CN102895669B - Cis-platinum complex and preparation method thereof - Google Patents
Cis-platinum complex and preparation method thereof Download PDFInfo
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- CN102895669B CN102895669B CN201210430624.8A CN201210430624A CN102895669B CN 102895669 B CN102895669 B CN 102895669B CN 201210430624 A CN201210430624 A CN 201210430624A CN 102895669 B CN102895669 B CN 102895669B
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Abstract
The invention discloses a cis-platinum complex and a preparation method thereof. Cis-platinum and a polymer with the structure of formula (I) are used as raw materials for preparing the cis-platinum complex, wherein a polymer molecule with the structure of formula (I) contains a poly (L-glutamic acid-co-L-lysine) segment, so that the prepared cis-platinum complex has excellent biocompatibility and is degradable; meanwhile, the poly (L-glutamic acid-co-L-lysine) segment can further prevent the cis-platinum complex from being influenced by a blood circulation system in an aqueous medium, so that the cis-platinum complex has excellent stability; and the terminal of the branched chain of the cis-platinum complex provided by the invention contains an amino group, so that the cis-platinum complex has excellent solubility. In addition, the prepared cis-platinum complex contains a carboxy group, so that the cis-platinum complex has excellent pH value sensitivity, the carboxy group tends to deprotonation in the environment with a lower pH value so as to be beneficial to promoting the drug release and improve the efficacy of drugs.
Description
Technical field
The present invention relates to polymer drug technical field, relate in particular to a kind of Platinum complexes and preparation method thereof.
Background technology
Cis-diaminedichloroplatinum, being called for short cisplatin (CDDP) is a kind of metal complex with active anticancer, is found first in nineteen sixty-five by people such as B.Rosenborg.Cisplatin has that anticancer spectrum is wide, effect is strong, have synergism with multiple antitumor drug and without features such as cross resistances, therefore cisplatin is one of medicine the most frequently used in combined chemotherapy.At present, cisplatin has good result to treatment genital system tumor, incidence cancer, bladder cancer, pulmonary carcinoma, malignant lymphoma etc.Cisplatin is oral invalid, and method in clinical application mostly is the mode administration with intravenous drip.But after intravenous injection, cisplatin is dissolved in rapidly in blood plasma and in the whole body that distributes, especially liver, kidney, intestine and small intestine and skin, causes its toxic and side effects large, can cause nephrotoxicity, bone marrow depression and gastrointestinal side effect etc.Meanwhile, the half-life of cisplatin in blood is short, and the ratio that reaches lesions position is very low, and drug effect is poor.
For the half-life of prolong drug in blood, and reduce the non-specific adsorption effect between medicine and albumen, thereby improve cisplatin drug effect, research worker often adopts the carrier of macromolecular material as drug conveying.The macromolecule carrier that has micron and nanoscale developing rapidly in the recent period, as: micelle, vesicle and nano-particle etc., this family macromolecule carrier can make drug molecule effectively be scattered in carrier, then utilizes the various response modes of carrier, realizes the conveying of medicine and control discharging.The interior environment main manifestations of tumor cell is " three low height ", that is: hypoxia, low sugar, low pH value and homoglutathion concentration, wherein low pH value particularly significantly, late period, endosome and lysosomal pH value can be low to moderate 5.0(Advanced Functional Materials, 19 (22): 3580 ~ 3589), and tumor locus has, and rich blood vessel, blood vessel wall gap are wider, poor structural integrity, the features such as lymphatic return disappearance, can cause macromole class material and lipid granule to have high-permeability and anelasticity.Therefore, nanometer to the pharmaceutical carrier of micron-scale has significant EPR effect, i.e. " infiltration of enhancing and retention effect ".Utilize this passive target mode of EPR effect, can make medicine effectively assemble at tumor locus, reduce the toxic and side effects of non-lesions position simultaneously.
The mode that researcher utilizes polymer support to support medicine has been developed cisplatin formulations, but the product also not going on the market at present.Wherein, studying the most deep is the people such as Kataoka, and the compound cisplatin micelle of Polyethylene Glycol-b-polyglutamic acid (NC-6004) that they prepare has entered clinical second phase research.But gained micelle is to be formed by the crosslinked action between polyamino acid side chain, the lyophilized powder that the complex obtaining forms after lyophilizing is difficult to redissolve.Stenzel etc. utilize " sulfydryl-alkynyl " and " sulfydryl-thiazolinyl " Click reaction to introduce TGA and dimercaptosuccinic acid at polymer lateral chain, obtain complex (Biomacromolecules 12 (5): 1738-1751), this complex has good dissolubility, but its polymer biological compatibility as carrier is poor, cannot degrade, limit it and further applied.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of Platinum complexes and preparation method thereof, and the Platinum complexes preparing has good biocompatibility and dissolubility.
The invention provides a kind of Platinum complexes, coordinate and form with the polymer with formula I structure by cisplatin:
Wherein, m is the degree of polymerization, 20≤m≤100; N is the degree of polymerization, 20≤n≤100;
R
1be selected from CH
3(CH
2) rNH-, 3≤r≤7.
Preferably, described in, having in the polymer of formula I structure the mol ratio of Pt in carboxyl and cisplatin is 5 ~ 20:1.
Preferably, described in, having in the polymer of formula I structure the mol ratio of Pt in carboxyl and cisplatin is 8 ~ 16:1.
The preparation method that the invention provides a kind of Platinum complexes, comprises the following steps:
By cisplatin and the polymer mixed with formula I structure, there is complex reaction, obtain Platinum complexes;
Wherein, m is the degree of polymerization, 20≤m≤100; N is the degree of polymerization, 20≤n≤100;
R
1be selected from CH
3(CH
2) rNH-, 3≤r≤7.
Preferably, described in, having in the polymer of formula I structure the mol ratio of Pt in carboxyl and cisplatin is 5 ~ 20:1.
Preferably, described in, having in the polymer of formula I structure the mol ratio of Pt in carboxyl and cisplatin is 8 ~ 16:1.
Preferably, described complex reaction for to carry out in aqueous medium.
Preferably, described aqueous medium is selected from any one or a few in distilled water, normal saline, buffer solution, tissue culture medium and body fluid.
The polymer preferably, with formula I structure is prepared in accordance with the following methods:
A) will have the monomer of formula II structure and the monomer of formula III structure mixes with initiator, carry out random copolymerization reaction, obtain having the polymer of formula IV structure, described initiator has formula (V) structure;
B) polymer with formula IV structure is carried out to deprotection, obtain having the polymer of formula I structure;
CH
3(CH
2) rNH
2(V), wherein, 3≤r≤7;
In formula IV, R
1be selected from CH
3(CH
2) rNH-, 3≤r≤7;
M and n are the degree of polymerization, 20≤m≤100,20≤n≤100.
Preferably, described initiator is selected from any one or a few in n-butylamine, n-hexylamine and 1-Aminooctane.
Compared with prior art, the present invention, take cisplatin and the polymer with formula I structure as raw material, prepares Platinum complexes.Wherein, the polymer molecule with formula I structure contains poly-(Pidolidone-co-L-lysine) segment, makes the Platinum complexes of preparation have good biocompatibility, degradable; Meanwhile, its poly-(Pidolidone-co-L-lysine) segment also can protect Platinum complexes in aqueous medium, avoids the impact of blood circulation, makes it have good stability; And Platinum complexes provided by the invention, its chain end contains amino, thereby has good dissolubility.In addition, Platinum complexes prepared by the present invention contains carboxyl, and it has good pH value sensitivity, and in lower pH value environment, carboxyl is tending towards deprotonation, is conducive to promote the release of medicine, improves the curative effect of medicine.
Platinum complexes to preparation carries out current potential overturn point mensuration, and result shows to control ratio and the cisplatin loading of polymer Glutamic Acid and lysine, the pH value can change its current potential generation upset time.In the time that the pH value of its current potential generation upset is less than 6.8, polymer belt positive electricity, is conducive to enter cell, improves curative effect; In the time that the pH value of its current potential generation upset is 7.4, polymer belt is born point, is conducive to circulate for a long time in vivo.
Accompanying drawing explanation
Fig. 1 is the changing trend diagram of the current potential overturn point of the polymer with formula I structure prepared of the embodiment of the present invention;
Fig. 2 is the changing trend diagram of the current potential overturn point of the Platinum complexes of the embodiment of the present invention 8 ~ 10 preparations;
Fig. 3 is that Platinum complexes prepared by the embodiment of the present invention 8 is to discharge the curve chart of cisplatin at 5.3 o'clock at pH;
Fig. 4 is the changing trend diagram of the current potential overturn point of the Platinum complexes of the embodiment of the present invention 11 ~ 13 preparations;
Fig. 5 is the changing trend diagram of the current potential overturn point of the Platinum complexes of the embodiment of the present invention 14 ~ 16 preparations.
The specific embodiment
The invention provides a kind of Platinum complexes, coordinate and form with the polymer with formula I structure by cisplatin:
Wherein, m is the degree of polymerization, 20≤m≤100; N is the degree of polymerization, 20≤n≤100;
R
1be selected from CH
3(CH
2) rNH-, 3≤r≤7.
The present invention, take cisplatin and the polymer with formula I structure as raw material, prepares Platinum complexes.Wherein, the polymer molecule with formula I structure contains poly-(Pidolidone-co-L-lysine) segment, makes the Platinum complexes of preparation have good biocompatibility, degradable; Meanwhile, its poly-(Pidolidone-co-L-lysine) segment also can protect Platinum complexes in aqueous medium, avoids the impact of blood circulation, makes it have good stability; And Platinum complexes provided by the invention, its chain end contains amino, thereby has good dissolubility.In addition, Platinum complexes prepared by the present invention contains carboxyl, and it has good pH value sensitivity, and in lower pH value environment, carboxyl is tending towards deprotonation, is conducive to promote the release of medicine, improves the curative effect of medicine.
Platinum complexes provided by the invention is coordinated and is formed by cisplatin and the polymer with formula I structure, wherein, described in there is in the polymer of formula I structure the mol ratio of Pt in carboxyl and cisplatin and be preferably 5 ~ 20:1, more preferably 8 ~ 16:1.
Platinum complexes provided by the invention, can coordinate the molecule inner complex forming for cisplatin and the polymer with formula I structure, can be also its intermolecular coordination compound, and the present invention there is no particular restriction to this.
The present invention also provides a kind of preparation method of Platinum complexes, comprises the following steps:
By cisplatin and the polymer mixed with formula I structure, there is complex reaction, obtain Platinum complexes;
Wherein, m is the degree of polymerization, 20≤m≤100; N is the degree of polymerization, 20≤n≤100;
R
1be selected from CH
3(CH
2) rNH-, 3≤r≤7.
The present invention, take cisplatin and the polymer with formula I structure as raw material, prepares Platinum complexes.Wherein, the present invention does not have specific (special) requirements to the source of described cisplatin, can be for generally commercially available.
In the present invention, the form of the described polymer with formula I structure is not particularly limited, is preferably lyophilized powder.The present invention is also not particularly limited the source of the described polymer with formula I structure, preferably preparation in accordance with the following methods:
A) will have the monomer of formula II structure and the monomer of formula III structure mixes with initiator, carry out random copolymerization reaction, obtain having the polymer of formula IV structure, described initiator has formula (V) structure;
B) polymer with formula IV structure is carried out to deprotection, obtain having the polymer of formula I structure;
CH
3(CH
2) rNH
2(V), wherein, 3≤r≤7;
In formula IV, R
1be selected from CH
3(CH
2) rNH-, 3≤r≤7;
M and n are the degree of polymerization, 20≤m≤100,20≤n≤100.
First will there is the monomer of formula II structure and the monomer of formula III structure mixes with initiator, carry out random copolymerization reaction, obtain having the polymer of formula IV structure.
Wherein, the preferably preparation in accordance with the following methods of monomer that there is formula II structure described in: the glutamic acid (formula (a)) of benzylalcohol protection is carried out to NCA synthetic reaction with triphosgene, the monomer of (II) structure that obtains thering is formula.The source of the glutamic acid of the present invention to described benzylalcohol protection there is no particular restriction, can, for generally commercially available, also can prepare according to the preparation method of benzylalcohol protection glutamic acid well known to those skilled in the art.The present invention there is no particular restriction to the source of described triphosgene, can be for generally commercially available.The present invention there is no particular restriction to the condition of described NCA reaction, can be NCA synthetic reaction condition well known to those skilled in the art.
The described monomer with formula III structure is preparation in accordance with the following methods preferably: the lysine (formula (b)) of benzyloxycarbonyl group protection is carried out to NCA synthetic reaction with triphosgene, the monomer of (III) structure that obtains having formula.The source of the lysine of the present invention to described benzyloxycarbonyl group protection there is no particular restriction, can, for generally commercially available, also can prepare according to the preparation method of benzyloxycarbonyl group protection lysine well known to those skilled in the art.
Described initiator is preferably any one or a few in n-butylamine, n-hexylamine and 1-Aminooctane, more preferably n-hexylamine.The present invention does not have specific (special) requirements to the source of described initiator, can be for generally commercially available.
First the present invention will have the monomer of formula II structure and the monomer of formula III structure mixes with initiator, the present invention is not particularly limited described hybrid mode, be preferably and will there is the monomer of formula II structure and the monomer of formula III structure with after dissolution with solvents, add the solution of initiator, carry out random copolymerization reaction.Described solvent is preferably DMF.The solution of described initiator is preferably the DMF solution of initiator.The temperature of described random copolymerization reaction is preferably 15 ℃ ~ 35 ℃, more preferably 20 ℃ ~ 25 ℃; The time of described random copolymerization reaction is preferably 1 day ~ and 5 days, more preferably 2 days ~ 3 days.
The present invention preferably carries out described random copolymerization reaction under the condition of inert gas shielding, and described noble gas is preferably argon.
Obtain having after the polymer of formula IV structure, carried out deprotection, obtain having the polymer of formula I structure.Described deprotection is specially:
To there is the acetum hybrid reaction of the polymer of formula IV structure and trifluoroacetic acid, HBr, obtain having the polymer of formula I structure.
Wherein, the present invention does not have particular restriction to the source of described trifluoroacetic acid, can be for generally commercially available.The source of the acetum of the present invention to described HBr does not have particular restriction, can be for generally commercially available.The mass ratio of the acetum of described polymer, trifluoroacetic acid and the HBr with formula IV structure is preferably 1:5 ~ 15:1 ~ 5.The order by merging of the acetum of the present invention to the described polymer with formula IV structure and trifluoroacetic acid, HBr there is no particular restriction, be preferably first and with trifluoroacetic acid, the polymer with formula IV structure dissolved completely, then add the acetum of trifluoroacetic acid and HBr.
Obtain having after the polymer of formula I structure, preferably extremely do not have after tart flavour completely with ether sedimentation dialysis, lyophilization obtains the lyophilized powder of the polymer with formula I structure.
Obtain having after the polymer of formula I structure, it is mixed with cisplatin, complex reaction occurs, obtain Platinum complexes.
In the present invention, described in there is formula I structure polymer be the carrier that supports cisplatin, the Pt in cisplatin with described in there is the polymer of formula I structure carboxyl form Platinum complexes by coordinate bond; Preferably, all cisplatin molecules with described in there is the polymer formation coordinate bond of formula I structure, but the carboxyl that is not necessarily limited to whole cisplatin molecules and polymer forms coordinate bond, also comprises between part cisplatin molecule and supports on carrier material with hydrophobic interaction or other any physics modes.When cisplatin molecule and coordination compound form coordinate bond, can be to coordinate in molecule, can be also intermolecular cooperation, and the present invention there is no particular restriction to this.In the carboxyl of the described polymer with formula I structure and cisplatin, the mol ratio of Pt is preferably 5 ~ 20:1, more preferably 8 ~ 16:1.
In the preparation method of Platinum complexes of the present invention, preferably under lucifuge condition, the polymer with formula I structure is dissolved in to aqueous medium in and regulate pH value, then add cisplatin, carry out complex reaction, after dialysis, obtain Platinum complexes micelle.Described aqueous medium is preferably any one or a few in distilled water, normal saline, buffer solution, tissue culture medium and body fluid, more preferably distilled water.The pH value of described distilled water is preferably 6.5 ~ 8.5, and more preferably 7.5 ~ 8.0.The carboxyl concentration of the described polymer with formula I structure is preferably 0.01mM ~ 100mM, and more preferably 0.05mM ~ 60mM, most preferably is 0.1mM ~ 20mM.
The polymer with formula I structure is dissolved in after aqueous medium, preferably its pH value is adjusted to 6.5 ~ 9.0, be more preferably adjusted to 7.5 ~ 8.5.Then add cisplatin to carry out complex reaction, the time of described complex reaction is preferably 24 hours ~ and 72 hours, more preferably 48 hours ~ 72 hours; The temperature of described complex reaction is preferably 20 ℃ ~ 40 ℃, more preferably 30 ℃ ~ 40 ℃.After complex reaction completes, dialyse, the time of described dialysis is preferably 12h ~ 56h, more preferably 20h ~ 30h; After preferably it being changed to water 1 ~ 6 time, obtain Platinum complexes micelle.
According to the preparation method of Platinum complexes provided by the invention, the Platinum complexes obtaining is preferably present in aqueous medium with the form of micelle, and the hydrodynamic radius of described micelle is preferably 10nm ~ 1000nm, more preferably 10nm ~ 200nm.
The Platinum complexes preparing is carried out to current potential overturn point mensuration, result shows, the current potential of Platinum complexes provided by the invention has pH sensitivity, controls ratio and the cisplatin loading of polymer Glutamic Acid and lysine, the pH value can change its current potential generation upset time.In the time that the pH value of its current potential generation upset is less than 6.8, polymer belt positive electricity, is conducive to enter cell, improves curative effect; In the time that the pH value of its current potential generation upset is 7.4, polymer belt is born point, is conducive to circulate for a long time in vivo.
The present invention, take cisplatin and the polymer with formula I structure as raw material, prepares Platinum complexes.Wherein, the polymer molecule with formula I structure contains poly-(Pidolidone-co-L-lysine) segment, makes the Platinum complexes of preparation have good biocompatibility, degradable; Meanwhile, its poly-(Pidolidone-co-L-lysine) segment also can protect Platinum complexes in aqueous medium, avoids the impact of blood circulation, makes it have good stability; And Platinum complexes provided by the invention, its chain end contains amino, thereby has good dissolubility.In addition, Platinum complexes prepared by the present invention contains carboxyl, and it has good pH value sensitivity, and in lower pH value environment, carboxyl is tending towards deprotonation, is conducive to promote the release of medicine, improves the curative effect of medicine.
In order to further illustrate the present invention, below in conjunction with embodiment, Platinum complexes provided by the invention and preparation method thereof is described in detail.
Embodiment 1
Get a there-necked flask, add a magneton, one bottleneck is filled in the rubber stopper of a tape drum bulb glass pipe, one bottleneck adds plug seal, another bottleneck connects a union elbow, puts up after device evacuation roasting bottle on one side on one side, is full of afterwards argon in bottle, three times so repeatedly, under last inflated condition, be cooled to room temperature.Continue drum from glass tubing one end and enter argon; under argon shield, add the refined oxolane of 200mL (THF); under bubbling state, add again the glutamic acid 20g of benzylalcohol protection; 26 degrees Celsius of oil baths are stirred; after 20min, add 8g triphosgene; continue to stir 30min, naturally cool to room temperature, continue during this time air-blowing state.Product is carried out to sedimentation with 2L absolute ether, subzero 80 degrees Celsius of freezing 24h, sucking filtration obtains white solid afterwards,, is transferred in 1L separatory funnel the dissolution of solid obtaining by 600mL ethyl acetate, and frozen water is washed three times.Organic layer is transferred in 1L conical flask, adds enough anhydrous magnesium sulfates, dry 24h under room temperature.Separately get an ampulla, according to the roasting bottle of above-mentioned steps evacuation applying argon gas, dry before ethyl acetate organic solution is filtered so far in ampulla, add afterwards cold-trap, vacuum pumps whole ethyl acetate, the white powder solid of (II) structure that finally obtains thering is formula, and note is BLG-NCA.
Embodiment 2
Get a there-necked flask, add a magneton, one bottleneck is filled in the rubber stopper of a tape drum bulb glass pipe, one bottleneck adds plug seal, another bottleneck connects a union elbow, puts up after device evacuation roasting bottle on one side on one side, is full of afterwards argon in bottle, three times so repeatedly, under last inflated condition, be cooled to room temperature.Continue drum from glass tubing one end and enter argon; under argon shield, add the refined oxolane of 300mL (THF); under bubbling state, add again the lysine 30g of benzyloxycarbonyl group protection; 26 degrees Celsius of oil baths are stirred; after 20min, add 12g triphosgene; continue to stir 30min, naturally cool to room temperature, continue during this time air-blowing state.Product is carried out to sedimentation with 3L absolute ether, subzero 80 degrees Celsius of freezing 24h, sucking filtration obtains white solid afterwards,, is transferred in 1L separatory funnel the dissolution of solid obtaining by 600mL ethyl acetate, and frozen water is washed three times.Organic layer is transferred in 1L conical flask, adds enough anhydrous magnesium sulfates, dry 24h under room temperature.Separately get an ampulla, according to the roasting bottle of above-mentioned steps evacuation applying argon gas, dry before ethyl acetate organic solution is filtered so far in ampulla, add afterwards cold-trap, vacuum pumps whole ethyl acetate, the white powder solid of (III) structure that finally obtains thering is formula, and note is CBZ-Lys-NCA.
Get an ampulla, add a magneton, evacuation roasting bottle on one side on one side, applying argon gas in bottle afterwards, three times so repeatedly, finally be evacuated, by bottle fast transfer to glove box, and the CBZ-Lys-NCA that adds respectively BLG-NCA prepared by 1.552g embodiment 1 and 0.448g embodiment 2 to prepare, to after bottle seal, take out, then in bottle, adding 12mL DMF to incite somebody to action wherein solid dissolves completely, squeeze into the DMF solution 0.756g that concentration is the n-hexylamine of 0.0975mmol/g with syringe, add afterwards 3mLDMF, stirring reaction 3 days under room temperature, then product is carried out to sedimentation with 200mL absolute ether, obtain white opacity thing, subzero 80 degrees Celsius of freeze overnight, it was carried out after centrifugal obtaining white solid in second day, then it is carried out to vacuum drying and obtain polymer.The polymer obtaining is transferred in beaker, add appropriate trifluoroacetic acid that it is dissolved completely, the acetum (33wt%) of adding afterwards a certain amount of trifluoroacetic acid and HBr makes sample: trifluoroacetic acid: the mass ratio of HBr/ acetic acid is 1:10:3, after one hour with the absolute ether sedimentation of 10 times of amounts, obtain afterwards white solid, after vacuum drying 24h, samples with water is dissolved, in the bag filter of 3500mL, dialyse, after there is no tart flavour completely, lyophilization, obtains the white lyophilized powder of the polymer with formula I structure.
The above-mentioned polymer with formula I structure is carried out to nuclear magnetic resonance, NMR test, and result of calculation shows, in formula I, and m=70, n=19, R
1for CH
3(CH
2)
5nH-, is designated as PGA
70-co-PLys
19.
The polymer P GA with formula I structure that utilizes Zeta-Potential potentiometer test implementation example 3 to prepare
70-co-PLys
19current potential overturn point, measure its variation tendency, the results are shown in Figure 1, Fig. 1 and be the changing trend diagram of the current potential overturn point of the polymer with formula I structure prepared by the embodiment of the present invention, wherein, curve a is the polymer P GA with formula I structure that the embodiment of the present invention 3 provides
70-co-PLys
19the changing trend diagram of current potential overturn point.As shown in Figure 1, polymer P GA
70-co-PLys
19there is pH value sensitivity.
Embodiment 4
Get an ampulla, add a magneton, evacuation roasting bottle on one side on one side, applying argon gas in bottle afterwards, three times so repeatedly, finally be evacuated, by bottle fast transfer to glove box, and the CBZ-Lys-NCA that adds respectively BLG-NCA prepared by 1.130g embodiment 1 and 0.870g embodiment 2 to prepare, to after bottle seal, take out, then in bottle, adding 12mL DMF to incite somebody to action wherein solid dissolves completely, squeeze into the DMF solution 0.734g that concentration is the n-hexylamine of 0.0975mmol/g with syringe, add afterwards 3mLDMF, stirring reaction 3 days under room temperature, then product is carried out to sedimentation with 200mL absolute ether, obtain white opacity thing, subzero 80 degrees Celsius of freeze overnight, it was carried out after centrifugal obtaining white solid in second day, then it is carried out to vacuum drying and obtain polymer.The polymer obtaining is transferred in beaker, add appropriate trifluoroacetic acid that it is dissolved completely, the acetum (33wt%) of adding afterwards a certain amount of trifluoroacetic acid and HBr makes sample: trifluoroacetic acid: the mass ratio of HBr/ acetic acid is 1:10:3, after one hour with the absolute ether sedimentation of 10 times of amounts, obtain afterwards white solid, after vacuum drying 24h, samples with water is dissolved, in the bag filter of 3500mL, dialyse, after there is no tart flavour completely, lyophilization, obtains the white lyophilized powder of the polymer with formula I structure.
The above-mentioned polymer with formula I structure is carried out to nuclear magnetic resonance, NMR test, and result of calculation shows, in formula I, and m=60, n=40, R
1for CH
3(CH
2)
5nH-, is designated as PGA
60-co-PLys
40.
The polymer P GA with formula I structure that utilizes Zeta-Potential potentiometer test implementation example 4 to prepare
60-co-PLys
40current potential overturn point, measure its variation tendency, the results are shown in Figure 1, Fig. 1 and be the changing trend diagram of the current potential overturn point of the polymer with formula I structure prepared by the embodiment of the present invention, wherein, curve b is the polymer P GA with formula I structure that the embodiment of the present invention 4 provides
60-co-PLys
40the changing trend diagram of current potential overturn point.As shown in Figure 1, polymer P GA
60-co-PLys
40there is pH value sensitivity.
Get an ampulla, add a magneton, evacuation roasting bottle on one side on one side, applying argon gas in bottle afterwards, three times so repeatedly, finally be evacuated, by bottle fast transfer to glove box, and the CBZ-Lys-NCA that adds respectively BLG-NCA prepared by 0.9277g embodiment 1 and 1.0723g embodiment 2 to prepare, to after bottle seal, take out, then in bottle, adding 12mL DMF to incite somebody to action wherein solid dissolves completely, squeeze into the DMF solution 0.723g that concentration is the n-hexylamine of 0.0975mmol/g with syringe, add afterwards 3mLDMF, stirring reaction 3 days under room temperature, then product is carried out to sedimentation with 200mL absolute ether, obtain white opacity thing, subzero 80 degrees Celsius of freeze overnight, it was carried out after centrifugal obtaining white solid in second day, then it is carried out to vacuum drying and obtain polymer.The polymer obtaining is transferred in beaker, add appropriate trifluoroacetic acid that it is dissolved completely, the acetum (33wt%) of adding afterwards a certain amount of trifluoroacetic acid and HBr makes sample: trifluoroacetic acid: the mass ratio of HBr/ acetic acid is 1:10:3, after one hour with the absolute ether sedimentation of 10 times of amounts, obtain afterwards white solid, after vacuum drying 24h, samples with water is dissolved, in the bag filter of 3500mL, dialyse, after there is no tart flavour completely, lyophilization, obtains the white lyophilized powder of the polymer with formula I structure.
The above-mentioned polymer with formula I structure is carried out to nuclear magnetic resonance, NMR test, and result of calculation shows, in formula I, and m=45, n=50, R
1for CH
3(CH
2)
5nH-, is designated as PGA
45-co-PLys
50.
The polymer P GA with formula I structure that utilizes Zeta-Potential potentiometer test implementation example 5 to prepare
45-co-PLys
50current potential overturn point, measure its variation tendency, the results are shown in Figure 1, Fig. 1 and be the changing trend diagram of the current potential overturn point of the polymer with formula I structure prepared by the embodiment of the present invention, wherein, curve c is the polymer P GA with formula I structure that the embodiment of the present invention 5 provides
45-co-PLys
50the changing trend diagram of current potential overturn point.As shown in Figure 1, polymer P GA
45-co-PLys
50there is pH value sensitivity.
Embodiment 6
Get an ampulla, add a magneton, evacuation roasting bottle on one side on one side, applying argon gas in bottle afterwards, three times so repeatedly, finally be evacuated, by bottle fast transfer to glove box, and the CBZ-Lys-NCA that adds respectively BLG-NCA prepared by 0.7316g embodiment 1 and 1.2684g embodiment 2 to prepare, to after bottle seal, take out, then in bottle, adding 12mL DMF to incite somebody to action wherein solid dissolves completely, squeeze into the DMF solution 0.713g that concentration is the n-hexylamine of 0.0975mmol/g with syringe, add afterwards 3mLDMF, stirring reaction 3 days under room temperature, then product is carried out to sedimentation with 200mL absolute ether, obtain white opacity thing, subzero 80 degrees Celsius of freeze overnight, it was carried out after centrifugal obtaining white solid in second day, then it is carried out to vacuum drying and obtain polymer.The polymer obtaining is transferred in beaker, add appropriate trifluoroacetic acid that it is dissolved completely, the acetum (33wt%) of adding afterwards a certain amount of trifluoroacetic acid and HBr makes sample: trifluoroacetic acid: the mass ratio of HBr/ acetic acid is 1:10:3, after one hour with the absolute ether sedimentation of 10 times of amounts, obtain afterwards white solid, after vacuum drying 24h, samples with water is dissolved, in the bag filter of 3500mL, dialyse, after there is no tart flavour completely, lyophilization, obtains the white lyophilized powder of the polymer with formula I structure.
The above-mentioned polymer with formula I structure is carried out to nuclear magnetic resonance, NMR test, and result of calculation shows, in formula I, and m=40, n=56, R
1for CH
3(CH
2)
5nH-, is designated as PGA
40-co-PLys
56.
The polymer P GA with formula I structure that utilizes Zeta-Potential potentiometer test implementation example 6 to prepare
40-co-PLys
56current potential overturn point, measure its variation tendency, the results are shown in Figure 1, Fig. 1 and be the changing trend diagram of the current potential overturn point of the polymer with formula I structure prepared by the embodiment of the present invention, wherein, curve d is the polymer P GA with formula I structure that the embodiment of the present invention 6 provides
40-co-PLys
56the changing trend diagram of current potential overturn point.As shown in Figure 1, polymer P GA
40-co-PLys
56there is pH value sensitivity.
Get an ampulla, add a magneton, evacuation roasting bottle on one side on one side, applying argon gas in bottle afterwards, three times so repeatedly, finally be evacuated, by bottle fast transfer to glove box, and the CBZ-Lys-NCA that adds respectively BLG-NCA prepared by 0.356g embodiment 1 and 1.644g embodiment 2 to prepare, to after bottle seal, take out, then in bottle, adding 12mL DMF to incite somebody to action wherein solid dissolves completely, squeeze into the DMF solution 0.693g that concentration is the n-hexylamine of 0.0975mmol/g with syringe, add afterwards 3mLDMF, stirring reaction 3 days under room temperature, then product is carried out to sedimentation with 200mL absolute ether, obtain white opacity thing, subzero 80 degrees Celsius of freeze overnight, it was carried out after centrifugal obtaining white solid in second day, then it is carried out to vacuum drying and obtain polymer.The polymer obtaining is transferred in beaker, add appropriate trifluoroacetic acid that it is dissolved completely, the acetum (33wt%) of adding afterwards a certain amount of trifluoroacetic acid and HBr makes sample: trifluoroacetic acid: the mass ratio of HBr/ acetic acid is 1:10:3, after one hour with the absolute ether sedimentation of 10 times of amounts, obtain afterwards white solid, after vacuum drying 24h, samples with water is dissolved, in the bag filter of 3500mL, dialyse, after there is no tart flavour completely, lyophilization, obtains the white lyophilized powder of the polymer with formula I structure.
The above-mentioned polymer with formula I structure is carried out to nuclear magnetic resonance, NMR test, and result of calculation shows, in formula I, and m=20, n=65, R
1for CH
3(CH
2)
5nH-, is designated as PGA
20-co-PLys
65.
The polymer P GA with formula I structure that utilizes Zeta-Potential potentiometer test implementation example 7 to prepare
20-co-PLys
65current potential overturn point, measure its variation tendency, the results are shown in Figure 1, Fig. 1 and be the changing trend diagram of the current potential overturn point of the polymer with formula I structure prepared by the embodiment of the present invention, wherein, curve e is the polymer P GA with formula I structure that the embodiment of the present invention 7 provides
20-co-PLys
65the changing trend diagram of current potential overturn point.As shown in Figure 1, polymer P GA
20-co-PLys
65there is pH value sensitivity.
By the PGA of preparation in 30mg embodiment 3
70-co-PLys
19be dissolved in 37ml distilled water, regulating pH value is 8.0, adds 5.5mg cisplatin, 37 degrees Celsius of lucifuge vibration 72h, and pure water dialysis 24h, changes water 3 times, obtains the micellar solution of Platinum complexes.Its Pt content utilizes inductivity coupled plasma mass spectrometry to measure, according to following formula computational envelope efficiency (DLE) and retention volume (DLC);
The encapsulation efficiency of the Platinum complexes obtaining is 88.6%, and retention volume is 0.43mmol/g.
Utilize the current potential overturn point of Platinum complexes prepared by Zeta-Potential potentiometer test implementation example 8, measure its variation tendency, the results are shown in Figure 2, Fig. 2 is the changing trend diagram of the current potential overturn point of the Platinum complexes of the embodiment of the present invention 8 ~ 10 preparations, wherein, curve a is the changing trend diagram of the current potential overturn point of the Platinum complexes prepared of the embodiment of the present invention 8.As shown in Figure 2, the Platinum complexes that the embodiment of the present invention 8 provides has good pH value sensitivity.
The Platinum complexes that the embodiment of the present invention 8 is provided carries out slow-release capability detection.Under the condition of 37 degrees Celsius, take Platinum complexes prepared by 5mg embodiment 8, be dissolved in the phosphate buffered solution that 5mL 0.01mol/L pH value is 5.3, then this solution is transferred to bag filter, the molecular cut off of bag filter used is 3500, dialyse with the phosphate buffer that 40mLpH value is 5.3, sample respectively 3mL at 5h, 12h, 24h, 48h, 72h, 96h, and to add 3mL pH value be 5.3 phosphate buffered solution; Utilize inductivity coupled plasma mass spectrometry to carry out quantitative analysis, obtain accumulative total and discharge the variation relation that percentage ratio increased along with the time, it is that Platinum complexes prepared by the embodiment of the present invention 8 is to discharge the curve chart of cisplatin at 5.3 o'clock at pH that release the results are shown in Figure 3, Fig. 3.As shown in Figure 3, the Platinum complexes that the embodiment of the present invention 8 provides has slow-release capability.
Embodiment 9
By the PGA of preparation in 30mg embodiment 3
70-co-PLys
19be dissolved in 37ml distilled water, regulating pH value is 8.0, adds 11.1mg cisplatin, 37 degrees Celsius of lucifuge vibration 72h, and pure water dialysis 24h, changes water 3 times, obtains the micellar solution of Platinum complexes.
Its Pt content utilizes inductivity coupled plasma mass spectrometry to measure, and according to the formula computational envelope efficiency (DLE) providing in embodiment 8 and retention volume (DLC), the encapsulation efficiency of the Platinum complexes obtaining is 63.4%, and retention volume is 0.536mmol/g.
Utilize the current potential overturn point of Platinum complexes prepared by Zeta-Potential potentiometer test implementation example 9, measure its variation tendency, the results are shown in Figure 2, Fig. 2 is the changing trend diagram of the current potential overturn point of the Platinum complexes of the embodiment of the present invention 8 ~ 10 preparations, wherein, curve b is the changing trend diagram of the current potential overturn point of the Platinum complexes prepared of the embodiment of the present invention 9.As shown in Figure 2, the Platinum complexes that the embodiment of the present invention 9 provides has good pH value sensitivity.
The detection method that adopts embodiment 8, the Platinum complexes that the embodiment of the present invention 9 is provided carries out slow-release capability detection.Testing result shows, the Platinum complexes that the embodiment of the present invention 9 provides has slow-release capability.
By the PGA of preparation in 30mg embodiment 3
70-co-PLys
19be dissolved in 37ml distilled water, regulating pH value is 8.0, adds 16.7mg cisplatin, 37 degrees Celsius of lucifuge vibration 72h, and pure water dialysis 24h, changes water 3 times, obtains the micellar solution of Platinum complexes.
Its Pt content utilizes inductivity coupled plasma mass spectrometry to measure, and according to the formula computational envelope efficiency (DLE) providing in embodiment 8 and retention volume (DLC), the encapsulation efficiency of the Platinum complexes obtaining is 64.4%, and retention volume is 0.535mmol/g.
Utilize the current potential overturn point of Platinum complexes prepared by Zeta-Potential potentiometer test implementation example 10, measure its variation tendency, the results are shown in Figure 2, Fig. 2 is the changing trend diagram of the current potential overturn point of the Platinum complexes of the embodiment of the present invention 8 ~ 10 preparations, wherein, curve c is the changing trend diagram of the current potential overturn point of the Platinum complexes prepared of the embodiment of the present invention 10.As shown in Figure 2, the Platinum complexes that the embodiment of the present invention 10 provides has good pH value sensitivity.
The detection method that adopts embodiment 8, the Platinum complexes that the embodiment of the present invention 10 is provided carries out slow-release capability detection.Testing result shows, the Platinum complexes that the embodiment of the present invention 10 provides has slow-release capability.
By the PGA of preparation in 40mg embodiment 4
60-co-PLys
40be dissolved in 37ml distilled water, regulating pH value is 8.0, adds 5.5mg cisplatin, 37 degrees Celsius of lucifuge vibration 72h, and pure water dialysis 24h, changes water 3 times, obtains the micellar solution of Platinum complexes.
Its Pt content utilizes inductivity coupled plasma mass spectrometry to measure, and according to the formula computational envelope efficiency (DLE) providing in embodiment 8 and retention volume (DLC), the encapsulation efficiency of the Platinum complexes obtaining is 47.3%, and retention volume is 0.246mmol/g.
Utilize the current potential overturn point of Platinum complexes prepared by Zeta-Potential potentiometer test implementation example 11, measure its variation tendency, the results are shown in Figure 4, Fig. 4 is the changing trend diagram of the current potential overturn point of the Platinum complexes of the embodiment of the present invention 11 ~ 13 preparations, wherein, curve a is the changing trend diagram of the current potential overturn point of the Platinum complexes prepared of the embodiment of the present invention 11.As shown in Figure 4, the Platinum complexes that the embodiment of the present invention 11 provides has good pH value sensitivity.
The detection method that adopts embodiment 8, the Platinum complexes that the embodiment of the present invention 11 is provided carries out slow-release capability detection.Testing result shows, the Platinum complexes that the embodiment of the present invention 11 provides has slow-release capability.
Embodiment 12
By the PGA of preparation in 40mg embodiment 4
60-co-PLys
40be dissolved in 37ml distilled water, regulating pH value is 8.0, adds 11.1mg cisplatin, 37 degrees Celsius of lucifuge vibration 72h, and pure water dialysis 24h, changes water 3 times, obtains the micellar solution of Platinum complexes.
Its Pt content utilizes inductivity coupled plasma mass spectrometry to measure, and according to the formula computational envelope efficiency (DLE) providing in embodiment 8 and retention volume (DLC), the encapsulation efficiency of the Platinum complexes obtaining is 33.2%, and retention volume is 0.263mmol/g.
Utilize the current potential overturn point of Platinum complexes prepared by Zeta-Potential potentiometer test implementation example 12, measure its variation tendency, the results are shown in Figure 4, Fig. 4 is the changing trend diagram of the current potential overturn point of the Platinum complexes of the embodiment of the present invention 11 ~ 13 preparations, wherein, curve b is the changing trend diagram of the current potential overturn point of the Platinum complexes prepared of the embodiment of the present invention 12.As shown in Figure 4, the Platinum complexes that the embodiment of the present invention 12 provides has good pH value sensitivity.
The detection method that adopts embodiment 8, the Platinum complexes that the embodiment of the present invention 12 is provided carries out slow-release capability detection.Testing result shows, the Platinum complexes that the embodiment of the present invention 12 provides has slow-release capability.
Embodiment 13
By the PGA of preparation in 40mg embodiment 4
60-co-PLys
40be dissolved in 37ml distilled water, regulating pH value is 8.0, adds 16.7mg cisplatin, 37 degrees Celsius of lucifuge vibration 72h, and pure water dialysis 24h, changes water 3 times, obtains the micellar solution of Platinum complexes.
Its Pt content utilizes inductivity coupled plasma mass spectrometry to measure, and according to the formula computational envelope efficiency (DLE) providing in embodiment 8 and retention volume (DLC), the encapsulation efficiency of the Platinum complexes obtaining is 30.7%, and retention volume is 0.144mmol/g.
Utilize the current potential overturn point of Platinum complexes prepared by Zeta-Potential potentiometer test implementation example 13, measure its variation tendency, the results are shown in Figure 4, Fig. 4 is the changing trend diagram of the current potential overturn point of the Platinum complexes of the embodiment of the present invention 11 ~ 13 preparations, wherein, curve c is the changing trend diagram of the current potential overturn point of the Platinum complexes prepared of the embodiment of the present invention 13.As shown in Figure 4, the Platinum complexes that the embodiment of the present invention 13 provides has good pH value sensitivity.
The detection method that adopts embodiment 8, the Platinum complexes that the embodiment of the present invention 13 is provided carries out slow-release capability detection.Testing result shows, the Platinum complexes that the embodiment of the present invention 13 provides has slow-release capability.
Embodiment 14
By the PGA of preparation in 40mg embodiment 5
45-co-PLys
50be dissolved in 30ml distilled water, regulating pH value is 8.0, adds 4.5mg cisplatin, 37 degrees Celsius of lucifuge vibration 72h, and pure water dialysis 24h, changes water 3 times, obtains the micellar solution of Platinum complexes.
Its Pt content utilizes inductivity coupled plasma mass spectrometry to measure, and according to the formula computational envelope efficiency (DLE) providing in embodiment 8 and retention volume (DLC), the encapsulation efficiency of the Platinum complexes obtaining is 14.4%, and retention volume is 0.052mmol/g.
Utilize the current potential overturn point of Platinum complexes prepared by Zeta-Potential potentiometer test implementation example 14, measure its variation tendency, the results are shown in Figure 5, Fig. 5 is the changing trend diagram of the current potential overturn point of the Platinum complexes of the embodiment of the present invention 14 ~ 16 preparations, wherein, curve a is the changing trend diagram of the current potential overturn point of the Platinum complexes prepared of the embodiment of the present invention 14.As shown in Figure 5, the Platinum complexes that the embodiment of the present invention 14 provides has good pH value sensitivity.
The detection method that adopts embodiment 8, the Platinum complexes that the embodiment of the present invention 14 is provided carries out slow-release capability detection.Testing result shows, the Platinum complexes that the embodiment of the present invention 14 provides has slow-release capability.
Embodiment 15
By the PGA of preparation in 40mg embodiment 5
45-co-PLys
50be dissolved in 30ml distilled water, regulating pH value is 8.0, adds 8.1mg cisplatin, 37 degrees Celsius of lucifuge vibration 72h, and pure water dialysis 24h, changes water 3 times, obtains the micellar solution of Platinum complexes.
Its Pt content utilizes inductivity coupled plasma mass spectrometry to measure, and according to the formula computational envelope efficiency (DLE) providing in embodiment 8 and retention volume (DLC), the encapsulation efficiency of the Platinum complexes obtaining is 14.8%, and retention volume is 0.072mmol/g.
Utilize the current potential overturn point of Platinum complexes prepared by Zeta-Potential potentiometer test implementation example 15, measure its variation tendency, the results are shown in Figure 5, Fig. 5 is the changing trend diagram of the current potential overturn point of the Platinum complexes of the embodiment of the present invention 14 ~ 16 preparations, wherein, curve b is the changing trend diagram of the current potential overturn point of the Platinum complexes prepared of the embodiment of the present invention 15.As shown in Figure 5, the Platinum complexes that the embodiment of the present invention 15 provides has good pH value sensitivity.
The detection method that adopts embodiment 8, the Platinum complexes that the embodiment of the present invention 15 is provided carries out slow-release capability detection.Testing result shows, the Platinum complexes that the embodiment of the present invention 15 provides has slow-release capability.
By the PGA of preparation in 40mg embodiment 5
45-co-PLys
50be dissolved in 30ml distilled water, regulating pH value is 8.0, adds 9.0mg cisplatin, 37 degrees Celsius of lucifuge vibration 72h, and pure water dialysis 24h, changes water 3 times, obtains the micellar solution of Platinum complexes.
Its Pt content utilizes inductivity coupled plasma mass spectrometry to measure, and according to the formula computational envelope efficiency (DLE) providing in embodiment 8 and retention volume (DLC), the encapsulation efficiency of the Platinum complexes obtaining is 15.7%, and retention volume is 0.118mmol/g.
Utilize the current potential overturn point of Platinum complexes prepared by Zeta-Potential potentiometer test implementation example 16, measure its variation tendency, the results are shown in Figure 5, Fig. 5 is the changing trend diagram of the current potential overturn point of the Platinum complexes of the embodiment of the present invention 14 ~ 16 preparations, wherein, curve c is the changing trend diagram of the current potential overturn point of the Platinum complexes prepared of the embodiment of the present invention 16.As shown in Figure 5, the Platinum complexes that the embodiment of the present invention 16 provides has good pH value sensitivity.
The detection method that adopts embodiment 8, the Platinum complexes that the embodiment of the present invention 16 is provided carries out slow-release capability detection.Testing result shows, the Platinum complexes that the embodiment of the present invention 16 provides has slow-release capability.
From above-described embodiment, Platinum complexes provided by the invention has higher drug loading and good encapsulation efficiency, and has good pH sensitivity and good slow-release capability.
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (10)
1. a Platinum complexes, is characterized in that, is coordinated and forms with the polymer with formula I structure by cisplatin:
Wherein, m is the degree of polymerization, 20≤m≤100; N is the degree of polymerization, 20≤n≤100;
R
1be selected from CH
3(CH
2) rNH-, 3≤r≤7.
2. Platinum complexes according to claim 1, is characterized in that, described in to have in the polymer of formula I structure the mol ratio of Pt in carboxyl and cisplatin be 5～20:1.
3. Platinum complexes according to claim 1, is characterized in that, described in to have in the polymer of formula I structure the mol ratio of Pt in carboxyl and cisplatin be 8～16:1.
4. a preparation method for Platinum complexes, is characterized in that, comprises the following steps:
By cisplatin and the polymer mixed with formula I structure, there is complex reaction, obtain Platinum complexes;
Wherein, m is the degree of polymerization, 20≤m≤100; N is the degree of polymerization, 20≤n≤100;
R
1be selected from CH
3(CH
2) rNH-, 3≤r≤7.
5. preparation method according to claim 4, is characterized in that, described in to have in the polymer of formula I structure the mol ratio of Pt in carboxyl and cisplatin be 5～20:1.
6. preparation method according to claim 4, is characterized in that, described in to have in the polymer of formula I structure the mol ratio of Pt in carboxyl and cisplatin be 8～16:1.
7. preparation method according to claim 4, is characterized in that, described complex reaction for to carry out in aqueous medium.
8. preparation method according to claim 7, is characterized in that, described aqueous medium is selected from any one or a few in distilled water, normal saline, buffer solution, tissue culture medium and body fluid.
9. preparation method according to claim 4, is characterized in that, described in there is formula I structure polymer prepare in accordance with the following methods:
A) will have the monomer of formula II structure and the monomer of formula III structure mixes with initiator, carry out random copolymerization reaction, obtain polymer, described initiator has formula (V) structure;
B) by steps A) polymer that obtains carries out deprotection, obtains having the polymer of formula I structure;
CH
3(CH
2) rNH
2(V), wherein, 3≤r≤7.
10. preparation method according to claim 9, is characterized in that, described initiator is selected from any one or a few in n-butylamine, n-hexylamine and 1-Aminooctane.
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| CN102604082A (en) * | 2012-02-15 | 2012-07-25 | 中国科学院长春应用化学研究所 | Cis-platinum coordination compound and preparation method thereof |
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Effective date of registration: 20170116 Address after: Changzhou City, Jiangsu province Hehai road 213000 No. 9 Patentee after: Changzhou Institute of Energy Storage Materials & Devices Address before: 130022 Changchun people's street, Jilin, No. 5625 Patentee before: Changchun Applied Chemistry Inst., Chinese Academy of Sciences |