CN104784700B - A kind of medicine carries the preparation method of compound, micella and micella altogether - Google Patents
A kind of medicine carries the preparation method of compound, micella and micella altogether Download PDFInfo
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- CN104784700B CN104784700B CN201510226344.9A CN201510226344A CN104784700B CN 104784700 B CN104784700 B CN 104784700B CN 201510226344 A CN201510226344 A CN 201510226344A CN 104784700 B CN104784700 B CN 104784700B
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Abstract
The invention provides the preparation method that a kind of medicine carries compound, micella and micella altogether, medicine carries compound and is combined by cis-platinum, adriamycin and multi-arm copolymer altogether, and multi-arm copolymer has Formulas I structure.The medicine carries compound and forms micella in an aqueous medium altogether; PEG block is in the outer core of micella in multi-arm copolymer; polyglutamic acid block or aspartic acid block are in the kernel of micella in multi-arm copolymer; cis-platinum and adriamycin, which are among this two parts, to be protected; stabilizing it property is preferable, and unexpected release phenomenon will not occur.In addition, the carboxyl of cis-platinum and multi-arm copolymer is coordinated, there is crosslinked action, add the stability of micella；In tumor tissues or near tumor cells, adriamycin and Platinol cisplatin with quick release and can play drug effect, so as to improve curative effect of medication, reduce toxic side effect.Test result indicates that when the medicine carries compound through lung's direct administration treatment mouse melanoma metastatic lung cancer altogether, there is the effect of good suppression tumour growth.
Description
Technical field
The present invention relates to polymer drug field, more particularly to a kind of medicine carries the preparation of compound, micella and micella altogether
Method.
Background technology
Adriamycin (DOX) also known as doxorubicin, it is a kind of common anthraquinone antibiotic, is mainly used in malignant tumour and controls
Treat.Adriamycin has high toxicity and good dissolubility, it has also become the malignant tumour such as treatment acute leukemia, breast cancer, lung cancer
Medicine, be clinically widely used.But because the biological half-life of adriamycin is short, and with non-specific point
The features such as cloth, limits its effective use.In addition, the toxic side effect of adriamycin (such as cardiac damage, suppresses bone marrow growth, caused
Alopecia etc.) limit its dosage in treating malignant tumor.
In order to improve drug effect, high polymer material is often used in the carrier as drug delivery.Develop rapidly in the recent period
It is the macromolecule carrier of micron and nanoscale, such as：Micella, vesica and nano particle etc., this kind of macromolecule carrier can be effective
Drug molecule is distributed to wherein, using the various response modes of carrier, realizes conveying and the control release of medicine.Such as the patent No.
A kind of high molecule bonding adriamycin medicine, its Nano capsule and its preparation side are disclosed for 200810050407.X Chinese patent
Method, wherein, the PEG-PLA-Dox bonding medicine of preparation is the carboxylic using polyethylene glycol-polylactic acid block copolymer
The amino of base and adriamycin, which is condensed, to be formed covalent bond and realizes what adriamycin supported.
At present, existing a variety of modes that cancer therapy drug is supported using polymer support physics enter clinical research, Shao Shuoyi
Through listing, such as support the Doxil of adriamycin using liposome and utilize the Abraxane of protein encapsulation taxol.But existing
In cancer therapy drug, only a small number of such as Doxil are the adriamycin medicines prepared with physics loading mode, and using other carriers with
The research that the mode of electrostatic interaction supports adriamycin is less, far can not meet the needs in market.
The content of the invention
In view of this, it is an object of the invention to provide the preparation method that a kind of medicine carries compound, micella and micella altogether,
The compound realizes that medicine carries, has good biocompatibility altogether, and directly can be used for lung by the approach of pulmonary administration
The treatment of metastatic tumor.
The invention provides a kind of medicine to carry compound altogether, is combined by cis-platinum, adriamycin and multi-arm copolymer, described
Multi-arm copolymer has Formulas I structure：
In Formulas I, the R is-CH2COOH or-CH2CH2COOH；
a≥1；b≥1；5≤p≤200；20≤q≤250.
Preferably, the mass ratio of the multi-arm copolymer and Pt in cis-platinum is less than 15.
Preferably, the mass ratio of the multi-arm copolymer and adriamycin is less than 20.
Preferably, the multi-arm copolymer and Pt in cis-platinum mass ratio are more than 0.5 and less than 15；
The mass ratio of the multi-arm copolymer and adriamycin is more than 0.5 and less than 20.
Preferably, the preparation method of the multi-arm copolymer comprises the following steps：
By polyethyleneimine, mono methoxy polyethylene glycol and amino acid N-carboxyanhydrides hybrid reaction, deprotection, obtain
To multi-arm copolymer；
Amino acid N-the carboxyanhydrides are acid in glutamic acid N-carboxyanhydrides or aspartic acid N- carboxyl rings
Acid anhydride；
The polyethyleneimine has Formula II structure；
M and n is the degree of polymerization；The number-average molecular weight of the polyethyleneimine is 300~35000Da.
Carry complexes micelle altogether the invention provides a kind of medicine, including the medicine described in above-mentioned technical proposal carry altogether it is compound
Thing and aqueous medium.
Preferably, the aqueous medium includes water, physiological saline, cushioning liquid, tissue culture medium or body fluid.
The invention provides the preparation method that a kind of medicine carries complexes micelle altogether, comprise the following steps：By cis-platinum, Ah mould
Plain and with Formulas I structure multi-arm copolymer is compound in an aqueous medium, obtains medicine and carries complexes micelle altogether；
In Formulas I, R is-CH2COOH or-CH2CH2COOH；
a≥1；b≥1；5≤p≤200；20≤q≤250.
Preferably, the mass ratio of the multi-arm copolymer and Pt in cis-platinum is less than 15.
Preferably, the mass ratio of the multi-arm copolymer and adriamycin is less than 20.
The invention provides a kind of medicine to carry compound altogether, is combined by cis-platinum, adriamycin and multi-arm copolymer, described
Multi-arm copolymer has Formulas I structure.Medicine provided by the invention carries compound and forms micella, PEG block in an aqueous medium altogether
Outer core in micella, polyglutamic acid block or aspartic acid block are in the kernel of micella in multi-arm copolymer, cis-platinum and Ah
Mycin is among this two parts and is protected, and therefore, its stability is preferable, and unexpected release phenomenon will not occur.In addition, cis-platinum
It is coordinated with the carboxyl of multi-arm copolymer, there is crosslinked action, adds the stability of micella；In tumor tissues or tumour
Cell peripheral, adriamycin and Platinol cisplatin with quick release and can play drug effect, so as to improve curative effect of medication, reduce toxic side effect.It is real
Test result to show, medicine provided by the present invention carries compound and is directly administered treatment mouse melanoma metastatic lung cancer through lung altogether
When, the effect with good suppression tumour growth.
Brief description of the drawings
The hydrogen nuclear magnetic resonance spectrogram of multi-arm copolymer prepared by Fig. 1 embodiment of the present invention 1.
Embodiment
The invention provides a kind of medicine to carry compound altogether, is combined by cis-platinum, adriamycin and multi-arm copolymer, described
Multi-arm copolymer has Formulas I structure：
In Formulas I, the R is-CH2COOH or-CH2CH2COOH；
a≥1；b≥1；5≤p≤200；20≤q≤250.
Medicine provided by the invention carries compound altogether includes cis-platinum.Cis-platinum (CDDP) also known as cisplatin, resist
Cancer effect is stronger, is a kind of non-specific cell cycle medicine, can be acted on a variety of cancer therapy drugs, in the absence of crossing drug resistant
Property, it is a kind of one of current important medicine of combined chemotherapy antitumor agent, for treating Several Kinds of Malignancy, such as thyroid gland
Cancer, breast cancer, malignant lymphoma, rhinocarcinoma, prostate cancer and carcinoma of testis etc..But because it has Toxicity of Kidney, limit its application.
Adriamycin and Platinol cisplatin is wrapped up using macromolecule carrier, can not only its relatively low toxic side effect, and can be in tumor environment
Slow Slow release down, extend circulation time, so as to reach the purpose for improving drug effect.The present invention is not special to the source of cis-platinum
Limitation, using cis-platinum well known to those skilled in the art, can such as use its commercial goods.
Medicine provided by the invention carries compound altogether includes adriamycin.The present invention is not special to the source of the adriamycin
Limitation, using adriamycin well known to those skilled in the art, can such as use its commercial goods.
Medicine provided by the invention carries compound altogether includes multi-arm copolymer.In the present invention, the multi-arm copolymer tool
There is Formulas I structure：
In Formulas I, the R is-CH2COOH or-CH2CH2COOH；
a≥1；b≥1；5≤p≤200；20≤q≤250.
In the present invention, a is the degree of polymerization, a >=1；Preferably, 5≤a≤200；It is highly preferred that 10≤a≤150；
In the present invention, the b is the degree of polymerization, b >=1；Preferably, 5≤b≤200；It is highly preferred that 10≤b≤150；
In the present invention, the p is the degree of polymerization, 5≤p≤200；Preferably, 20≤p≤150；
In the present invention, the q is the degree of polymerization, 5≤q≤200；Preferably, 20≤q≤150.
In a particular embodiment of the present invention, the structural formula of the multi-arm copolymer is as shown in formula 101 or formula 102：
In the present invention, the mass ratio of the multi-arm copolymer and Pt in cis-platinum is preferably smaller than 15；More preferably greater than 0.5 and
Less than 15；Most preferably greater than 1 and less than 10；
The mass ratio of the multi-arm copolymer and adriamycin is preferably smaller than 20, more preferably higher than 0.5 and less than 20, optimal
Elect as more than 1 and less than 15.
The present invention does not have special limitation to the preparation method of the multi-arm copolymer with Formulas I structure, using this area skill
The technical scheme of the multi-arm copolymer with Formulas I structure is prepared known to art personnel.In the present invention, it is described that there is Formulas I
The preparation method of the multi-arm copolymer of structure preferably includes following steps：
By polyethyleneimine, amido polyethyleneglycol derivative and amino acid N-carboxylic acid ring inner-acid anhydride hybrid reaction, it is deprotected,
Obtain multi-arm copolymer；
Amino acid N-the carboxyanhydrides are acid in glutamic acid N-carboxyanhydrides or aspartic acid N- carboxyl rings
Acid anhydride；
The polyethyleneimine has Formula II structure；
M and n is the degree of polymerization；The number-average molecular weight of the polyethyleneimine is 300~35000Da.
In the present invention, the number-average molecular weight of the polyethyleneimine (PEI) is 300~35000Da, preferably 600~
25000Da.The present invention does not have special limitation to the source of the polyethyleneimine, using well known to those skilled in the art poly-
Aziridine, it can such as use its commercial goods.
In the present invention, the amido polyethyleneglycol derivative is preferably mono methoxy polyethylene glycol-acid amides-propionic acid amber
Imide ester (mPEG-NHS)；In a particular embodiment of the present invention, the molecular weight of the amido polyethyleneglycol derivative is preferred
For 1000Da~15000Da, more preferably 2000Da~10000Da.The present invention comes to the amido polyethyleneglycol derivative
Source does not have special limitation, using amido polyethyleneglycol derivative well known to those skilled in the art, can such as use it
Commercial goods.
In the present invention, the amino acid N-carboxylic acid ring inner-acid anhydride is amino acid N CA, sour in the amino acid N-carboxylic acid ring
Acid anhydride is glutamic acid N-carboxyanhydrides (glutamic acid N CA) or aspartic acid N- carboxyanhydrides (aspartic acid NCA).This hair
The bright source to the glutamic acid N CA or aspartic acid NCA does not have special limitation, using paddy well known to those skilled in the art
Propylhomoserin NCA or aspartic acid NCA.Polyaminoacid family macromolecule carrier has the structure and property similar with natural polypeptides,
It is a kind of with biological degradability, good biocompatibility, and the modifiable high polymer material of its side base, is obtained in medicine is carried
To being widely applied.
The present invention carries out polyethyleneimine, polyethylene glycol and amino acid hybrid reaction preferably under conditions of anhydrous and oxygen-free.
In the present invention, the polyethyleneimine, polyethylene glycol and amino acid are preferably reacted in organic solvent；It is described organic molten
Agent preferably includes N,N-dimethylformamide, dioxane, chloroform or dimethyl sulfoxide (DMSO)；More preferably N, N- dimethyl methyl
Acid amides or dimethyl sulfoxide (DMSO).
The present invention is preferably by polyethyleneimine and mono methoxy polyethylene glycol elder generation hybrid reaction, then added into reaction product
Amino acid N CA reacts.In the present invention, the mol ratio of the polyethylene glycol and polyethyleneimine is preferably 1：0.1~100, more
Preferably 1：0.5~50；The temperature of polyethyleneimine and the polyethylene glycol hybrid reaction is preferably room temperature, without being heated
Or cooling；The time of polyethyleneimine and the polyethylene glycol hybrid reaction is preferably 24h~72h, more preferably 48h~72h.
The present invention is preferably dialysed the product that polyethyleneimine and mono methoxy polyethylene glycol hybrid reaction obtain, and is freeze-dried,
Obtain mPEG-PEI.In a particular embodiment of the present invention, present invention preferably employs 7,000Da bag filter, deionized water is used
Dialyse 72h, changes water 6~8 times.
The present invention preferably removes water the product that freeze-drying obtains with dry toluene, then dissolves, then mixed with amino acid N CA
Close reaction.In the present invention, the mol ratio of the polyethyleneimine and amino acid N CA is preferably 1：1~100, more preferably 1：
20~80；The temperature that the reaction product and amino acid N CA of polyethyleneimine and polyethylene glycol are reacted is preferably room temperature, without
Heated or cooled；The time that the reaction product and amino acid N CA of polyethyleneimine and polyethylene glycol are reacted is preferably
24h~72h, more preferably 48h~72h.
The present invention is preferably by polyethyleneimine, amido polyethyleneglycol derivative and amino acid N carboxylic acid inner-acid anhydride hybrid reaction
Product settled, precipitum is deprotected.The present invention does not have special limitation to the method for sedimentation, using this area
Sedimentation techniques scheme known to technical staff.In a particular embodiment of the present invention, present invention preferably employs absolute ether
Settled；The volume ratio of the absolute ether and reaction product is more than 10.
The form of multiarm polymers of the present invention is not particularly limited, preferably solution or freeze-dried powder, is more preferably frozen
Dry powder.
The method that the present invention is deprotected to the precipitum with protection group is not particularly limited, and generally bromination hydroacetic acid is molten
Liquid method.In the present invention, the time of the deprotection is preferably 1h~6h, more preferably 1h~4h.
In the present invention, the hydrogen bromide acetic acid solution method specifically includes following steps：
At room temperature, the precipitum with protection group is dissolved in dichloroacetic acid, under stirring condition into obtained solution
The hydrogen bromide acetic acid solution that hydrogen bromide mass content is 33% is added, stirring reaction, reaction product is settled with ether, filtering,
Washing, dissolved with DMF after drying, dialysed in pure water, be freeze-dried, obtain the multi-arm with Formulas I structure
The freeze-dried powder of copolymer.
The present invention does not have special limitation to the method for the dialysis and frozen dried, using known to those skilled in the art
Dialysis and frozen dried technical scheme；In the present invention, the interception for the bag filter that the dialysis uses is preferably
3000Da~7000Da, more preferably 4000Da~6000Da.
Carry complexes micelle altogether present invention also offers a kind of medicine, including the medicine described in above-mentioned technical proposal carry altogether it is multiple
Compound and aqueous medium.
In the present invention, the medicine described in above-mentioned technical proposal carry altogether compound have polyethyleneimine, polyglutamic acid or
Aspartic acid and polyethylene glycol, wherein, polyethyleneimine triggers glutamic acid or aspartic acid polymerization as initiator, forms multi-arm
Controllable polymer, can act on forming hydrophobic inner core with medicine, and polyethylene glycol is hydrophilic segment.Therefore, in aqueous medium
In, nano-micelle can be self-assembled into.In the present invention, the cis-platinum and multi-arm copolymer be by coordination it is compound and
Into adriamycin with multi-arm copolymer is combined by electrostatic interaction.
The hydrodynamic radius of described complexes micelle in an aqueous medium is preferably 10nm~100nm, more preferably
For 10nm~500nm.
The aqueous medium is preferably distilled water, physiological saline, cushioning liquid, tissue culture medium or body fluid, is more preferably
Distilled water, physiological saline and cushioning liquid；The dosage of the aqueous medium is preferably 20~100mL, more preferably 50~
100mL.In a particular embodiment of the present invention, the pH value of distilled water or cushioning liquid is preferably 6.0~8.0, more preferably 7.0
~7.6.
Present invention also offers the preparation method that a kind of medicine carries complexes micelle altogether, comprise the following steps：By cis-platinum, Ah
Mycin and with Formulas I structure multi-arm copolymer it is compound in an aqueous medium, obtain medicine and carry complexes micelle altogether；
In Formulas I, R is-CH2COOH or-CH2CH2COOH；
a≥1；b≥1；5≤p≤200；20≤q≤250.
In the present invention, the cis-platinum, adriamycin, have Formulas I structure multi-arm copolymer and aqueous medium species and
Cis-platinum described in source and above-mentioned technical proposal, adriamycin, the multi-arm copolymer with Formulas I structure and aqueous medium species and come
Source is consistent, will not be repeated here.In the present invention, the mass ratio of the multi-arm copolymer and Pt in cis-platinum is preferably smaller than 15；More
Preferably greater than 0.5 and less than 15；Most preferably greater than 1 and less than 10；The mass ratio of the multi-arm copolymer and adriamycin is preferably small
In 20, more preferably higher than 0.5 and less than 20, most preferably more than 1 and less than 15.
The present invention is not particularly limited to the addition sequences of the cis-platinum, adriamycin and multiarm polymers, can first will be suitable
Platinum reacts with multiarm polymers, then adds adriamycin；Or first react adriamycin and multiarm polymers, then add suitable
Platinum；Cis-platinum, adriamycin and multiarm polymers can also be added reaction together.
In the present invention, the reaction time of the cis-platinum and multiarm polymers is preferably 24h~72h, more preferably 48~
72h；The reaction time of the adriamycin and multiarm polymers is preferably 12h~72h, more preferably 24h~72h；The cis-platinum,
Adriamycin and the compound temperature of multi-arm copolymer with Formulas I structure are preferably 20 DEG C~40 DEG C, are more preferably carried out at room temperature,
It need not be heated or be cooled.Cis-platinum, adriamycin and recombination process is excellent in an aqueous medium with the multi-arm copolymer of Formulas I structure
Elect as and carried out under the conditions of lucifuge.
In the present invention, the medicine carries complexes micelle and can also existed in the form of dry powder altogether, preferably according to following
Method is handled：
Medicine is total to and carries the dialysis of complexes micelle lucifuge, lyophilized obtain required medicine and carry complexes micelle dry powder altogether.
In the present invention, the dialysis time is preferably 24h~72h, more preferably 48h~72h, change waterside number preferably 6~
10 times, more preferably 6~8 times.
In the present invention, in the presence of the medicine carries complexes micelle in the form of dry powder altogether, as medicine carries compound altogether
Thing.The preparation method that the present invention carries compound to medicine altogether does not have special limitation, and the present invention is preferably carried altogether by said medicine
Complexes micelle is dried, you can is obtained medicine and is carried compound altogether.
The invention provides a kind of medicine to carry compound altogether, is combined by cis-platinum, adriamycin and multi-arm copolymer, described
Multi-arm copolymer has Formulas I structure.Medicine provided by the invention carries compound and forms micella, PEG block in an aqueous medium altogether
Outer core in micella, polyglutamic acid block or aspartic acid block are in the kernel of micella in multi-arm copolymer, cis-platinum and Ah
Mycin is among this two parts and is protected, and therefore, its stability is preferable, and unexpected release phenomenon will not occur.In addition, cis-platinum
It is coordinated with the carboxyl of multi-arm copolymer, there is crosslinked action, adds the stability of micella；In tumor tissues or tumour
Cell peripheral, adriamycin and Platinol cisplatin with quick release and can play drug effect, so as to improve curative effect of medication, reduce toxic side effect.It is real
Test result to show, medicine provided by the present invention carries compound and is directly administered treatment mouse melanoma metastatic lung cancer through lung altogether
When, the effect with good suppression tumour growth.
In order to further illustrate the present invention, a kind of medicine provided by the invention is carried altogether with reference to embodiment compound,
The preparation method of micella and micella is described in detail, but they can not be interpreted as into limiting the scope of the present invention.
Embodiment 1
The mPEG-NHS that 5.0g number-average molecular weights are 2000Da is added into dry reaction bottle, adds 50mL anhydrous N, N- bis-
NMF dissolves, and adds the polyethyleneimine that 1.5g molecular weight is 600Da, 24h is stirred at room temperature, in 7000Da dialysis
With deionized water dialysis 72h in bag, change water 6~8 times, be freeze-dried, obtain mPEG-PEI；
MPEG-PEI 2.6g are weighed, with toluene azeotropic water removing 3h, vacuum is drained, and adds the anhydrous N of 60mL, N- dimethyl methyls
Acid amides dissolves, and weighs in the reaction ampulla that 10.48g glutamic acid Ns CA is dried to another, vacuum is evacuated to, with syringe plus 60mL
Dry DMF is dissolved, and quickly mPEG-PEI is added into glutamic acid N CA, reacts 72h at ambient temperature.By product with 10 times
Absolute ether sedimentation more than volume, filters, washing, the compound with protection group is obtained after drying.
The compound that protection group is carried described in 2g is taken, is dissolved in 20mL dichloroacetic acid, adds 6mL hydrogen bromide mass concentrations
For 33% hydrogen bromide acetic acid solution, reaction 1h is stirred at room temperature, the excessive ether of products therefrom is settled, filtering, very
Sky is pumped through night to drying, is dissolved, is put into 7000Da bag filters with DMF, dialyse 72h, freeze-drying, room
Constant weight is dried under vacuum under temperature.
The present invention carries out nmr analysis to obtained multi-arm copolymer, as a result as shown in figure 1, Fig. 1 is the embodiment of the present invention 1
The hydrogen nuclear magnetic resonance spectrogram of the multi-arm copolymer of preparation, passes through nmr analysis and calculating, the results showed that, obtained in embodiment 1
The yield of multi-arm copolymer is 65%.
Embodiment 2
The mPEG-NHS that 5.0g number-average molecular weights are 5000Da is added into dry reaction bottle, adds 50mL anhydrous N, N- bis-
NMF dissolves, and adds the polyethyleneimine that 0.6g molecular weight is 600Da, 24h is stirred at room temperature, in 7000Da dialysis
With deionized water dialysis 72h in bag, change water 6~8 times, be freeze-dried, obtain mPEG-PEI；
MPEG-PEI2.8g is weighed, with toluene azeotropic water removing 3h, vacuum is drained, and adds 60mL anhydrous N, N- dimethyl formyls
Amine solvent, weigh in the reaction ampulla that 5.24g glutamic acid Ns CA is dried to another, be evacuated to vacuum, it is anhydrous with syringe plus 30mL
DMF is dissolved, and quickly mPEG-PEI is added into glutamic acid N CA, reacts 72h at ambient temperature.By product with 10 times of volumes
Absolute ether sedimentation above, is filtered, washing, obtains carrying the compound of protection group after drying.
The compound that protection group is carried described in 2g is taken, is dissolved in 20mL dichloroacetic acid, adds 6mL hydrogen bromide mass concentrations
For 33% hydrogen bromide acetic acid solution, reaction 1h is stirred at room temperature, the excessive ether of products therefrom is settled, filtering, very
Sky is pumped through night to drying, is dissolved, is put into 7000Da bag filters with DMF, dialyse 72h, freeze-drying, room
Constant weight is dried under vacuum under temperature.
The present invention carries out nmr analysis and calculating to obtained multi-arm copolymer, the results showed that, what is obtained in embodiment 2 is more
The yield of arm copolymer is 70%.
Embodiment 3
The mPEG-NHS that 5.0g number-average molecular weights are 10000Da is added into dry reaction bottle, adds 50mL anhydrous N, N-
Dimethylformamide dissolves, and adds the polyethyleneimine that 0.3g molecular weight is 600Da, 24h is stirred at room temperature, in the saturating of 7000Da
Analyse in bag with deionized water dialysis 72h, change water 6~8 times, be freeze-dried, obtain mPEG-PEI；
MPEG-PEI 2.65g are weighed, with toluene azeotropic water removing 3h, vacuum is drained, and adds the anhydrous N of 60mL, N- dimethyl methyls
Acid amides dissolves, and weighs in the reaction ampulla that 2.62g glutamic acid Ns CA is dried to another, is evacuated to vacuum, with syringe plus 30mL without
Water DMF is dissolved, and quickly mPEG-PEI is added into glutamic acid N CA, reacts 72h at ambient temperature.By product with 10 times of bodies
The absolute ether sedimentation of the product above, filters, washing, the compound with protection group is obtained after drying.
The compound that protection group is carried described in 2g is taken, is dissolved in 20mL dichloroacetic acid, adds 6mL hydrogen bromide mass concentrations
For 33% hydrogen bromide acetic acid solution, reaction 1h is stirred at room temperature, the excessive ether of products therefrom is settled, filtering, very
Sky is pumped through night to drying, is dissolved, is put into 7000Da bag filters with DMF, dialyse 72h, freeze-drying, room
Constant weight is dried under vacuum under temperature.
The present invention carries out nmr analysis and calculating to obtained multi-arm copolymer, the results showed that, what is obtained in embodiment 3 is more
The yield of arm copolymer is 72%.
Embodiment 4
The mPEG-NHS that 5.0g number-average molecular weights are 2000Da is added into dry reaction bottle, adds 50mL anhydrous N, N- bis-
NMF dissolves, and adds the polyethyleneimine that 1.5g molecular weight is 600Da, 24h is stirred at room temperature, in 7000Da dialysis
With deionized water dialysis 72h in bag, change water 6~8 times, be freeze-dried, obtain mPEG-PEI；
MPEG-PEI 2.6g are weighed, with toluene azeotropic water removing 3h, vacuum is drained, and adds the anhydrous N of 60mL, N- dimethyl methyls
Acid amides dissolves, and weighs in the reaction ampulla that 9.92g aspartic acids NCA is dried to another, vacuum is evacuated to, with syringe plus 60mL
Dry DMF is dissolved, and quickly mPEG-PEI is added into aspartic acid NCA, reacts 72h at ambient temperature.By product with 10
Absolute ether sedimentation more than times volume, filters, washing, the compound with protection group is obtained after drying.
The compound that protection group is carried described in 2g is taken, is dissolved in 20mL dichloroacetic acid, adds 6mL hydrogen bromide mass concentrations
For 33% hydrogen bromide acetic acid solution, reaction 1h is stirred at room temperature, the excessive ether of products therefrom is settled, filtering, very
Sky is pumped through night to drying, is dissolved, is put into 7000Da bag filters with DMF, dialyse 72h, freeze-drying, room
Constant weight is dried under vacuum under temperature.
The present invention carries out nmr analysis and calculating to obtained multi-arm copolymer, the results showed that, what is obtained in embodiment 4 is more
The yield of arm copolymer is 69%.
Embodiment 5
The mPEG-NHS that 5.0g number-average molecular weights are 5000Da is added into dry reaction bottle, adds 50mL anhydrous N, N- bis-
NMF dissolves, and adds the polyethyleneimine that 0.6g molecular weight is 600Da, 24h is stirred at room temperature, in 7000Da dialysis
With deionized water dialysis 72h in bag, change water 6~8 times, be freeze-dried, obtain mPEG-PEI；
MPEG-PEI 2.8g are weighed, with toluene azeotropic water removing 3h, vacuum is drained, and adds the anhydrous N of 60mL, N- dimethyl methyls
Acid amides dissolves, and weighs in the reaction ampulla that 4.96g aspartic acids NCA is dried to another, vacuum is evacuated to, with syringe plus 30mL
Dry DMF is dissolved, and quickly mPEG-PEI is added into aspartic acid NCA, reacts 72h at ambient temperature.By product with 10
Absolute ether sedimentation more than times volume, filters, washing, the compound with protection group is obtained after drying.
The compound that protection group is carried described in 2g is taken, is dissolved in 20mL dichloroacetic acid, adds 6mL hydrogen bromide mass concentrations
For 33% hydrogen bromide acetic acid solution, reaction 1h is stirred at room temperature, the excessive ether of products therefrom is settled, filtering, very
Sky is pumped through night to drying, is dissolved, is put into 7000Da bag filters with DMF, dialyse 72h, freeze-drying, room
Constant weight is dried under vacuum under temperature.
The present invention carries out nmr analysis and calculating to obtained multi-arm copolymer, the results showed that, what is obtained in embodiment 5 is more
The yield of arm copolymer is 72%.
Embodiment 6
The mPEG-NHS that 5.0g number-average molecular weights are 10000Da is added into dry reaction bottle, adds 50mL anhydrous N, N-
Dimethylformamide dissolves, and adds the polyethyleneimine that 0.3g molecular weight is 600Da, 24h is stirred at room temperature, 7,000Da's
With deionized water dialysis 72h in bag filter, change water 6~8 times, be freeze-dried, obtain mPEG-PEI；
MPEG-PEI 2.65g are weighed, with toluene azeotropic water removing 3h, vacuum is drained, and adds the anhydrous N of 60mL, N- dimethyl methyls
Acid amides dissolves, and weighs in the reaction ampulla that 2.48g aspartic acids NCA is dried to another, vacuum is evacuated to, with syringe plus 30mL
Dry DMF is dissolved, and quickly mPEG-PEI is added into aspartic acid NCA, reacts 72h at ambient temperature.By product with 10
Absolute ether sedimentation more than times volume, filters, washing, the compound with protection group is obtained after drying；
The compound that protection group is carried described in 2g is taken, is dissolved in 20mL dichloroacetic acid, adds 6mL hydrogen bromide mass concentrations
For 33% hydrogen bromide acetic acid solution, reaction 1h is stirred at room temperature, the excessive ether of products therefrom is settled, filtering, very
Sky is pumped through night to drying, is dissolved, is put into 7000Da bag filters with DMF, dialyse 72h, freeze-drying, room
Constant weight is dried under vacuum under temperature.
The present invention carries out nmr analysis and calculating to obtained multi-arm copolymer, the results showed that, the multi-arm that embodiment 6 obtains
The yield of copolymer is 67%.
Embodiment 7
The mPEG-NHS that 5.0g number-average molecular weights are 10000Da is added into dry reaction bottle, adds 50mL anhydrous N, N-
Dimethylformamide dissolves, and adds the polyethyleneimine that 0.9g molecular weight is 1800Da, 24h is stirred at room temperature, 7000Da's
With deionized water dialysis 72h in bag filter, change water 6~8 times, be freeze-dried, obtain mPEG-PEI；
MPEG-PEI2.95g is weighed, with toluene azeotropic water removing 3h, vacuum is drained, and adds the anhydrous N of 60mL, N- dimethyl methyls
Acid amides dissolves, and weighs in the reaction ampulla that 2.62g glutamic acid Ns CA is dried to another, is evacuated to vacuum, with syringe plus 30mL without
Water DMF is dissolved, and quickly mPEG-PEI is added into glutamic acid N CA, reacts 72h at ambient temperature.By product with 10 times of bodies
The absolute ether sedimentation of the product above, filters, washing, the compound with protection group is obtained after drying.
The compound that protection group is carried described in 2g is taken, is dissolved in 20mL dichloroacetic acid, adds 6mL hydrogen bromide mass concentrations
For 33% hydrogen bromide acetic acid solution, reaction 1h is stirred at room temperature, the excessive ether of products therefrom is settled, filtering, very
Sky is pumped through night to drying, is dissolved, is put into 7000Da bag filters with DMF, dialyse 72h, freeze-drying, room
Constant weight is dried under vacuum under temperature.
The present invention carries out nmr analysis and calculating to obtained multi-arm copolymer, the results showed that, what is obtained in embodiment 7 is more
The yield of arm copolymer is 64%.
Embodiment 8
The mPEG-NHS that 5.0g number-average molecular weights are 10000Da is added into dry reaction bottle, adds 100mL anhydrous N, N-
Dimethylformamide dissolves, and adds the polyethyleneimine that 12.5g molecular weight is 25000Da, 24h is stirred at room temperature, in 7000Da
Bag filter in deionized water dialyse 72h, change water 6~8 times, be freeze-dried, obtain mPEG-PEI；
MPEG-PEI8.75g is weighed, with toluene azeotropic water removing 3h, vacuum is drained, and adds the anhydrous N of 100mL, N- dimethyl methyls
Acid amides dissolves, and weighs in the reaction ampulla that 2.62g glutamic acid Ns CA is dried to another, is evacuated to vacuum, with syringe plus 30mL without
Water DMF is dissolved, and quickly mPEG-PEI is added into glutamic acid N CA, reacts 72h at ambient temperature.By product with 10 times of bodies
The absolute ether sedimentation of the product above, filters, washing, the compound with protection group is obtained after drying.
The compound that protection group is carried described in 2g is taken, is dissolved in 20mL dichloroacetic acid, adds 6mL hydrogen bromide mass concentrations
For 33% hydrogen bromide acetic acid solution, reaction 1h is stirred at room temperature, the excessive ether of products therefrom is settled, filtering, very
Sky is pumped through night to drying, is dissolved, is put into 7000Da bag filters with DMF, dialyse 72h, freeze-drying, room
Constant weight is dried under vacuum under temperature.
The present invention carries out nmr analysis and calculating to obtained multi-arm copolymer, the results showed that, what is obtained in embodiment 8 is more
The yield of arm copolymer is 67%.
Embodiment 9
The mPEG-NHS that 5.0g number-average molecular weights are 10,000Da is added into dry reaction bottle, adds 50mL anhydrous N, N-
Dimethylformamide dissolves, and adds the polyethyleneimine that 0.3g molecular weight is 600Da, 24h is stirred at room temperature, 7,000Da's
With deionized water dialysis 72h in bag filter, change water 6~8 times, be freeze-dried, obtain mPEG-PEI；
MPEG-PEI 2.65g are weighed, with toluene azeotropic water removing 3h, vacuum is drained, and adds the anhydrous N of 60mL, N- dimethyl methyls
Acid amides dissolves, and weighs in the reaction ampulla that 1.31g glutamic acid Ns CA is dried to another, is evacuated to vacuum, with syringe plus 30mL without
Water DMF is dissolved, and quickly mPEG-PEI is added into glutamic acid N CA, reacts 72h at ambient temperature.By product with 10 times of bodies
The absolute ether sedimentation of the product above, filters, washing, the compound with protection group is obtained after drying.
The compound that protection group is carried described in 2g is taken, is dissolved in 20mL dichloroacetic acid, adds 6mL hydrogen bromide mass concentrations
For 33% hydrogen bromide acetic acid solution, reaction 1h is stirred at room temperature, the excessive ether of products therefrom is settled, filtering, very
Sky is pumped through night to drying, is dissolved, is put into 7000Da bag filters with DMF, dialyse 72h, freeze-drying, room
Constant weight is dried under vacuum under temperature.
The present invention carries out nmr analysis and calculating to obtained multi-arm copolymer, the results showed that, what is obtained in embodiment 9 is more
The yield of arm copolymer is 61%.
Embodiment 10
The mPEG-NHS that 5.0g number-average molecular weights are 10000Da is added into dry reaction bottle, adds 50mL anhydrous N, N-
Dimethylformamide dissolves, and adds the polyethyleneimine that 0.3g molecular weight is 600Da, 24h is stirred at room temperature, in the saturating of 7000Da
Analyse in bag with deionized water dialysis 72h, change water 6~8 times, be freeze-dried, obtain mPEG-PEI.
MPEG-PEI 2.65g are weighed, with toluene azeotropic water removing 3h, vacuum is drained, and adds the anhydrous N of 60mL, N- dimethyl methyls
Acid amides dissolves, and weighs in the reaction ampulla that 5.24g glutamic acid Ns CA is dried to another, is evacuated to vacuum, with syringe plus 60mL without
Water DMF is dissolved, and quickly mPEG-PEI is added into glutamic acid N CA, reacts 72h at ambient temperature.By product with 10 times of bodies
The absolute ether sedimentation of the product above, filters, washing, the compound with protection group is obtained after drying.
The compound that protection group is carried described in 2g is taken, is dissolved in 20mL dichloroacetic acid, adds 6mL hydrogen bromide mass concentrations
For 33% hydrogen bromide acetic acid solution, reaction 1h is stirred at room temperature, the excessive ether of products therefrom is settled, filtering, very
Sky is pumped through night to drying, is dissolved, is put into 7000Da bag filters with DMF, dialyse 72h, freeze-drying, room
Constant weight is dried under vacuum under temperature.
The present invention carries out nmr analysis and calculating to obtained multi-arm copolymer, the results showed that, obtained in embodiment 10
The yield of multi-arm copolymer is 76%.
Embodiment 11
The multiarm polymers that 100mg embodiments 3 obtain are dissolved in 60mL deionized waters, adjust pH value 7.0~8.0,
Adriamycin 10mg is added, 24h is stirred under the conditions of 37 DEG C of lucifuges, cis-platinum 10mg is then added, is stirred under the conditions of 37 DEG C of lucifuges
72h, pure water dialysis 24h, changes water 6~8 times to remove free adriamycin and Platinol cisplatin, is supported adriamycin and Platinol cisplatin jointly
Complexes micelle, the micella is freeze-dried to obtain composite powder preparation.
Obtained composite powder is redissolved, embodiment 11 is determined under the conditions of 480nm using ultraviolet-visible spectrum and obtained
Micella in adriamycin content, pass through below equation calculate adriamycin it is common load micella in embedding amount (DLC)：
DLC%=carries quality × 100% of the quality of adriamycin in micella/carry altogether micella altogether
Platinum content is determined by inductive coupling plasma emission spectrograph (ICP-OES), and following public affairs are shown in its DLC calculating
Formula：
DLC%=carries quality × 100% of the quality of Pt in micella/carry altogether micella altogether
In the micella that embodiment 11 obtains, the embedding amount of adriamycin is 5.43%, and the embedding amount of cis-platinum is 4.79%.
Obtained freeze-dried powder is redissolved, and carries out potential test, its Zeta potential is -18.6 ± 3.6mV.
After freeze-dried powder redissolves, by concentration dilution to 0.1mg/mL, using dynamic scattering analysis, the stream of carrier micelle is determined
Mechanics radius, the results showed that, the hydromechanical radius for the carrier micelle that embodiment 11 obtains is between 10nm~200nm.
Embodiment 12
The multiarm polymers that 100mg embodiments 3 obtain are dissolved in 60mL deionized waters, adjust pH value 7.0~8.0,
Adriamycin 15mg is added, 24h is stirred under the conditions of 37 DEG C of lucifuges, cis-platinum 10mg is then added, is stirred under the conditions of 37 DEG C of lucifuges
72h, pure water dialysis 24h, changes water 6~8 times to remove free adriamycin and Platinol cisplatin, is supported adriamycin and Platinol cisplatin jointly
Complexes micelle, the micella is freeze-dried to obtain composite powder preparation.
Obtained composite powder is redissolved, embodiment 12 is determined under the conditions of 480nm using ultraviolet-visible spectrum and obtained
Micella in adriamycin content, platinum content pass through inductive coupling plasma emission spectrograph (ICP-OES) determine.
In the micella that embodiment 12 obtains, the embedding amount of adriamycin is 7.93%, and the embedding amount of cis-platinum is 4.36%.
Obtained freeze-dried powder is redissolved, and carries out potential test, its Zeta potential is -19.34 ± 5.4mV.
After freeze-dried powder redissolves, by concentration dilution to 0.1mg/mL, using dynamic scattering analysis, the stream of carrier micelle is determined
Mechanics radius, the results showed that, the hydromechanical radius for the carrier micelle that embodiment 12 obtains is between 15nm~200nm.
Embodiment 13
The multiarm polymers that 100mg embodiments 3 obtain are dissolved in 60mL deionized waters, adjust pH value 7.0~8.0,
Adriamycin 20mg is added, 24h is stirred under the conditions of 37 DEG C of lucifuges, cis-platinum 10mg is then added, is stirred under the conditions of 37 DEG C of lucifuges
72h, pure water dialysis 24h, changes water 6~8 times to remove free adriamycin and Platinol cisplatin, is supported adriamycin and Platinol cisplatin jointly
Complexes micelle, the micella is freeze-dried to obtain composite powder preparation.
Obtained composite powder is redissolved, embodiment 13 is determined under the conditions of 480nm using ultraviolet-visible spectrum and obtained
Micella in adriamycin content, platinum content pass through inductive coupling plasma emission spectrograph (ICP-OES) determine.
In the micella that embodiment 13 obtains, the embedding amount of adriamycin is 11.3%, and the embedding amount of cis-platinum is 4.37%.
Obtained freeze-dried powder is redissolved, and carries out potential test, its Zeta potential is -21.1 ± 2.3mV.
After freeze-dried powder redissolves, by concentration dilution to 0.1mg/mL, using dynamic scattering analysis, the stream of carrier micelle is determined
Mechanics radius, the results showed that, the hydromechanical radius for the carrier micelle that embodiment 13 obtains is between 20nm~250nm.
Embodiment 14
The multiarm polymers that 100mg embodiments 3 obtain are dissolved in 60mL deionized waters, adjust pH value 7.0~8.0,
Adriamycin 15mg is added, 24h is stirred under the conditions of 37 DEG C of lucifuges, cis-platinum 7.5mg is then added, is stirred under the conditions of 37 DEG C of lucifuges
72h, pure water dialysis 24h, changes water 6~8 times to remove free adriamycin and Platinol cisplatin, is supported adriamycin and Platinol cisplatin jointly
Complexes micelle, the micella is freeze-dried to obtain composite powder preparation.
Obtained composite powder is redissolved, embodiment 14 is determined under the conditions of 480nm using ultraviolet-visible spectrum and obtained
Micella in adriamycin content, platinum content pass through inductive coupling plasma emission spectrograph (ICP-OES) determine.
In the micella that embodiment 14 obtains, the embedding amount of adriamycin is 7.69%, and the embedding amount of cis-platinum is 3.24%.
Obtained freeze-dried powder is redissolved, and carries out potential test, its Zeta potential is -16.74 ± 5.0mV.
After freeze-dried powder redissolves, by concentration dilution to 0.1mg/mL, using dynamic scattering analysis, the stream of carrier micelle is determined
Mechanics radius, the results showed that, the hydromechanical radius for the carrier micelle that embodiment 14 obtains is between 10nm~150nm.
Embodiment 15
The multiarm polymers that 100mg embodiments 3 obtain are dissolved in 60mL deionized waters, adjust pH value 7.0~8.0,
Adriamycin 15mg is added, 24h is stirred under the conditions of 37 DEG C of lucifuges, cis-platinum 15mg is then added, is stirred under the conditions of 37 DEG C of lucifuges
72h, pure water dialysis 24h, changes water 6~8 times to remove free adriamycin and Platinol cisplatin, is supported adriamycin and Platinol cisplatin jointly
Complexes micelle, the micella is freeze-dried to obtain composite powder preparation.
Obtained composite powder is redissolved, embodiment 15 is determined under the conditions of 480nm using ultraviolet-visible spectrum and obtained
Micella in adriamycin content, platinum content pass through inductive coupling plasma emission spectrograph (ICP-OES) determine.
In the micella that embodiment 15 obtains, the embedding amount of adriamycin is 7.21%, and the embedding amount of cis-platinum is 6.89%.
Obtained freeze-dried powder is redissolved, and carries out potential test, its Zeta potential is -23.17 ± 3.6mV.
After freeze-dried powder redissolves, by concentration dilution to 0.1mg/mL, using dynamic scattering analysis, the stream of carrier micelle is determined
Mechanics radius, the results showed that, the hydromechanical radius for the carrier micelle that embodiment 15 obtains is between 20nm~250nm.
Embodiment 16
The multiarm polymers that 100mg embodiments 3 obtain are dissolved in 60mL deionized waters, adjust pH value 7.0~8.0,
Cis-platinum 10mg is added, 72h is stirred under the conditions of 37 DEG C of lucifuges, adriamycin 15mg is then added, is stirred under the conditions of 37 DEG C of lucifuges
24h, pure water dialysis 24h, changes water 6~8 times to remove free adriamycin and Platinol cisplatin, is supported adriamycin and Platinol cisplatin jointly
Complexes micelle, the micella is freeze-dried to obtain composite powder preparation.
Obtained composite powder is redissolved, embodiment 16 is determined under the conditions of 480nm using ultraviolet-visible spectrum and obtained
Micella in adriamycin content, platinum content pass through inductive coupling plasma emission spectrograph (ICP-OES) determine.
In the micella that embodiment 16 obtains, the embedding amount of adriamycin is 7.94%, and the embedding amount of cis-platinum is 4.76%.
Obtained freeze-dried powder is redissolved, and carries out potential test, its Zeta potential is -20.28 ± 4.1mV.
After freeze-dried powder redissolves, by concentration dilution to 0.1mg/mL, using dynamic scattering analysis, the stream of carrier micelle is determined
Mechanics radius, the results showed that, the hydromechanical radius for the carrier micelle that embodiment 16 obtains is between 10nm~150nm.
Embodiment 17
The multiarm polymers that 100mg embodiments 3 obtain are dissolved in 60mL deionized waters, adjust pH value 7.0~8.0,
Adriamycin 15mg is added, cis-platinum 10mg is then added, the stirring reaction 72h under the conditions of 37 DEG C of lucifuges, pure water dialysis 24h, changes water 6
With free adriamycin and Platinol cisplatin of going out, the complexes micelle of adriamycin and Platinol cisplatin is supported jointly, by the micella~8 times
Freeze-drying obtains composite powder preparation.
Obtained composite powder is redissolved, embodiment 17 is determined under the conditions of 480nm using ultraviolet-visible spectrum and obtained
Micella in adriamycin content, platinum content pass through inductive coupling plasma emission spectrograph (ICP-OES) determine.
In the micella that embodiment 17 obtains, the embedding amount of adriamycin is 7.42%, and the embedding amount of cis-platinum is 4.67%.
Obtained freeze-dried powder is redissolved, and carries out potential test, its Zeta potential is -18.38 ± 4.6mV.
After freeze-dried powder redissolves, by concentration dilution to 0.1mg/mL, using dynamic scattering analysis, the stream of carrier micelle is determined
Mechanics radius, the results showed that, the hydromechanical radius for the carrier micelle that embodiment 17 obtains is between 15nm~200nm.
Comparative example 1
The multiarm polymers that 100mg embodiments 3 obtain are dissolved in 60mL deionized waters, adjust pH value 7.0~8.0,
Adriamycin 15mg is added, 24h is stirred under the conditions of 37 DEG C of lucifuges, water is changed 6~8 times to remove free adriamycin, obtains single load
Adriamycin micella, the micella is freeze-dried to obtain powder formulation.
Obtained powder is redissolved, determines the micella that comparative example 1 obtains under the conditions of 480nm using ultraviolet-visible spectrum
The content of middle adriamycin.
In the micella that comparative example 1 obtains, the embedding amount of adriamycin is 10.26%.
Obtained freeze-dried powder is redissolved, and carries out potential test, its Zeta potential is -20.14 ± 4.2mV.
After freeze-dried powder redissolves, by concentration dilution to 0.1mg/mL, using dynamic scattering analysis, the stream of carrier micelle is determined
Mechanics radius, the results showed that, the hydromechanical radius for the carrier micelle that comparative example 1 obtains is between 10nm~100nm.
Comparative example 2
The multiarm polymers that 100mg embodiments 3 obtain are dissolved in 60mL deionized waters, adjust pH value 7.0~8.0,
Cis-platinum 10mg is added, 72h is stirred under the conditions of 37 DEG C of lucifuges, changes water 6~8 times to remove free cis-platinum, obtains single load cis-platinum
Micella, the micella is freeze-dried to obtain powder formulation.
Obtained powder is redissolved, platinum content is determined by inductive coupling plasma emission spectrograph (ICP-OES).
In the micella that comparative example 2 obtains, the embedding amount of adriamycin is 10.26%.
Obtained freeze-dried powder is redissolved, and carries out potential test, its Zeta potential is -15.63 ± 3.9mV.
After freeze-dried powder redissolves, by concentration dilution to 0.1mg/mL, using dynamic scattering analysis, the stream of carrier micelle is determined
Mechanics radius, the results showed that, the hydromechanical radius for the carrier micelle that comparative example 2 obtains is between 10nm~100nm.
Embodiment 18
B16F10 cells are placed in the DMEM nutrient solutions containing 10% hyclone, are 37 DEG C, volume fraction in temperature
In 5% CO2gas incubator, to pass on or changing every other day fresh medium.When cell fusion degree is 80~90%, pancreas is used
Protease digestion, per hole 1 × 104Cell density is planted in 96 well culture plates, overnight incubation.The common load that embodiment 9 is obtained
Single micella for carrying medicine that micella, comparative example 1 and the comparative example 2 of medicine obtain, various concentrations are diluted to using culture medium and added
In 96 orifice plates, cultivate 48 hours；After 48h, the MTT solution that 20 μ L concentration are 5mg/mL is added per hole, continues to cultivate 4h；Then will
Nutrient solution is discarded, and 160 μ LDMSO solution are added per hole, vibrates l0min.With ELIASA (Bio-Rad), detection light is inhaled under 492nm
Receive, and cell survival rate is calculated using equation below：
Cell survival rate (%)=A/C × 100%,
Wherein A is the absorption value in cell sample hole after addition material effects；C is undressed cell absorption value.
As a result show, with the increase of drug concentration, cytotoxicity increase；Compared with single load group, its toxicity shows load group altogether
Write enhancing.
Embodiment 19
(1) culture of B16F10 cells
Cell culture condition is 37 DEG C, and volume fraction is that cell is placed in containing 10% tire in 5% CO2gas incubator
In the DMEM nutrient solutions of cow's serum, fresh medium is passed on or changed every other day.
(2) tumor inoculation
C57 male mice of the weight for 18~20g or so is selected, when cell fusion degree is 80~90%, uses tryptose
Enzymic digestion, washed twice and counted with PBS, pass through tail vein injection 1 × 104/ only.
(3) transfection in vivo
Since the 7th day, by embodiment 12, embodiment 13, embodiment 14, embodiment 15, embodiment 16, embodiment 17,
The glucose solution of medicinal composition prepared by comparative example 1, comparative example 2 injects directly to lung through pulmonary delivery device, wherein,
Adriamycin equivalent dosage be 20 μ g/ only/time, cis-platinum equivalent dosage be 20 μ g/ only/time, weekly treatment once, totally 4
It is secondary.Free adriamycin, free cis-platinum group are set in addition, and control group is 5% glucose solution.
(4) measure of therapeutic effect
After treating the 28th day, mouse euthanasia, take out lung and weigh.As a result it is as shown in table 1.
The medicinal composition of medicinal composition and the preparation of comparative example 1~2 is carried made from the embodiment 12~17 of table 1 altogether to small
The therapeutic effect of mouse melanin pulmonary metastases
As can be seen from Table 1, the medicinal composition provided by the invention that carries altogether is directly administered through mouse lung, is had to lung cancer
Preferable therapeutic effect.
As seen from the above embodiment, the invention provides a kind of medicine to carry compound altogether, is total to by cis-platinum, adriamycin and multi-arm
Polymers is combined, and the multi-arm copolymer has Formulas I structure.Medicine provided by the invention carries compound in an aqueous medium altogether
Micella is formed, PEG block is in the outer core of micella, and polyglutamic acid block or aspartic acid block are in micella in multi-arm copolymer
Kernel, cis-platinum and adriamycin be among this two parts and be protected, and therefore, its stability is preferable, will not occur to release suddenly
Put phenomenon.In addition, the carboxyl of cis-platinum and multi-arm copolymer is coordinated, there is crosslinked action, add the stability of micella；
Tumor tissues or near tumor cells, adriamycin and Platinol cisplatin with quick release and can play drug effect, so as to improve curative effect of medication,
Reduce toxic side effect.Test result indicates that medicine provided by the present invention carry altogether compound through lung be directly administered treatment mouse it is black
During melanoma metastatic lung cancer, there is the effect of good suppression tumour growth.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (8)
1. a kind of medicine carries compound altogether, it is combined by cis-platinum, adriamycin and multi-arm copolymer, the multi-arm copolymer has
Formulas I structure：
In Formulas I, the R is-CH2COOH or-CH2CH2COOH；
a≥1；b≥1；5≤p≤200；20≤q≤250；
The mass ratio of the multi-arm copolymer and Pt in cis-platinum is less than 15；
The mass ratio of the multi-arm copolymer and adriamycin is less than 20.
2. medicine according to claim 1 carries compound altogether, it is characterised in that the multi-arm copolymer and Pt in cis-platinum
Mass ratio is more than 0.5 and less than 15；
The mass ratio of the multi-arm copolymer and adriamycin is more than 0.5 and less than 20.
3. medicine according to claim 1 carries compound altogether, it is characterised in that the preparation method bag of the multi-arm copolymer
Include following steps：
By polyethyleneimine, polyethylene glycol and amino acid N-carboxyanhydrides hybrid reaction, deprotection, multi-arm copolymerization is obtained
Thing；
Amino acid N-the carboxyanhydrides are glutamic acid N-carboxyanhydrides or aspartic acid N- carboxyanhydrides；
The polyethyleneimine has Formula II structure；
M and n is the degree of polymerization；The number-average molecular weight of the polyethyleneimine is 300~35000Da.
4. a kind of medicine carries complexes micelle altogether, including the medicine described in claims 1 to 3 any one carries compound and water altogether
Property medium.
5. medicine according to claim 4 carries complexes micelle altogether, it is characterised in that the aqueous medium includes distillation
Water, physiological saline, cushioning liquid, tissue culture medium or body fluid.
6. a kind of medicine carries the preparation method of complexes micelle altogether, comprise the following steps：
By cis-platinum, adriamycin and have the multi-arm copolymer of Formulas I structure compound in an aqueous medium, obtain medicine and carry compound altogether
Micella；
In Formulas I, R is-CH2COOH or-CH2CH2COOH；
a≥1；b≥1；5≤p≤200；20≤q≤250；
The mass ratio of the multi-arm copolymer and Pt in cis-platinum is less than 15；
The mass ratio of the multi-arm copolymer and adriamycin is less than 20.
7. preparation method according to claim 6, it is characterised in that the mass ratio of the multi-arm copolymer and Pt in cis-platinum
It is less than 15 more than 0.5.
8. preparation method according to claim 6, it is characterised in that the mass ratio of the multi-arm copolymer and adriamycin is big
It is less than 20 in 0.5.
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| CN109908084B (en) * | 2019-04-11 | 2021-06-25 | 临沂大学 | Platinum cross-linked camptothecin prodrug micelle nano-drug as well as preparation method and application thereof |
| CN110339163B (en) * | 2019-07-25 | 2021-12-07 | 沈阳信康药物研究有限公司 | Cisplatin-polyglutamic acid complex micelle and preparation method thereof |
| CN110755639A (en) * | 2019-11-13 | 2020-02-07 | 浙江大学 | Polyethylene glycol-dendritic polylysine/anhydride-cisplatin compound and preparation method and application thereof |
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| "Biodegradable cationic PEG-PEI-PBLG hyperbranched block copolymer: synthesis and micelle characterization";HuaYu Tian et al.;《Biomaterials》;20041215;第26卷;第4209-4217页 * |
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