic delivering Download PDFInfo
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- CN105693544B CN105693544B CN201610124031.7A CN201610124031A CN105693544B CN 105693544 B CN105693544 B CN 105693544B CN 201610124031 A CN201610124031 A CN 201610124031A CN 105693544 B CN105693544 B CN 105693544B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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Abstract
The invention discloses a kind of small molecule material for antineoplastic delivering and preparation method thereof and medicine application is carried, its small molecule material is connected with diamines by peptide bond by the D glucono-delta-lactones of two molecule carboxylated and formed.The small molecule material of the present invention is used for taxol, Doxorubicin, the delivering of the antineoplastics such as camptothecine, it can be by being self-assembly of nano-micelle in water by the prodrug bonded together to form with these medicines, improve the water solubility and biocompatibility of medicine, and the passive target under tumour EPR effects, improve medicine the effect of and bioavilability.
Description
Technical field
The present invention relates to organic chemistry and nanometer pharmaceutical technology field, specifically a kind of antineoplastic that is used for delivers
Small molecule material and preparation method and carry medicine application.
Background technology
As Global Environmental Problems increasingly highlight, mankind's behavioral activity increase related to carcinogenicity, global tumor invasion
Rate persistently raises.Chemotherapy is still one of Main Means for the treatment of tumour at present, and traditional antineoplastic is due to water solubility
Difference, lack the reason such as tumor tissues targeting and toxic side effect, clinical practice is restricted.In order to overcome these limitations to obtain
More preferable therapeutic effect, antineoplastic is achieved into many gratifying achievements by practice of pharmacy.Such as will be antitumor
Medicine carries out the general good water solubility of prodrug made from chemical coupling, tool targeting with water soluble polymer.Separately there is researcher to resist
Tumour medicine makes inclusion enclave, or liposome, also has researcher to make macromolecule micelle, vesica and high molecular nanometer grain.Although
The nanosystems that the studies above obtains show tolerance increase in Study of cytotoxicity, water-soluble improved, preferably in vitro
The gratifying results such as the target administration that histocompatbility and utilization EPR effects obtain, but said system also respectively has certainly
Oneself weak point, some building-up processes are complicated, cost is higher is unfavorable for industrialized production, and some drugloading rates are too low, some chis
Very little too small or too big, then rate of releasing drug is too small or too big for some.
Nano-micelle prodrug administration nano-drug administration system is that solve traditional anti-tumor medicine and its derivative poorly water-soluble, be also easy to produce
Multidrug resistance, do not have one of method for the problems such as targeting and therapeutic index are poor, the system is made up of two parts, positioned at core
The heart is usually lipophilic antineoplastic, and what it is positioned at core periphery is then hydrophilic molecule.Formed after nano-micelle
A certain amount of free antineoplastic can also be added under certain conditions, and the medicine can be identical or be not
With, so as to open a road for drug combination, the drugloading rate of nano-micelle prodrug system can be dramatically increased.Nano-micelle
Prodrug can form 20-200nm particle diameter, and such size will not both enter between Normal tissue vascular because of too small in vivo
Gap also will not can not enter the vascular space of tumor tissues because of too big, so as to not produce or seldom produce under toxic side effect
Play stronger targeted therapy effect.
This system of nano-micelle prodrug is the advantages of combining both liposome and Macromolecule Prodrug：Liposome typically wraps
Free cancer therapy drug is wrapped up in, drugloading rate is bigger；And Macromolecule Prodrug typically has an acid-sensitive or thermo-responsive, but the system one
As building-up process complexity drugloading rate it is relatively low.Research also shows that nano-micelle prodrug typically has more compared with other drugs system
Circulation time, more preferable stability and targeting inside length.
Through being connected to the water-soluble sugar analog derivative of existing literature exploration discovery, fat-soluble antineoplastic and certain length
The prodrug enabled to is self-assembly of nano-micelle in aqueous, reduces the toxic side effect of medicine, and carboxylated can enter one
The water solubility and drugloading rate of step enhancing Macromolecule Prodrug, have higher application prospect.
The content of the invention
It is an object of the invention to provide a kind of small molecule material and preparation method, this method be maltonic acid-δ-
On the basis of lactone, two molecule glucose acid are connected by diamines, then by glucose carboxylated, form the small molecule material
Material.
It is a further object of the present invention to provide a kind of application of small molecule material in antineoplastic delivering, i.e., for anti-
The problems such as poorly water-soluble of tumour medicine, using above-mentioned small molecule material, design, synthesize, assembling nano-micelle prodrug, improving
The water solubility and bioavilability of antineoplastic, and using the EPR effect passive targets of tumour, improve the medicine of tumor locus
Thing concentration, poisonous side effect of medicine is reduced, to obtain more preferable antitumor curative effect.
Realizing the concrete technical scheme of the object of the invention is：
A kind of small molecule material for antineoplastic delivering, it is characterised in that the small molecule material has as follows
Structure：
Wherein：M=2,3,4,5 or 6；N=2,3 or 4.Small molecule material is connected the nano-micelle particle diameter energy to be formed with medicine
Enough control between 100~200nm, particle diameter distribution PDI is 0.1~0.3.
A kind of preparation method of above-mentioned small molecule material, feature are that this method includes step in detail below：
1) didextrose saccharic acid acid amides GTG is prepared
Dry DMF is added in single neck round-bottom flask equipped with magnet rotor, nitrogen stream protection is lower to be added
Enter maltonic acid-delta-lactone GAL and anhydrous diamines.1g maltonic acid-delta-lactone corresponds to N,N-dimethylformamide
30mL, the mol ratio of maltonic acid-delta-lactone and anhydrous diamines is 2: 1, by above-mentioned reaction system under nitrogen protective condition
12h is reacted under the conditions of 80 DEG C.After reaction terminates, there are a large amount of white solid matters to occur in system, after being down to room temperature, add about
Acetone (chemistry is pure), 1g maltonic acid-delta-lactone correspond to acetone 30mL, and more white solid matters separate out.Use incipient fusion
Glass funnel (G3) filters, and gained white solid is washed after 3 times with a small amount of acetone on filter cake is placed in 6h in 45 DEG C of vacuum drying chambers and obtains
White solid didextrose saccharic acid acid amides GTG；
2) carboxylated didextrose saccharic acid acid amides CAG is prepared
Added in the single neck pear shape bottle of drying equipped with magnet rotor and dry dimethyl sulfoxide (DMSO), didextrose sugar is added under nitrogen stream
Sour acid amides GTG, dicarboxylic anhydride and DMAP, 1g didextrose saccharic acid acid amides correspond to dimethyl sulfoxide (DMSO) 10mL, didextrose sugar
Sour acid amides is 1: 13: 1.1 with the mol ratio of dicarboxylic anhydride and DMAP.The reaction reacts 24h under the conditions of 65 DEG C.Will
Reacted solution rotating is concentrated by evaporation to about half solvent.Room temperature is cooled to, is slowly added to solvent equivalent under fast stirring
Deionized water, then by this dilution loaded on molecular cut off be 1000 bag filter in dialyse, be freeze-dried to obtain cotton-shaped coffee
Coffee color solid carboxylated didextrose saccharic acid acid amides CAG.
A kind of load medicine application of above-mentioned small molecule material, the load medicine, which is applied, includes step in detail below：
Dry DMF is added in single neck pear shape bottle equipped with magnet rotor, is sequentially added under nitrogen stream
Carboxylated didextrose saccharic acid acid amides, antineoplastic, DMAP, with ice-water bath by reaction system after solution dissolved clarification
0 DEG C is cooled to, slowly adds 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides by several times.1g carboxylated didextroses
Saccharic acid acid amides corresponds to 10~15mL of DMF, carboxylated didextrose saccharic acid acid amides and antineoplastic, 4- diformazans
Aminopyridine, the mol ratio of 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides are 1: 1: 1.1: 4, are warmed to room temperature
16h is reacted, under high degree of agitation, reaction system is slowly poured into 0.3mol/L sodium bicarbonate solution, the Portugal of 1g carboxylated two
Saccharic acid acid amides corresponds to 20~30mL of sodium bicarbonate solution, by obtained solution loaded on the bag filter that molecular cut off is 10000
Middle dialysis, it is freeze-dried to obtain coffee-like fluffy solid CAG-Drug.CAG-Drug is in aqueous by being self-assembly of nanometer
Micella.Its particle diameter, particle diameter distribution and surface charge are determined by dynamic light scattering, and nano-micelle shape is observed with transmission electron microscope
Looks, its drugloading rate and hemolytic are determined with ultraviolet absorption method, the cytotoxicity of nano-micelle is determined with the methods of CCK 8.
The dialysis refers to：Reaction solution after filtering is placed in by the bag filter that selective retention molecular weight is 1000 or 10000
Dialysed 48~60 hours in deionized water, change a water within every 3 hours, change a water within every 12 hours after 12 hours, then freezing is dry
It is dry.
Described load medicine application, the load medicine are applied suitable for hydroxyl (- OH), amino (- NH2) antineoplastic pass
Send.
The hydroxyl (- OH), amino (- NH2) antineoplastic for taxol, Docetaxel, adriamycin, camplotheca acuminata
Alkali or gemcitabine.
The small molecule nano-micelle prodrug of the present invention promotes ester bond to crack under acidic cancer environment, and antineoplastic is from load
Discharged on body, sustained drug is accumulated in tumor tissues, the application in terms for the treatment of lung cancer, breast cancer.
The small molecule prodrugs that small molecule material and the antineoplastic of the present invention is formed being capable of self assembly shape in aqueous
Into nano-micelle, the water solubility of medicine is improved, passive target tumor locus, reduce the toxic side effect of medicine, improve the life of medicine
Thing availability, to overcome the undesirable bottleneck of chemotherapeutics clinical practice.
Brief description of the drawings
Fig. 1 is didextrose saccharic acid acid amides of the present invention1H NMR scheme；
Fig. 2 is small molecule material of the present invention1H NMR scheme；
Fig. 3 is that small molecule material of the present invention carries prodrugs of paclitaxel1H NMR scheme；
Fig. 4 is the grain size distribution that small molecule material of the present invention carries prodrugs of paclitaxel；
Fig. 5 is the surface potential figure that small molecule material of the present invention carries prodrugs of paclitaxel；
Fig. 6 is the transmission electron microscope picture that small molecule material of the present invention carries prodrugs of paclitaxel；
Fig. 7 is the hemolytic figure that small molecule material of the present invention carries prodrugs of paclitaxel；
Fig. 8 is the vitro cytotoxicity figure that small molecule material of the present invention carries prodrugs of paclitaxel；
Fig. 9 is that small molecule material of the present invention carries result of the test inside prodrugs of paclitaxel.
Embodiment
In order to be better understood from the present invention, below with embodiment come the present invention is furture elucidated, but present disclosure is not
It is limited only to Examples below.
Embodiment 1
N, N '-(ethane -1,2- diyls)-didextrose saccharic acid acid amides preparation
The DMF that 150mL is dried is added in single neck round-bottom flask equipped with magnet rotor, nitrogen stream is protected
Shield is lower to add maltonic acid-delta-lactone (5.0g, 0.028mol) and anhydrous ethylenediamine (0.945mL, 0.014mol).In nitrogen
Above-mentioned reaction system is reacted into 12h under the conditions of 80 DEG C under protective condition.After reaction terminates, there are a large amount of white solid things in system
Matter occurs, and after being down to room temperature, adds about 150mL reagent pure acetones, more white solid matters separate out.Use sintered glass funnel
(G3) filter, at 45 DEG C after gained white solid washes 3 times with 50mL acetone on filter cake, 6h is dried under the conditions of 0.01mPa.Gained is white
Color solid N, N '-(ethane -1,2- diyl)-didextrose saccharic acid acid amides are 5.2g, yield 89%.
The N that will be obtained, N '-(ethane -1,2- diyl)-didextrose saccharic acid acid amides are dissolved in deuterated water, in the core of Brooker 400,000,000
Hydrogen spectrum scanning is carried out under magnetic resonance device, nuclear magnetic spectrum is as shown in Figure 1.
Embodiment 2
It is prepared by carboxylated N, N '-(ethane -1,2- diyls)-didextrose saccharic acid acid amides
50mL is added in the single neck pear shape bottle of drying equipped with magnet rotor and dries dimethyl sulfoxide (DMSO), N is added under nitrogen stream,
N '-(ethane -1,2- diyl)-didextrose saccharic acid acid amides (5.0g, 0.012mol), succinic anhydride (14.42g, 0.144mol), 4-
Dimethylamino naphthyridine (0.46g, 0.012mol).The reaction system after 24h is reacted under the conditions of 65 DEG C when being cooled to 55~60 DEG C
Rotary evaporation is concentrated into about 30mL.It is cooled to after room temperature and is slowly added to about 30mL deionized waters under fast stirring, then will be dilute
Release liquid and pour into the dialysis membrane that molecular cut off is 1000 and dialysed 36h with deionized water, change a water during beginning per 3h, after 12h
A water is changed per 12h.Freeze-drying obtains the N of cotton-shaped coffee-like solid carboxylated, N '-(ethane -1,2- diyls)-didextrose sugar
Sour acid amides 14.12g (yield 83%).
By the N of obtained carboxylated, N '-(ethane -1,2- diyl)-didextrose saccharic acid acid amides is dissolved in deuterated water, in cloth Shandong
Hydrogen spectrum scanning is carried out under gram 400,000,000 NMRs, nuclear magnetic spectrum is as shown in Figure 2.
Embodiment 3
Prepare small molecule material paclitaxel loaded prodrug
The DMF that 30mL is dried is added in single neck pear shape bottle equipped with magnet rotor, under nitrogen stream successively
The N of addition carboxylated, N '-(ethane -1,2- diyl)-didextrose saccharic acid acid amides (2.0g, 1.14mmol), taxol (1.2g,
1.41mmol), DMAP 0.17g (1.41mmol), after dissolved clarification with ice-water bath by reaction system be cooled to 0 DEG C with
Under, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (1.1g, 5.74mmol), time interval are added in four batches
For 5min.Start timing after reaction system is warmed to room temperature, reaction [silica gel plate is monitored with TLC；Mobile phase is chloroform：First
Alcohol=10: 1, Rf(taxol)=0.55, Rf(prodrug)=0.0], under the strong stirring of about 16 hours reaction time, reaction system is delayed
Slowly 50mL sodium bicarbonate solutions (0.3mol/L) are added to, pay attention to this process it is noted that adding speed and addition, otherwise have
A large amount of bubbles are released, and are taken a large amount of products out of and are caused yield to be remarkably decreased.Retention molecule is added to after temperature is cooled to room temperature
In measuring in the dialysis membrane for 10000, dialyse 36h (just having started to change a water in every 3 hours, change a water in 12 hours after 12 hours).
The liquid level in dialysis membrane is noted too that while in the process, is shunted if necessary.After dialysis terminates, with 0.45 μm of filtering head mistake
Filter, is freeze-dried to obtain coffee-like cotton-shaped small molecule material paclitaxel loaded prodrug (3.17g, 99.06%).
It is 35% that obtained small molecule, which carries prodrugs of paclitaxel and measures drug loading with ultraviolet spectrophotometry, maximum in water
Solubility is 200mg/mL.
Obtained small molecule load prodrugs of paclitaxel is dissolved with deuterated water, carried out under the NMR of Brooker 400,000,000
Hydrogen spectrum scanning, nuclear magnetic spectrum are as shown in Figure 3.
Embodiment 4
Configure small molecule and carry prodrugs of paclitaxel 1mg/mL, ultrasound stands 2 minutes after 5 minutes, with Malvern laser particle analyzer
Its particle size, particle diameter distribution and surface potential are determined, Fig. 4 shows nano particle footpath narrowly distributing, particle size about 114nm.Fig. 5
It is -23.3 to show average surface current potential.
Embodiment 5
The nano-micelle transmission electron microscope picture that small molecule paclitaxel loaded prodrug is self-assembly of refers to Fig. 6, and Fig. 6 shows nanometer
The spherical and size that is shaped as of particle is 90nm or so.
Embodiment 6
Small molecule material carries the hemolytic evaluation of prodrugs of paclitaxel
The red blood cell suspension of fresh rat is taken, is 2% (v/v) red blood cell suspension with normal saline volume ratio,
2% suspension prepared and a series of small molecule material of concentration are carried into prodrugs of paclitaxel solution, polyoxyethylene groups castor-oil plant
The solution of red blood cells of oil and Tween 80 mixes.Two groups of negative controls and positive control are set in addition, 37 DEG C of constant temperature are placed in after being mixed
Incubated in case.Start every observation in 15 minutes once, after 4 times every observation in 1 hour once.After 3 hours, by sample solution from
With 2000r/min pelleted by centrifugation 5 minutes in scheming, gentle aspiration supernatant determines absorbance A value under 416nm wavelength.According to
Equation below calculates hemolysis rate：Hemolysis rate=(sample A values-negative control A values)/(positive control A values-negative control A values) ×
100%, wherein 9% physiological saline is negative control, distilled water is positive control.
Molecular material carries the hemolytic of prodrugs of paclitaxel as shown in fig. 7, under 10mg/mL concentration, small molecule material
Material carries prodrugs of paclitaxel and does not have hemolytic still, has very strong adaptability to red blood cell.
Embodiment 7
Small molecule carries the Cytotoxic evaluation of prodrugs of paclitaxel
Using CCK-8 methods, by the good non-small cell lung cancer H460 cells of growth conditions with certain density kind in 96 orifice plates
In, 37 DEG C are placed in, 5%CO2Constant incubator in cultivate 24 hours after add the small molecule materials of concentration a series of, taxol
And small molecule material carries prodrugs of paclitaxel sample, 10 microlitres of CCK-8 solution, 37 DEG C of constant temperature are added per hole after continuing culture 48 hours
4h is placed in concussion case, the absorbance (OD) of each hole cell liquid on 96 orifice plates is determined with ELIASA, cell survival rate is according to following
Formula is calculated：
Cell survival rate=(OD samples/OD controls) Χ 100%
OD samples：To add the absorbance of the cell liquid of each concentration samples
OD is compareed：For the absorbance of blank nutrient solution
Each sample sets 6 Duplicate Samples, cell survival rate as shown in figure 8, explanation small molecule material to cell substantially without
Lethal effect, and small molecule material carries prodrugs of paclitaxel compared to active compound, there is obvious reduction in cytotoxicity.
Embodiment 8
Small molecule carries result of the test inside prodrugs of paclitaxel
In order to evaluate antitumor activity inside CAG-PTX nano-micelle prodrugs deeper into ground, by the nanometer of various dose
Micelle prodrug is entered by tail vein injection in the nude mouse of Non-small cell lung carcinoma model.Usually, by 36 6-8 weeks big, bodies
Weight is that 20-25g nude mice is randomly divided into 6 groups, every group 6.0.1mL is injected by the left shoulder position of nude mice and contains 4 × 106It is personal
Non-small cell lung cancer cell.The nude mice for having injected cancer cell is placed in Animal House and raised according to associated international standards, with trip
The volume of slide calliper rule periodic measurement tumour is marked, until volume reaches 100 cubic millimeters of (mm3) when begin through nude mice tail vein injection
The medicine or reference substance of respective amount.The volume calculation formula of wherein tumor tissues is：V=W2L/2, wherein W are the most wide of tumour
Numerical value, L are the most long numerical value of tumour, and unit is millimeter (mm).The volume of the body weight of measurement nude mice and tumour daily, Zhi Daosheng
The gross tumor volume of reason saline control group reaches 3000mm3。
Anti-tumor experiment result directly reflects life of the medicine in complexity inside the nude mouse tumor model of non-small cell lung cancer
The effect of tumour cell is killed under the conditions of reason.From experimental result as can be seen that CAG-PTX nano-micelle prodrugs in vivo anti-swollen
Clearly, the volume of the nude mice of physiological saline group tumour in 11 days is via 100mm under identical experiment condition for knurl effect3
Rapidly increase to 1500mm3, non-small cell lung cancer volume increases very rapid in this experiment, there is the tumour of physiological saline group
Volume increased 100mm in one day3, this is probably because different nude mice constitutions is different or inoculation non-small cell lung cancer cell
When quantity it is larger caused by, but the gross tumor volume of experimental group is substantially suppressed, and when dosage is 300mg/kg
The body weight of nude mice is not affected, but the growth of tumour substantially receives suppression, and growth is very slow, after the 9th day
300mg/kg experimental group has gross tumor volume to decline, and the gross tumor volume increase of 250mg/kg groups is more slow, experimental rat
Body weight be not affected, show while CAG-PTX nano-micelle prodrugs are reaching therapeutic effect not produce tight
The toxic side effect of weight, the tolerance of the prodrug are fine.And when the maximum tolerated dose for doing nude mice is tested, medication is up to
The body weight of nude mice does not still decline during 500mg/kg dosage, and the physiological status of nude mice is still very good.Fig. 9 swells for mouse
Knurl Volume Changes figure.
Claims (4)
1. a kind of small molecule material for antineoplastic delivering, it is characterised in that the small molecule material has knot as follows
Structure：
Wherein：M=2,3,4,5 or 6；N=2,3 or 4；Small molecule material is connected the nano-micelle particle diameter to be formed with medicine and can controlled
For system between 100~200nm, particle diameter distribution PDI is 0.1~0.3.
2. the preparation method of small molecule material described in a kind of claim 1, it is characterised in that this method includes step in detail below：
1) didextrose saccharic acid acid amides GTG is prepared
Dry DMF is added in single neck round-bottom flask equipped with magnet rotor, nitrogen stream protection is lower to add D-
Glucono-δ-lactone GAL and anhydrous diamines；1g maltonic acid-delta-lactone corresponds to DMF 30mL, D-
The mol ratio of glucono-δ-lactone and anhydrous diamines is 2:1, by above-mentioned reaction system in 80 DEG C of bars under nitrogen protective condition
12h is reacted under part；After reaction terminates, there are a large amount of white solid matters to occur in system, after being down to room temperature, add chemistry pure third
Ketone, 1g maltonic acid-delta-lactone correspond to acetone 30mL, and more white solid matters separate out；With sintered glass funnel mistake
Filter, gained white solid is washed after 3 times with chemical pure acetone on filter cake is placed in 6h in 45 DEG C of vacuum drying chambers and obtains the Portugal of white solid two
Saccharic acid acid amides GTG；
2) carboxylated didextrose saccharic acid acid amides CAG is prepared
Added in the single neck pear shape bottle of drying equipped with magnet rotor and dry dimethyl sulfoxide (DMSO), didextrose saccharic acid acyl is added under nitrogen stream
Amine GTG, dicarboxylic anhydride and catalyst DMAP, 1g didextrose saccharic acid acid amides correspond to dimethyl sulfoxide (DMSO) 10mL, didextrose
Saccharic acid acid amides is 1 with the mol ratio of dicarboxylic anhydride and DMAP:13:1.1；The reaction reacts 24h under the conditions of 65 DEG C；
Reacted solution rotating is concentrated by evaporation to half solvent；Room temperature is cooled to, is slowly added to solvent equivalent under fast stirring
Deionized water, then by this dilution loaded on molecular cut off be 1000 bag filter in dialyse, be freeze-dried to obtain cotton-shaped coffee
Coffee color solid carboxylated didextrose saccharic acid acid amides CAG.
3. the load medicine application of small molecule material described in a kind of claim 1, it is characterised in that the load medicine, which is applied, to be included in detail below
Step：
Dry DMF is added in single neck pear shape bottle equipped with magnet rotor, carboxyl is sequentially added under nitrogen stream
Change didextrose saccharic acid acid amides, antineoplastic, DMAP, reaction system is cooled with ice-water bath after solution dissolved clarification
To 0 DEG C, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides are slowly added by several times；1g carboxylated didextrose saccharic acids
Acid amides corresponds to 10~15mL of DMF, carboxylated didextrose saccharic acid acid amides and antineoplastic, 4- dimethylaminos
Pyridine, the mol ratio of 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides are 1:1:1.1:4, it is warmed to room temperature reaction
16h, under high degree of agitation, reaction system is slowly poured into the sodium bicarbonate solution that concentration is 0.3mol/L, 1g carboxylated two
Glucose saccharic acid acid amides corresponds to 20~30mL of sodium bicarbonate solution, by obtained solution loaded on the dialysis that molecular cut off is 10000
Dialysed in bag, be freeze-dried to obtain coffee-like fluffy solid CAG-Drug；CAG-Drug is received by being self-assembly of in aqueous
Rice glue beam；Its particle diameter, particle diameter distribution and surface charge are determined by dynamic light scattering, and nano-micelle is observed with transmission electron microscope
Pattern, its drugloading rate and hemolytic are determined with ultraviolet absorption method, the cytotoxicity of nano-micelle is determined with the methods of CCK 8；Wherein, should
Carry the delivering that medicine applies the antineoplastic suitable for hydroxyl, amino；
The hydroxyl, the antineoplastic of amino are taxol, Docetaxel, adriamycin, camptothecine or gemcitabine.
4. preparation method according to claim 2, it is characterised in that the dialysis refers to：Selective retention molecular weight is 1000
Bag filter the reaction solution after filtering be placed in deionized water dialysed 48~60 hours, a water is changed within every 3 hours, after 12 hours
Change a water within every 12 hours, be then freeze-dried.
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| CN104736179A (en) * | 2012-05-07 | 2015-06-24 | 日东电工株式会社 | Polymer conjugates with a linker |
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| CN102811742A (en) * | 2010-03-11 | 2012-12-05 | 日东电工株式会社 | Carbohydrate-polyamino acid-drug conjugates |
| CN104736179A (en) * | 2012-05-07 | 2015-06-24 | 日东电工株式会社 | Polymer conjugates with a linker |
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