CN103394095A - [Dichloro-1,2-cyclohexanediamine]platinum complex and preparation method thereof - Google Patents
[Dichloro-1,2-cyclohexanediamine]platinum complex and preparation method thereof Download PDFInfo
- Publication number
- CN103394095A CN103394095A CN2013103614301A CN201310361430A CN103394095A CN 103394095 A CN103394095 A CN 103394095A CN 2013103614301 A CN2013103614301 A CN 2013103614301A CN 201310361430 A CN201310361430 A CN 201310361430A CN 103394095 A CN103394095 A CN 103394095A
- Authority
- CN
- China
- Prior art keywords
- cyclohexanediamine
- chloro
- platinum
- alkyl
- independently
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a [dichloro-1,2-cyclohexanediamine]platinum complex, and the complex is obtained from the complex reactions between dichloro-1,2-cyclohexanediamine and a polymer which has the structure of the formula (I). The [Dichloro-1,2-cyclohexanediamine]platinum has a cyclohexanediamine structure, a stable inner-core structure is formed because of the accumulation and hydrophobic effect after the [Dichloro-1,2-cyclohexanediamine]platinum cooperate with a polymer, and the stability of the [Dichloro-1,2-cyclohexanediamine]platinum is good under physiology conditions. The complex can effectively avoid the problems of sudden release and non-specific interaction of [Dichloro-1,2-cyclohexanediamine]platinum after [Dichloro-1,2-cyclohexanediamine]platinum enters the blood circulation system through intravenous route. The complex can be assembled to form a micelle structure; accumulation of the complex on the tumor locations can be achieved through strengthening osmotic and retention effects, and thus the goals of reducing toxic and by effects and improving curative effects are achieved. Furthermore, the adopted complex has a good biological compatibility, is capable of degrading in human bodies, and thus the prepared [Dichloro-1,2-cyclohexanediamine]platinum has a good solubility.
Description
Technical field
The present invention relates to the polymer drug field, particularly two is chloro-1, and the 2-cyclohexanediamine closes platinum complex and preparation method thereof.
Background technology
Oxaliplatin (oxalate base-1, the 2-cyclohexanediamine closes platinum) be the cancer therapy drug with cytotoxicity, because its oncotherapy spectrum is wider, with cisplatin without cross resistance, become the representative of third generation platinum medicine, in 2002, by the approval of U.S. food Drug Administration, be used for clinical practice.
Oxaliplatin needs to produce two chloro-1 through hydrolysis after entering in body, the 2-cyclohexanediamine closes platinum or hydration 1, the 2-cyclohexanediamine closes platinum, and then be combined and play antitumor action (B.Desoize with DNA or RNA, et al.Critical Reviews in Oncology/Hematology, therefore 42 (2002) 317-325), two is chloro-1, and the 2-cyclohexanediamine closes the prodrug that platinum (DACHPt) can be considered as oxaliplatin.As the homologue of oxaliplatin, two is chloro-1, and the 2-cyclohexanediamine closes platinum and wants high a lot of than the functioning efficiency of oxaliplatin, but therefore its dissolubility and poor stability do not find broad application.
Prior art discloses the multiple mode of utilizing polymer support to support medicine and has developed two chloro-ly 1, and the 2-cyclohexanediamine closes the method for platinum preparation.The PEGization liposome that utilizes as the I.Han report supports two chloro-1, the 2-cyclohexanediamine closes platinum derivatives can improve its therapeutic effect, yet this loading mode just has the drug release over 50% after 2 hours in phosphate buffered solution, therefore can't guarantee the long cyclicity after medicine enters blood.The seminar of Kataoka utilizes Polyethylene Glycol-b-polyglutamic acid compound two chloro-1, the 2-cyclohexanediamine closes DACHPt micelle (H.Cabral prepared by platinum, et al.Journal of Control Release, 101 (2005) 223-232) can stablize and support platinum medicine, and realize building up concentration than the tumor locus of high 20 times of oxaliplatin.But its gained micelle is through crosslinked action, to form between linear polyamino acid side chain, and the lyophilized powder of the method gained complex after lyophilizing is difficult to redissolve, thereby limited its further application.
Summary of the invention
The technical problem that the present invention solves is to provide a kind of two chloro-1, the 2-cyclohexanediamine closes platinum complex, has good dissolubility, stable existence under physiological condition, and can effectively avoid because intravenous injection enters the problems such as the sudden outburst that occurs after blood circulation and non-specific interaction.
The invention discloses a kind of two chloro-ly 1, the 2-cyclohexanediamine closes platinum complex, and by two chloro-1, the 2-cyclohexanediamine closes platinum and coordinates formation with the polymer with formula (I) structure,
In formula (I), R
1Independently be selected from the straight chained alkyl of C2～C10, branched alkyl, phenyl or the R ' of C3～C10-CO-, R ' independently is selected from the straight chained alkyl of C2～C10, branched alkyl or the phenyl of C3～C10;
R
2Independently be selected from the alkyl of the C1～C20 of the alkyl of H atom, C1～C20 or replacement;
R
3Independently be selected from H atom or cation;
L independently is selected from-CH
2-or-CH
2-CH
2-;
M is the degree of polymerization, 40≤m≤250; X, y, z are the degree of polymerization, 10≤x+y+z≤5000,5%≤y/ (x+y+z)≤80%.
Preferably, R
2Independently be selected from the alkyl of the C1～C10 of the alkyl of C1～C10 or replacement, the substituent group of the alkyl of described replacement is selected from one or more in ketal, acetal, hydroxyl, aldehyde radical, amino, sulfydryl and saccharide residue;
R
3Independently be selected from H atom, metal cation or organic cation.
Preferably, R
3Independently be selected from subgroup, amine ion or the aminoacid ion of H atom, sodium ion, potassium ion, magnesium.
Preferably, 30≤x+y+z≤300,5%≤y/ (x+y+z)≤50%.
Preferably, R
1For C6 alkyl, R
2For methyl, R
3For hydrogen atom or sodium ion, L are-CH
2-CH
2-.
The invention also discloses a kind of two chloro-ly 1, the 2-cyclohexanediamine closes the preparation method of platinum complex, comprises the following steps:
Two is chloro-1, and the 2-cyclohexanediamine closes platinum, with the polymer with formula (I) structure, complex reaction occurs in aqueous medium, generates two chloro-ly 1, and the 2-cyclohexanediamine closes platinum complex;
In formula (I), R
1Independently be selected from the straight chained alkyl of C2～C10, branched alkyl, phenyl or the R ' of C3～C10-CO-, R ' independently is selected from the straight chained alkyl of C2～C10, branched alkyl or the phenyl of C3～C10;
R
2Independently be selected from the alkyl of the C1～C20 of the alkyl of H atom, C1～C20 or replacement;
R
3Independently be selected from H atom or cation;
L independently is selected from-CH
2-or-CH
2-CH
2-;
M is the degree of polymerization, 40≤m≤250; X, y, z are the degree of polymerization, 10≤x+y+z≤5000,5%≤y/ (x+y+z)≤80%.
Preferably, described two is chloro-1, and the 2-cyclohexanediamine closes platinum and also comprises other derivants with 1,2-cyclohexanediamine part.
Preferably, the carboxyl of described polymer with formula (I) structure and two chloro-1, the 2-cyclohexanediamine closes the mol ratio of Pt in platinum less than 20.
Preferably, the carboxyl of described polymer with formula (I) structure and two chloro-1, the 2-cyclohexanediamine closes the mol ratio of Pt in platinum less than 10.
Preferably, described aqueous medium is water, normal saline, buffer solution, tissue culture medium or body fluid.
Compared with prior art, it is two chloro-1 that the present invention utilizes, and it is two chloro-1 that the 2-cyclohexanediamine closes that platinum and the polymer with formula (I) structure prepare, and the 2-cyclohexanediamine closes platinum complex.Described two is chloro-1, and the 2-cyclohexanediamine closes platinum and has the cyclohexanediamine structure, its with can form stable inner core due to accumulation and hydrophobic interaction after polymer coordinates, good at the physiological condition stability inferior; Described coordination compound can effectively be avoided because intravenous injection enters after blood circulation occur two chloro-1, and the 2-cyclohexanediamine closes the problems such as the sudden outburst of platinum and non-specific interaction; Described coordination compound can be assembled formation micellar structure, can permeate and retention effect (EPR effect) is realized the accumulation at tumor locus by enhancing, thus the purpose that realizes reducing toxic and side effects and improve therapeutic effect.Secondly, the polymer that adopts has good biocompatibility, but vivo degradation; Described polymer adopts grafting method side chain keyed jointing Polyethylene Glycol, and therefore two of preparation is chloro-1, and the 2-cyclohexanediamine closes platinum complex and has good dissolubility.
The accompanying drawing explanation
Fig. 1 embodiment of the present invention 2 preparation two chloro-1, the 2-cyclohexanediamine closes the hydrodynamic radius scattergram of platinum complex;
Fig. 2 is the two chloro-1 of the embodiment of the present invention 2 preparation, and the 2-cyclohexanediamine closes the releasing curve diagram of platinum complex when pH=7.4 and pH=5.5;
Fig. 3 is the two chloro-1 of the embodiment of the present invention 2 preparation, and the 2-cyclohexanediamine closes the light scattering diagram of platinum complex micelle;
In Fig. 4 embodiment of the present invention 2, two of preparation is chloro-1, and the 2-cyclohexanediamine closes platinum complex and the naked medicine of oxaliplatin to the Effect tests of A549 cell figure as a result.
The specific embodiment
In order further to understand the present invention, below in conjunction with embodiment, the preferred embodiment of the invention is described, but should be appreciated that these are described is for further illustrating the features and advantages of the present invention, rather than limiting to the claimed invention.
The embodiment of the invention discloses a kind of two chloro-ly 1, the 2-cyclohexanediamine closes platinum complex, and by two chloro-1, the 2-cyclohexanediamine closes platinum and coordinates formation with the polymer with formula (I) structure,
In formula (I), R
1Independently be selected from the straight chained alkyl of C2～C10, branched alkyl, phenyl or the R ' of C3～C10-CO-, R ' independently is selected from the straight chained alkyl of C2～C10, branched alkyl or the phenyl of C3～C10, R
1Be preferably straight chained alkyl, the branched alkyl of C4～C8, the phenyl of C3～C8, more preferably the C6 alkyl;
R
2Independently be selected from the alkyl of the C1～C20 of the alkyl of H atom, C1～C20 or replacement, be preferably the alkyl of the C1～C10 of the alkyl of H atom, C1～C10 or replacement, the substituent group of the alkyl of described replacement is selected from one or more in ketal, acetal, hydroxyl, aldehyde radical, amino, sulfydryl and saccharide residue;
R
3Independently be selected from H atom or cation, be preferably H atom, metal cation or organic cation, more preferably the subgroup of H atom, sodium ion, potassium ion, magnesium, amine ion or aminoacid ion, most preferably be H atom or sodium ion;
L independently is selected from-CH
2-or-CH
2-CH
2-;
M is the degree of polymerization, and 40≤m≤250 are preferably 45≤m≤200; X, y, z are the degree of polymerization, 10≤x+y+z≤5000 are preferably 30≤x+y+z≤300, more preferably 50≤x+y+z≤250; 5%≤y/ (x+y+z)≤80%, be preferably 5%≤y/ (x+y+z)≤50%.
In the present invention, the polymer that has formula (I) structure is preferably R
1For n-hexyl, R
2For methyl, R
3For the H atom, L is-CH
2-.At this moment, polymer has the structure of formula (I-a).
M is the degree of polymerization, and 40≤m≤250 are preferably 45≤m≤200; X, y, z are the degree of polymerization, 10≤x+y+z≤5000 are preferably 30≤x+y+z≤300, more preferably 50≤x+y+z≤250; 5%≤y/ (x+y+z)≤80%, be preferably 5%≤y/ (x+y+z)≤50%.
In the present invention, the polymer that has formula (I) structure is preferably R
1For n-hexyl, R
2For methyl, R
3For the H atom, L is-CH
2-CH
2-.At this moment, polymer has the structure of formula (I-b).
M is the degree of polymerization, and 40≤m≤250 are preferably 45≤m≤200; X, y, z are the degree of polymerization, 10≤x+y+z≤5000 are preferably 30≤x+y+z≤300, more preferably 50≤x+y+z≤250; 5%≤y/ (x+y+z)≤80%, be preferably 5%≤y/ (x+y+z)≤50%.
In the present invention, the polymer that has formula (I) structure is preferably R
1For n-hexyl, R
2For H atom, R
3For the H atom, L is-CH
2-.At this moment, polymer has the structure of formula (I-c).
M is the degree of polymerization, and 40≤m≤250 are preferably 45≤m≤200; X, y, z are the degree of polymerization, 10≤x+y+z≤5000 are preferably 30≤x+y+z≤300, more preferably 50≤x+y+z≤250; 5%≤y/ (x+y+z)≤80%, be preferably 5%≤y/ (x+y+z)≤50%.
In the present invention, the polymer that has formula (I) structure is preferably R
1For n-hexyl, R
2For H atom, R
3For the H atom, L is-CH
2-CH
2-.At this moment, polymer has the structure of formula (I-d).
M is the degree of polymerization, and 40≤m≤250 are preferably 45≤m≤200; X, y, z are the degree of polymerization, 10≤x+y+z≤5000 are preferably 30≤x+y+z≤300, more preferably 50≤x+y+z≤250; 5%≤y/ (x+y+z)≤80%, be preferably 5%≤y/ (x+y+z)≤50%.
The embodiment of the invention also discloses a kind of two chloro-1, the 2-cyclohexanediamine closes the preparation method of platinum complex, comprise the following steps: two chloro-1, the 2-cyclohexanediamine closes platinum, with the polymer with formula (I) structure, complex reaction occurs in aqueous medium, generate two chloro-ly 1, the 2-cyclohexanediamine closes platinum complex;
In formula (I), R
1Independently be selected from the straight chained alkyl of C2～C10, branched alkyl, phenyl or the R ' of C3～C10-CO-, R ' independently is selected from the straight chained alkyl of C2～C10, branched alkyl or the phenyl of C3～C10, R
1Be preferably straight chained alkyl, the branched alkyl of C4～C8, the phenyl of C3～C8, more preferably the C6 alkyl;
R
2Independently be selected from the alkyl of the C1～C20 of the alkyl of H atom, C1～C20 or replacement; be preferably the alkyl of the C1～C10 of the alkyl of H atom, C1～C10 or replacement, the substituent group of the alkyl of described replacement is selected from one or more in ketal, acetal, hydroxyl, aldehyde radical, amino, sulfydryl and saccharide residue;
R
3Independently be selected from H atom or cation, be preferably H atom, metal cation or organic cation, more preferably the subgroup of H atom, sodium ion, potassium ion, magnesium, amine ion or aminoacid ion, most preferably be H atom or sodium ion;
L independently is selected from-CH
2-or-CH
2-CH
2-;
M is the degree of polymerization, and 40≤m≤250 are preferably 45≤m≤200; X, y, z are the degree of polymerization, 10≤x+y+z≤5000 are preferably 30≤x+y+z≤300, more preferably 50≤x+y+z≤250; 5%≤y/ (x+y+z)≤80%, be preferably 5%≤y/ (x+y+z)≤50%.
In the present invention, described have the polymer of formula (I) structure for supporting two chloro-1, the 2-cyclohexanediamine closes the carrier of platinum, two chloro-1, at least one chloride ion that the 2-cyclohexanediamine closes platinum is substituted by the carboxyl in polymer shown in formula (I) as leaving group, remaining chloride ion is likely substituted by hydrone or remains unchanged, and another ligand 1, the 2-cyclohexanediamine remains unchanged.If be two chloro-1, the 2-cyclohexanediamine closes two carboxyl generation mating reactions of platinum and described polymer, and it can be for coordinating in molecule, also can be for intermolecular cooperation, and to this, the present invention there is no particular restriction.
Described two is chloro-1, and the 2-cyclohexanediamine closes platinum and has the cyclohexanediamine structure, its with can form stable inner core due to accumulation and hydrophobic interaction after polymer coordinates, good at the physiological condition stability inferior; And can effectively avoid because intravenous injection enters the problems such as the sudden outburst that occurs after blood circulation and non-specific interaction.
In the present invention, described two is chloro-1, and the 2-cyclohexanediamine closes platinum and preferably includes various stereomeric homologue (as Journal of Medicinal Chemistry, the report in 21 (1978) 1315-1318), and any platinum medicine with 1,2-cyclohexanediamine part.
In the present invention, described carboxyl with formula (I) structural polymer and two chloro-1, the 2-cyclohexanediamine closes the mol ratio (COO-/Pt) of platinum preferably less than 20, more preferably less than 10.
In the present invention two chloro-1, the 2-cyclohexanediamine closes in the preparation method of platinum complex, two chloro-1, the 2-cyclohexanediamine close platinum with the polymer with formula (I) structure in aqueous medium coordinate can be by the method for direct hybrid reaction, also can be by at first using silver nitrate pretreatment two chloro-1, the 2-cyclohexanediamine closes platinum and obtains two hydrations-1, and the 2-cyclohexanediamine closes platinum and further with the method for the polymer reaction with formula (I) structure, obtains.Be preferably during the polymer that will have formula (I) structure under the lucifuge bar is dissolved in aqueous medium, regulate pH value, add 1,2-cyclohexanediamine to close platinum, carry out mating reaction, after dialysis or ultrafiltration, obtain two chloro-ly 1, the 2-cyclohexanediamine closes the platinum complex micelle.Described aqueous medium is water, normal saline, buffer solution, tissue culture medium or body fluid, and the organic solvent in not affecting into the micelle limit of power that mix to add such as ethanol, acetonitrile, DMF etc., is preferably deionized water.The pH value of described deionized water is preferably 6.5～8.5, and more preferably 7.0～8.0.The concentration of the carboxyl of described polymer in aqueous medium is preferably 0.1mM～100mM, and more preferably 1mM～60mM, most preferably be 2mM～20mM.After polymer is dissolved in aqueous medium, preferably its pH value is adjusted to 6.0～10.0, more preferably is adjusted to 7.0～9.0; Then add two chloro-ly 1, the 2-cyclohexanediamine closes platinum generation mating reaction, and the time of described mating reaction is preferably 24～72 hours, more preferably 48～72 hours; The temperature of described mating reaction is preferably 20 ℃～40 ℃.
According to the present invention two chloro-1, the 2-cyclohexanediamine closes the preparation method of platinum complex, and what obtain is described two chloro-1, and the 2-cyclohexanediamine closes platinum complex and is present in aqueous medium with the form of micelle, the hydrodynamic radius of described micelle is preferably 10nm～2000nm, more preferably 10nm～300nm.
Utilize the coordination compound that the method obtains after sterilizing, concentrated, interpolation adjuvant etc. processed, directly with liquid form, preserving or, for intravenous injection, also it can carried out making the lyophilized powder preservation or using after post processing.In described freeze-drying process, can add a small amount of freeze drying protectant, as one or more in micromolecule aminoacid, maltose, sucrose, lactose, glucose, mannitol.
The present invention also is not particularly limited described source with polymer of formula (I) structure, preferably preparation in accordance with the following methods:
Polymer with formula (II) structure, under dehydrant and catalyst combined effect, with the polymer generation graft reaction with formula (III) structure, the polymer of (I) structure that obtains having formula;
In formula (II), R
1Independently be selected from the straight chained alkyl of C2～C10, branched alkyl, phenyl or the R ' of C3～C10-CO-, R ' independently is selected from the straight chained alkyl of C2～C10, branched alkyl or the phenyl of C3～C10, R
1Be preferably straight chained alkyl, the branched alkyl of C4～C8, the phenyl of C3～C8, more preferably the C6 alkyl;
R
3Independently be selected from H or cation, be preferably H atom, metal cation or organic cation, more preferably the subgroup of H atom, sodium ion, potassium ion, magnesium, amine ion or aminoacid ion, most preferably be H atom or sodium ion;
L independently is selected from-CH
2-or-CH
2-CH
2-;
N, z are the degree of polymerization, and 10≤n+z≤5000 are preferably 30≤n+z≤300, more preferably 50≤n+z≤250; 5%≤z/ (n+z)≤80%, be preferably 5%≤z/ (n+z)≤50%;
In formula (III), R
2Independently be selected from alkyl or substituted alkyl; be preferably the alkyl of the C1～C10 of the alkyl of H atom, C1～C10 or replacement, the substituent group of the alkyl of described replacement is selected from one or more in ketal, acetal, hydroxyl, aldehyde radical, amino, sulfydryl and saccharide residue;
M is the degree of polymerization, and 40≤m≤250 are preferably 45≤m≤200.
The present invention prepares the reaction of the polymer with formula (I) structure preferably under the condition of inert gas shielding; the polymer that has the polymer of formula (II) structure and have formula (III) structure with after dissolution with solvents under the effect of dehydrant and catalyst, the polymer of graft reaction (I) structure that obtains having formula occurs.Described reaction temperature is preferably room temperature; The described response time is preferably 1～5 day; Described noble gas is preferably nitrogen, and the logical nitrogen time is preferably 0.5～1 hour; Described solvent is preferably dimethyl sulfoxide, DMF or dioxane, more preferably dimethyl sulfoxide; Described dehydrant is preferably 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride or N, N-DIC or N, one or more of N'-dicyclohexylcarbodiimide, N more preferably, N-DIC; Described catalyst is preferably the 4-lutidines.Obtain preferred dialysis 72 hours after described polymer with formula (I) structure, change water 12 times, the lyophilized powder of the polymer of (I) structure that lyophilization obtains having formula.
When the present invention has the polymer of formula (I) structure in preparation, take polymer with formula (II) structure with have the polymer of formula (III) structure as raw material; The present invention is not particularly limited the source of block copolymer with formula (II) or formula (III) structure.Wherein, preferably preparation in accordance with the following methods of formula (II):
γ-benzyl-Pidolidone or γ-benzyl-L-Aspartic acid are reacted under the effect of triphosgene, generate γ-benzyl-Pidolidone-N-carboxylic acid anhydrides monomer or γ-benzyl-L-Aspartic acid-N-carboxylic acid anhydrides monomer; The present invention is preferably under inert gas conditions, γ-benzyl-Pidolidone or γ-benzyl-L-Aspartic acid are added in oxolane, add the triphosgene reaction, sedimentation in solvent again after reaction, obtain recrystallization after solid, drying obtains γ-benzyl-Pidolidone-N-carboxylic acid anhydrides monomer or γ-benzyl-L-Aspartic acid-N-carboxylic acid anhydrides monomer, described solvent is preferably petroleum ether or normal hexane; Described noble gas is preferably nitrogen; The present invention is to described sedimentation, recrystallization and drying mode unrestricted, and sedimentation well known to those skilled in the art, recrystallization or drying mode get final product.
After obtaining γ-benzyl-Pidolidone-N-carboxylic acid anhydrides monomer or γ-benzyl-L-Aspartic acid-N-carboxylic acid anhydrides monomer, under the effect of the initiator with formula (IV) structure, it is carried out to ring-opening polymerization, obtain formula (II) amino acid copolymer after removing benzyl; Perhaps under the effect of the initiator with formula (IV) structure, γ-benzyl-Pidolidone-N-carboxylic acid anhydrides monomer or γ-benzyl-L-Aspartic acid-N-carboxylic acid anhydrides monomer are carried out to ring-opening polymerization, after removing benzyl, with sodium ion, potassium ion or magnesium ion, be mixed to get formula (II) amino acid copolymer;
R
1-NH
2(IV)；
In formula (IV), R
1Independently be selected from the straight chained alkyl of C2～C10, branched alkyl, phenyl or the R ' of C3～C10-CO-, R ' independently is selected from the straight chained alkyl of C2～C10, branched alkyl or the phenyl of C3～C10, R
1Be preferably straight chained alkyl, the branched alkyl of C4～C8, the phenyl of C3～C8, more preferably the C6 alkyl.The present invention is preferably under inert gas conditions; the dimethyl formamide solution that will have the initiator of formula (IV) structure joins in the dimethyl formamide solution of γ-benzyl-Pidolidone-N-carboxylic acid anhydrides monomer or γ-benzyl-L-Aspartic acid-N-carboxylic acid anhydrides monomer; sedimentation in solvent after reaction; filtration obtains solid, after dry rear debenzylation protecting group, obtains formula (II) amino acid copolymer.Described solvent is preferably ether; Described noble gas is preferably nitrogen; The present invention is for described sedimentation, filtration and drying mode unrestricted, and sedimentation well known to those skilled in the art, filtration and drying mode get final product.
In order further to understand the present invention, chloro-1 to provided by the invention two below in conjunction with embodiment, the 2-cyclohexanediamine closes platinum complex and preparation method thereof and describes, and protection scope of the present invention is not limited by the following examples.
Embodiment 1
By γ-benzyl of 10g-Pidolidone, under the condition of dry inert gas, add in the 100ml anhydrous tetrahydro furan, fully reaction under the effect of 6.5g triphosgene, then add the petroleum ether sedimentation, obtain solid, after recrystallization, drying, finally obtain 7.85g γ-benzyl-Pidolidone-N-carboxylic acid anhydrides (BLG-NCA) monomer; Under the condition of noble gas, the dimethyl formamide of n-hexylamine (DMF) solution is joined in the DMF solution of BLG-NCA, the amount of substance of n-hexylamine and γ-benzyl-Pidolidone-N-carboxylic acid anhydrides (BLG-NCA) compares 1:140, after reaction, add the ether sedimentation, filtration obtains solid, after drying, obtains the degree of polymerization and be 140 the glutamic with benzyl protecting group; After Deprotection, obtain formula (II) topology convergence degree and be 140 glutamic, be designated as PLG
140.
To the 1.010g PLG that adds above-mentioned preparation in the reaction bulb of drying
140, the 2.020g number-average molecular weight is 5000 poly glycol monomethyl ether, is designated as mPEG
5k, with dmso solution the stirring of 20mL drying, logical nitrogen 0.5 hour, add 24.7mg4-lutidines and 0.31ml N under room temperature, nitrogen protection condition, the N-DIC, and room temperature, stirring reaction 3 days, obtain product; By product dialysis 72 hours, change water 12 times, after lyophilization, must have the polymer lyophilized powder of formula (I-b) structure.
Described polymer is carried out to the nuclear magnetic resonance, NMR test, and calculating percent grafting is 5.00%, and reaction conversion ratio is 93%.Described polymer y=7 with formula (I-b) structure, be designated as P (Glu)
140-g-(mPEG
5k)
7.
Embodiment 2
P (Glu) by 54.0mg embodiment 1 preparation
140-g-(mPEG
5k)
7Be dissolved in the 25mL distilled water, regulating pH value is 8.0 left and right, adds 24.6mg bis-chloro-1, and the 2-cyclohexanediamine closes platinum, 37 ℃ of lucifuge reaction 72h, pure water dialysis 24h, change water and to remove, dissociate two chloro-16 times, the 2-cyclohexanediamine closes platinum, obtains two chloro-ly 1, and the 2-cyclohexanediamine closes the micelle of platinum complex; By described two chloro-1, it is freezing rapidly under aseptic condition that the 2-cyclohexanediamine closes the micelle of platinum complex, and it is two chloro-1 that lyophilization obtains, and the 2-cyclohexanediamine closes the platinum complex lyophilized powder, and its conversion ratio is 85%.
Measure the hydrodynamic radius of micelle, the results are shown in Figure 1, Fig. 1 is two chloro-1 of the embodiment of the present invention 2 preparations, the 2-cyclohexanediamine closes the hydrodynamic radius scattergram of platinum complex, result shows, two is chloro-1, and the hydrodynamic radius that the 2-cyclohexanediamine closes the platinum complex micelle is 41nm.
Two chloro-1 by what obtain, the 2-cyclohexanediamine closes the platinum complex lyophilized powder and redissolves, and its Pt content utilizes inductivity coupled plasma mass spectrometry to measure, according to following formula computational envelope efficiency (DLE) and retention volume (DLC);
What prepare is two chloro-1, and the encapsulation efficiency that the 2-cyclohexanediamine closes platinum complex is 87.2%, and retention volume is 0.91mmol Pt/g.
These embodiment that embodiment 3 adds are different drug loading
P (Glu) by 54.0mg embodiment 1 preparation
140-g-(mPEG
5k)
7Be dissolved in the 25mL distilled water, regulating pH value is 8.0 left and right, adds 12.3mg bis-chloro-1, and the 2-cyclohexanediamine closes platinum, 37 ℃ of lucifuge reaction 72h, pure water dialysis 24h, change water and to remove, dissociate two chloro-16 times, the 2-cyclohexanediamine closes platinum, obtains two chloro-ly 1, and the 2-cyclohexanediamine closes the micelle of platinum complex; By described two chloro-1, it is freezing rapidly under aseptic condition that the 2-cyclohexanediamine closes the micelle of platinum complex, and it is two chloro-1 that lyophilization obtains, and the 2-cyclohexanediamine closes the platinum complex lyophilized powder, and its conversion ratio is 93%.
Embodiment 4
P (Glu) by 54.0mg embodiment 1 preparation
140-g-(mPEG
5k)
7Be dissolved in the 25mL distilled water, regulating pH value is 8.0 left and right, adds 6.2mg bis-chloro-1, and the 2-cyclohexanediamine closes platinum, 37 ℃ of lucifuge reaction 72h, pure water dialysis 24h, change water and to remove, dissociate two chloro-16 times, the 2-cyclohexanediamine closes platinum, obtains two chloro-ly 1, and the 2-cyclohexanediamine closes the micelle of platinum complex; By described two chloro-1, it is freezing rapidly under aseptic condition that the 2-cyclohexanediamine closes the micelle of platinum complex, and it is two chloro-1 that lyophilization obtains, and the 2-cyclohexanediamine closes the platinum complex lyophilized powder, and its conversion ratio is 98%.
Embodiment 5
P (Glu) by 54.0mg embodiment 1 preparation
140-g-(mPEG
5k)
7Be dissolved in the 25mL distilled water, regulating pH value is 8.0 left and right, adds 3.1mg bis-chloro-1, and the 2-cyclohexanediamine closes platinum, 37 ℃ of lucifuge reaction 72h, pure water dialysis 24h, change water and to remove, dissociate two chloro-16 times, the 2-cyclohexanediamine closes platinum, obtains two chloro-ly 1, and the 2-cyclohexanediamine closes the micelle of platinum complex; By described two chloro-1, it is freezing rapidly under aseptic condition that the 2-cyclohexanediamine closes the micelle of platinum complex, and it is two chloro-1 that lyophilization obtains, and the 2-cyclohexanediamine closes the platinum complex lyophilized powder, and its conversion ratio is 98%.
Embodiment 6
Under the condition of 37 ℃, take respectively two chloro-1 of 5mg embodiment 2 preparations, the 2-cyclohexanediamine closes platinum complex, be dissolved in the 5mL0.01M pH value and be 7.4 phosphate and pH value and be in 5.5 acetate buffer solution, then be transferred to bag filter, the molecular cut off of bag filter is 3500, with the buffer of the corresponding pH value of 40mL, dialyses, at 12h, 24h, 48h, 72h and the 120h 3mL that takes a sample respectively, and add the buffer of respective amount; 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, discharge result as shown in Figure 2.Fig. 2 is the two chloro-1 of the embodiment of the present invention 2 preparation, and the 2-cyclohexanediamine closes the releasing curve diagram of platinum complex when pH=7.4 and pH=5.5, and as shown in Figure 2, two is chloro-1, and the 2-cyclohexanediamine closes platinum complex to have under slow-release capability and acid pH and accelerate the feature that discharges.
Embodiment 7
Under the condition of 37 ℃, take the two chloro-1 of 5mg embodiment 2 preparation, the 2-cyclohexanediamine closes platinum complex, is dissolved in the 5mL0.01M pH value and is in 7.4 phosphate buffered solution, utilizes scattering strength and the particle diameter of dynamic light scattering technique test different time points.The results are shown in shown in Figure 3.Fig. 3 is the two chloro-1 of embodiment 2 preparation, and the 2-cyclohexanediamine closes the light scattering diagram of platinum complex micelle; (a) be the scattering strength variation within the testing time, (b) be the particle diameter result in the testing time.Result shows, within the time of 240h, scattering strength descends limited, and particle diameter does not have significant change substantially.Illustrate that thus two is chloro-1, the 2-cyclohexanediamine closes the stability that the platinum complex micelle has overlength.
Comparative example 1
According to document N.Nishiyama, et al.Cancer Research, the record of 63 (2003) 9877-8983, the stability of Platinum complexes wherein can only be remained 30 hours.
Comparative example 2
P (Glu) by 54.0mg embodiment 1 preparation
140-g-(mPEG
5k)
7Be dissolved in the 25mL distilled water, regulating pH value is 8.0 left and right, adds the 19.5mg cisplatin, 37 ℃ of lucifuges reaction 72h, and pure water dialysis 24h, change water 6 times to remove cisplatin, obtains the micelle of Platinum complexes; The micelle of described Platinum complexes is freezing rapidly under aseptic condition, and lyophilization obtains the Platinum complexes lyophilized powder, and its conversion ratio is 85%.
Under the condition of 37 ℃, take the Platinum complexes of the above-mentioned preparation of 5mg, be dissolved in the 5mL0.01M pH value and be in 7.4 phosphate buffered solution, utilize scattering strength and the particle diameter of dynamic light scattering technique test different time points.Experimental result shows, within the time of 60h, scattering strength drops to 0.2 by 1.0, and the micelle particle diameter obviously diminishes, and micelle decomposes gradually.Illustrate that thus Platinum complexes micelle stability is chloro-1 not as good as two, the 2-cyclohexanediamine closes the platinum complex micelle.
Embodiment 8
Collect logarithmic (log) phase A549 cell, adjust cell concentration, inoculate in 96 orifice plates, in every hole, contain 100 μ L(approximately 10
4Individual) cell, after 37 ℃ of cultivation 24h, abandon culture fluid;
With culture medium by two chloro-1 of embodiment 2 preparation, it is chloro-1 according to two respectively that the 2-cyclohexanediamine closes platinum complex, and it is the sample of 40 μ g/mL, 20 μ g/mL, 10 μ g/mL, 5 μ g/mL, 2.5 μ g/mL, 1.25 a μ g/mL6 concentration that the 2-cyclohexanediamine closes Pt concentration dilution in platinum; The same naked medicine of oxaliplatin being diluted respectively with culture medium is the sample that Pt concentration is respectively 40 μ g/mL, 20 μ g/mL, 10 μ g/mL, 5 μ g/mL, 2.5 μ g/mL, 1.25 a μ g/mL6 concentration;
Each sample is added to 96 orifice plates, and every hole adds 200 μ L, 6 multiple holes of every kind of concentration, and at 37 ℃, saturated humidity, 5%CO
2In cell culture incubator, cultivate 48h and 72h, to add 20 μ L concentration be the tetrazolium bromide of 5mg/mL in every hole afterwards, after continuing to cultivate 4h, stop cultivating, suck culture fluid in hole, every hole adds 150 μ L dimethyl sulfoxide, low-speed oscillation 10min, with microplate reader, detect the absorption value of each hole at the 492nm place, conversion obtains using the naked medicine platinum of oxaliplatin of each concentration and two chloro-1, and the 2-cyclohexanediamine closes the survival rate of cell after platinum complex, the results are shown in Figure 4.Fig. 4 is the two chloro-1 of the embodiment of the present invention 2 preparation, and the 2-cyclohexanediamine closes platinum complex and the naked medicine of oxaliplatin to the Effect tests of A549 cell figure as a result.In Fig. 4,
Survival rate for 48 hours inner cells of the naked medicine of oxaliplatin of using variable concentrations;
For using the two chloro-1 of variable concentrations, the 2-cyclohexanediamine closes the survival rate of 48 hours inner cells of platinum complex;
Survival rate for 72 hours inner cells of the naked medicine of oxaliplatin of using variable concentrations;
For using the two chloro-1 of variable concentrations, the 2-cyclohexanediamine closes the survival rate of 48 hours inner cells of platinum complex.As shown in Figure 4, two is chloro-1, and the 2-cyclohexanediamine closes platinum complex and has drug effect and the dosage-time-dependent relation suitable with the naked medicine of oxaliplatin.
Embodiment 9
6 Wistar rats are divided into to 2 groups (n=3, average weight is 240g) at random, tail vein injection oxaliplatin (Oxaliplatin) and two chloro-1 respectively, the 2-cyclohexanediamine closes platinum complex (take Pt calculating dosage as 3mg/kg).At predetermined time point (5min, 0.5,1,4,10,24h), by eye socket, collect blood sample to the centrifuge tube that contains heparin sodium, centrifugalize obtains serum.Get 200 μ L blood serum samples, after nitric acid digestion, standardize solution by inductivity coupled plasma mass spectrometry (ICP-MS) test platinum content, is investigated the blood substance dynamic metabolism of two kinds of medicines to 4mL.Result shows, two is chloro-1, and the 2-cyclohexanediamine closes the metabolism time of platinum complex in the Wistar rat blood and obviously extends, plasma drug level half-life (t
1/2) reach 2h.
100 μ L suspend 1.0 * 10 in the right front oxter injection of C57BL/6 mice (in 6 weeks, 15g, purchased from Jilin University's Experimental Animal Center)
6The PBS solution of individual B16F1 cell (Mus source K-1735).After 5 days, gross tumor volume rises to 30-70mm
3In time, start to treat for the first time, is labeled as the 0th day.Mice is weighed and measure the tumor volume, and be divided at random 3 groups, every group 6: Saline organizes (being matched group), oxaliplatin group (Oxaliplatin, Pt dosage: 3.0mg/kg), two chloro-1, the 2-cyclohexanediamine closes platinum complex group (DACHPt Micelles, Pt dosage 3.0mg/kg), at the 0th, 2,4,6,8 days, implement respectively tail vein injection.Measure major diameter (a) and the minor axis (b) of tumor, and the calculating gross tumor volume (V=a * b * b/2).In the 14th day, put to death whole mices, solution cuts tumor tissues and weighs, and calculates tumour inhibiting rate (TI).TI(%)=(Saline group average tumor quality-administration group average tumor quality)/Saline group average tumor quality * 100%.The oxaliplatin group is 30.2% to the melanomatous tumour inhibiting rate in Mus source, and two is chloro-1, and the tumour inhibiting rate that the 2-cyclohexanediamine closes the platinum complex group is 40.1%, demonstrates good tumor suppression effect.
Embodiment 11
(in 6 weeks, 15g) right front oxter injection 100 μ L suspend 1.0 * 10 in the Balb/C nude mice
6The PBS solution of individual A549 lung adenocarcinoma cell.After 20 days, gross tumor volume rises to 200mm
3In time, start to treat for the first time, is labeled as the 0th day.Mice is weighed and measure the tumor volume, and be divided at random 3 groups, every group 6: Saline organizes (being matched group), oxaliplatin group (Oxaliplatin, Pt dosage: 3.0mg/kg), two chloro-1, the 2-cyclohexanediamine closes platinum complex group (DACHPtMicelles, Pt dosage 3.0mg/kg), at the 0th, 4,8 days, implement respectively tail vein injection.Measure major diameter (a) and the minor axis (b) of tumor, and the calculating gross tumor volume (V=a * b * b/2).In the 14th day, put to death whole mices, solution cuts tumor tissues and weighs, and calculates tumour inhibiting rate (TI).TI(%)=(Saline group average tumor quality-administration group average tumor quality)/Saline group average tumor quality * 100%.The oxaliplatin group is 40.2% to the melanomatous tumour inhibiting rate in Mus source, and two is chloro-1, and the tumour inhibiting rate that the 2-cyclohexanediamine closes the platinum complex group is 49.7%, demonstrates good tumor suppression effect.
The explanation of above embodiment is just be used to 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.
To the above-mentioned explanation of the disclosed embodiments, make professional and technical personnel in the field can realize or use the present invention.Multiple modification to these embodiment will be apparent for those skilled in the art, and General Principle as defined herein can be in the situation that do not break away from the spirit or scope of the present invention, realization in other embodiments.Therefore, the present invention will can not be restricted to these embodiment shown in this article, but will meet the widest scope consistent with principle disclosed herein and features of novelty.
Claims (10)
- One kind two chloro-1, the 2-cyclohexanediamine closes platinum complex, by two chloro-1, the 2-cyclohexanediamine closes platinum and coordinates formation with the polymer with formula (I) structure,
In formula (I), R 1Independently be selected from the straight chained alkyl of C2～C10, branched alkyl, phenyl or the R ' of C3～C10-CO-, R ' independently is selected from the straight chained alkyl of C2～C10, branched alkyl or the phenyl of C3～C10;R 2Independently be selected from the alkyl of the C1～C20 of the alkyl of H atom, C1～C20 or replacement;R 3Independently be selected from H atom or cation;L independently is selected from-CH 2-or-CH 2-CH 2-;M is the degree of polymerization, 40≤m≤250; X, y, z are the degree of polymerization, 10≤x+y+z≤5000,5%≤y/ (x+y+z)≤80%. - 2. according to claim 1 two is chloro-1, and the 2-cyclohexanediamine closes platinum complex, it is characterized in that R 2Independently be selected from the alkyl of the C1～C10 of the alkyl of C1～C10 or replacement, the substituent group of the alkyl of described replacement is selected from one or more in ketal, acetal, hydroxyl, aldehyde radical, amino, sulfydryl and saccharide residue;R 3Independently be selected from H atom, metal cation or organic cation.
- 3. according to claim 2 two is chloro-1, and the 2-cyclohexanediamine closes platinum complex, it is characterized in that R 3Independently be selected from subgroup, amine ion or the aminoacid ion of H atom, sodium ion, potassium ion, magnesium.
- 4. according to claim 1 two is chloro-1, and the 2-cyclohexanediamine closes platinum complex, it is characterized in that 30≤x+y+z≤300,5%≤y/ (x+y+z)≤50%.
- 5. according to claim 1 two is chloro-1, and the 2-cyclohexanediamine closes platinum complex, it is characterized in that R 1For C6 alkyl, R 2For methyl, R 3For hydrogen atom or sodium ion, L are-CH 2-CH 2-.
- One kind two chloro-1, the 2-cyclohexanediamine closes the preparation method of platinum complex, comprises the following steps:Two is chloro-1, and the 2-cyclohexanediamine closes platinum, with the polymer with formula (I) structure, complex reaction occurs in aqueous medium, generates two chloro-ly 1, and the 2-cyclohexanediamine closes platinum complex;In formula (I), R 1Independently be selected from the straight chained alkyl of C2～C10, branched alkyl, phenyl or the R ' of C3～C10-CO-, R ' independently is selected from the straight chained alkyl of C2～C10, branched alkyl or the phenyl of C3～C10;R 2Independently be selected from the alkyl of the C1～C20 of the alkyl of H atom, C1～C20 or replacement;R 3Independently be selected from H atom or cation;L independently is selected from-CH 2-or-CH 2-CH 2-;M is the degree of polymerization, 40≤m≤250; X, y, z are the degree of polymerization, 10≤x+y+z≤5000,5%≤y/ (x+y+z)≤80%.
- 7. preparation method according to claim 6, is characterized in that, described two is chloro-1, and the 2-cyclohexanediamine closes platinum and also comprises other derivants with 1,2-cyclohexanediamine part.
- 8. preparation method according to claim 6, is characterized in that, the carboxyl of described polymer with formula (I) structure and two chloro-1, and the 2-cyclohexanediamine closes the mol ratio of Pt in platinum less than 20.
- 9. preparation method according to claim 6, is characterized in that, the carboxyl of described polymer with formula (I) structure and two chloro-1, and the 2-cyclohexanediamine closes the mol ratio of Pt in platinum less than 10.
- 10. preparation method according to claim 6, is characterized in that, described aqueous medium is water, normal saline, buffer solution, tissue culture medium or body fluid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310361430.1A CN103394095B (en) | 2013-08-19 | 2013-08-19 | Two chloro-1,2-cyclohexanediamine close platinum complex and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310361430.1A CN103394095B (en) | 2013-08-19 | 2013-08-19 | Two chloro-1,2-cyclohexanediamine close platinum complex and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103394095A true CN103394095A (en) | 2013-11-20 |
| CN103394095B CN103394095B (en) | 2016-03-23 |
Family
ID=49557939
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310361430.1A Active CN103394095B (en) | 2013-08-19 | 2013-08-19 | Two chloro-1,2-cyclohexanediamine close platinum complex and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103394095B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114441671A (en) * | 2021-12-23 | 2022-05-06 | 北京悦康科创医药科技股份有限公司 | Method for determining content of platinum impurity cyclohexanediamine dihydrate in oxaliplatin by combination of HPLC-ICP-MS |
| CN116731281A (en) * | 2023-07-05 | 2023-09-12 | 山东雷德新材料有限公司 | Self-lubricating modified TPU polymer and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1890295A (en) * | 2003-12-10 | 2007-01-03 | 株式会社东京大学Tlo | Coordination complex of diaminocyclohexaneplatinum(II) with block copolymer containing poly(carboxylic acid) segment and antitumor agent comprising the same |
| CN102863627A (en) * | 2012-10-10 | 2013-01-09 | 中国科学院长春应用化学研究所 | Cisplatin complex and preparation method thereof |
-
2013
- 2013-08-19 CN CN201310361430.1A patent/CN103394095B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1890295A (en) * | 2003-12-10 | 2007-01-03 | 株式会社东京大学Tlo | Coordination complex of diaminocyclohexaneplatinum(II) with block copolymer containing poly(carboxylic acid) segment and antitumor agent comprising the same |
| CN102863627A (en) * | 2012-10-10 | 2013-01-09 | 中国科学院长春应用化学研究所 | Cisplatin complex and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| HORACIO CABRAL ET AL.: "Preparation and biological properties of dichloro(1,2-diaminocyclohexane)platinum(II)(DACHPt)-loaded polymeric micelles", 《JOURNAL OF CONTROLLED RELEASE》 * |
| JIAN GONG ET AL.: "Polymeric micelles drug delivery system in oncology", 《JOURNAL OF CONTROLLED RELEASE》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114441671A (en) * | 2021-12-23 | 2022-05-06 | 北京悦康科创医药科技股份有限公司 | Method for determining content of platinum impurity cyclohexanediamine dihydrate in oxaliplatin by combination of HPLC-ICP-MS |
| CN114441671B (en) * | 2021-12-23 | 2023-05-30 | 北京悦康科创医药科技股份有限公司 | Method for measuring content of cyclohexanediamine dihydrate platinum impurities in oxaliplatin by HPLC-ICP-MS (high performance liquid chromatography-inductively coupled plasma-mass spectrometry) combination |
| CN116731281A (en) * | 2023-07-05 | 2023-09-12 | 山东雷德新材料有限公司 | Self-lubricating modified TPU polymer and preparation method thereof |
| CN116731281B (en) * | 2023-07-05 | 2024-01-09 | 山东雷德新材料有限公司 | Self-lubricating modified TPU polymer and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103394095B (en) | 2016-03-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102863627B (en) | Cisplatin complex and preparation method thereof | |
| Pan et al. | A dithiocarbamate-based H 2 O 2-responsive prodrug for combinational chemotherapy and oxidative stress amplification therapy | |
| CN106265510B (en) | The multistage target polymer micella and preparation method thereof of pH trigger-type drug release in a kind of tumour cell | |
| CN103768080B (en) | A kind of targeting preparation of overriding resistance tumor, preparation method and application | |
| EP2514441B1 (en) | Passive solid tumor targeting anticancer prodrug and preparation method thereof | |
| CN101897976A (en) | Medicament solubilization carrier and preparation method and application thereof | |
| CN104434791B (en) | A kind of preparation of modified bletilla polysaccharide derivates nanometer carrier and application technology | |
| WO2021169744A1 (en) | Fluorescent carbon quantum dot, and preparation method therefor and application thereof in preparation of antitumor drug sensitizer | |
| EP2958946A1 (en) | Near-infrared dye-conjugated hyaluronic acid derivative and contrast agent for optical imaging including them | |
| CN106729735B (en) | pH-sensitive polypeptide polymer and preparation method and application thereof | |
| CN102391517A (en) | Nanometer micelle capable of intelligently releasing medicine as well as preparation method and application thereof | |
| CN111053911A (en) | Reduction response type cross-linking agent and preparation and application of cross-linked hydroxyl drug molecule thereof | |
| CN108853515A (en) | Preparation method and application, the pharmaceutical composition of small peptide hydrogel | |
| CN106632272A (en) | Synthesis and applications of an albumin bounding type 5-fluorouracil prodrug | |
| CN103394095B (en) | Two chloro-1,2-cyclohexanediamine close platinum complex and preparation method thereof | |
| Ao et al. | STING agonist-based hydrogel enhances immune activation in synergy with radiofrequency ablation for hepatocellular carcinoma treatment | |
| CN114470231B (en) | Nanometer drug-carrying system for folic acid-hydroxyalkyl starch macromolecule stable co-carrying photosensitizer and small molecule prodrug, preparation and application thereof | |
| CN106554425B (en) | A kind of lipid Grafted Derivatives of poly sialic acid and its application | |
| CN108186571B (en) | Application of reversible cross-linked asymmetric vesicle in preparation of acute leukemia treatment drug | |
| CN112891533B (en) | Near-infrared light adjustable nitric oxide donor type nano-vesicle and preparation method and application thereof | |
| CN106554497A (en) | Water-soluble Cabazitaxel anti-cancer drug compounds and its preparation method and application | |
| Hu et al. | ROS-responsive and triple-synergistic mitochondria-targeted polymer micelles for efficient induction of ICD in tumor therapeutics | |
| CN110859805B (en) | Tumor-targeted radiotherapy sensitization liposome nano preparation and preparation method thereof | |
| CN103656669A (en) | Compound micelle-based nano-vector, and preparation method and application thereof | |
| CN107243000B (en) | Drug-loaded hybrid nanoparticles and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |