CN109161022A - Tetravalence platinum complex-ortho esters polymeric prodrugs, its micella and preparation method and application - Google Patents
Tetravalence platinum complex-ortho esters polymeric prodrugs, its micella and preparation method and application Download PDFInfo
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Abstract
The present invention relates to Macroscopic single crystal and medicine sustained and controlled release discharge technique fields, and in particular to a kind of tetravalence platinum complex-ortho esters polymeric prodrugs, its micella and preparation method and application；Tetravalence platinum complex-ortho esters the polymeric prodrugs have structure shown in formula (I):Wherein, n indicates the degree of polymerization, value range n=10-40；The present invention provides a kind of tetravalence platinum complex-ortho esters polymeric prodrugs, it includes the tetravalence platinum for having higher concentration, can long-time stable be present in blood.The original acid ester key acid for introducing hypersensitivity on the basis of reducible platinic simultaneously, can respond under the special reproducibility of tumour cell and pH environment, be broken, cause the release of anti-tumor drug.Therefore, prodrug provided by the invention has the characteristic in tumour cell with pH and reducing condition double-response, and drug selectivity is improved, and has the effects that targeting, synergic sensitizion, can reduce the toxic side effect and drug resistance of drug.
Description
Technical field
The present invention relates to Macroscopic single crystal and medicine sustained and controlled release discharge technique fields, and in particular to a kind of tetravalence platinum complex-
Ortho esters polymeric prodrugs, its micella and preparation method and application.
Background technique
Cancer be threaten human life and health major disease, the therapy approach of patient with advanced cancer mainly have chemotherapy or
Radiotherapy.Wherein chemotherapy is the abbreviation of chemotherapy, and the mechanism of action is the proliferation that cancer cell is prevented using chemicals, leaching
Profit, transfer, until final kill cancer cell.Cis-platinum be one kind be widely used in treating as oophoroma, prostate cancer, carcinoma of testis,
The anticancer drug of the acellular period specific of the entity tumors such as lung cancer, nasopharyngeal carcinoma, cancer of the esophagus, malignant lymphoma, breast cancer, energy
It is combined into cross key with DNA, DNA replication dna function is destroyed, makes Apoptosis.
Currently, clinically common divalent platinum as anti-cancer medicine lacks the selectivity to cancer cell, in use along with
The toxic side effects such as renal toxicity, ototoxicity, neurotoxicity, alopecia, and the problems such as drug resistance, cross resistance can be generated.
Summary of the invention
The technical problem to be solved in the present invention is that the toxic side effect of existing divalent platinum as anti-cancer medicine is big, is easy to produce drug resistance
Property.
In order to solve the above technical problems, the technical solution used in the present invention is: a kind of tetravalence platinum complex-ortho esters is poly-
Object prodrug is closed, there is structure shown in formula (I):
Wherein, n indicates the degree of polymerization, value range n=10-40.
The present invention also provides a kind of preparation methods of tetravalence platinum complex-ortho esters polymeric prodrugs, and steps are as follows:
(1) tetravalence platinum complex monomer, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, carboxyl is living
After agent, anhydrous triethylamine, anhydrous N,N-dimethylformamide are according to the molal volume ratio mixing of 1:2.5:2.5:0.5-1:3-6
Carry out priming reaction；
(2) diamido ortho-ester monomer is added into activation reaction product and anhydrous N,N-dimethylformamide is polymerize
Reaction, obtains polymeric prodrugs；
The ingredient proportion of the diamido ortho-ester monomer and anhydrous N,N-dimethylformamide is 1:2-5；
The molar ratio example of the tetravalence platinum complex monomer and diamido ortho-ester monomer is 1:1.
Further, the tetravalence platinum complex monomer is two carboxyl end group cis-platinums, and chemical formula is Pt (NH3)2Cl2
(OOCCH2CH2CO2H)2, there is structure shown in formula (I I):
The diamido ortho-ester monomer is 4,4 '-two-two-(2- amino ethoxy -1,3- dioxolanes) of methylene oxygroup.
Further, the carboxyl activator is selected from one of n-hydroxysuccinimide, EDC, NHS.
Further, the reaction process of the step (1) is in room temperature, drying, is protected from light, reacts 4-6h under stirring condition.
Further, the reaction process of the step (2) is to be protected from light, be stirred to react 2-4 days in a nitrogen environment.
The present invention also provides a kind of tetravalence platinum complex-ortho esters polymeric prodrugs micellas, by tetravalence platinum as described above
Complex-ortho esters polymeric prodrugs or the tetravalence platinum complex-ortho acid ester polymer prepared by preparation method as described above
Prodrug is prepared.
The present invention also provides a kind of preparation sides of tetravalence platinum complex as described above-ortho esters polymeric prodrugs micella
Method, it is characterised in that: sufficiently dissolve polymeric prodrugs with dimethyl sulfoxide, carry out dialysis treatment later, obtain the cooperation of tetravalence platinum
Object-ortho esters polymeric prodrugs micella.
The present invention also provides a kind of tetravalence platinum complex-ortho esters polymeric prodrugs as described above to exist as pharmaceutical carrier
Prepare the application in anti-tumor drug.
Further, the application is achieved by the steps of: tetravalence platinum complex-ortho esters polymeric prodrugs and drug
Carrier is placed in dimethyl sulfoxide by the mass ratio mixing of 8-12:1, is dialysed to be placed in bag filter after completely dissolution, is obtained four
Valence platinum complex-ortho esters polymer medicament carrying micelle；
The pharmaceutical carrier is one of camptothecine, taxol, adriamycin, 5 FU 5 fluorouracil.
The beneficial effects of the present invention are: in fact, there is reproducibility paddy for the environment of tumour cell is compared with normal cell
The features such as concentration of the sweet peptide of Guang is higher, and pH is lower.Based on this, the present invention provides a kind of tetravalence platinum complex-ortho acid polyisocyanate polyaddition
Object prodrug, it includes the tetravalence platinum for having higher concentration, can long-time stable be present in blood.Simultaneously in reducible tetravalence platinum
On the basis of introduce hypersensitivity original acid ester key acid, sound can be made under the special reproducibility of tumour cell and pH environment
It answers, is broken, cause the release of anti-tumor drug.Therefore, prodrug provided by the invention have in tumour cell with pH and
The characteristic of reducing condition double-response, drug selectivity are improved, and are had the effects that targeting, synergic sensitizion, can be reduced drug
Toxic side effect and drug resistance.
In addition, tetravalence platinum complex is octoploids structure, for divalent platinum as anti-cancer medicine, reactivity is lower, and has
Replacement kinetics inertia is not easy that substitution reaction occurs with intracellular glutathione, the biomolecule such as albumen, can be complete
Arrival cancer cell.Due to tetravalence platinum complex lipophilicity with higher, it is easy to be absorbed by cancer cell.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of polymeric prodrugs in the embodiment of the present invention 1；
Fig. 2 is the grain size distribution of prodrug micelle OCM in the embodiment of the present invention 2；
Fig. 3 is the transmission electron microscope picture of prodrug micelle OCM in the embodiment of the present invention 2；
Fig. 4 is the critical micell curve of prodrug micelle OCM in the embodiment of the present invention 3；
Fig. 5 be in the embodiment of the present invention 5 DOX of the Pt of prodrug micelle OCM and its carrier micelle OCM/D in condition of different pH
Under release profiles；
Fig. 6 is releasing under Pt the and DOX condition of different pH of carrier micelle OCM/D in the presence of DTT in the embodiment of the present invention 6
Put curve；
Fig. 7 be in the embodiment of the present invention 7 prodrug micelle OCM to the toxicity test result figure of HepG2 cell；
Fig. 8 be in the embodiment of the present invention 7 carrier micelle OCM/D to the toxicity test result figure of HepG2 cell；
Fig. 9 be in the embodiment of the present invention 8 prodrug micelle OCM to the toxicity test result figure of H22 cell；
Figure 10 be in the embodiment of the present invention 8 carrier micelle OCM/D to the toxicity test result figure of H22 cell；
Figure 11 be in the embodiment of the present invention 9 carrier micelle OCM/D to the qualitative detection of HepG2 and H22 cellular uptake situation
Result figure；
Figure 12 be in the embodiment of the present invention 9 carrier micelle OCM/D to the quantitative detection of HepG2 and H22 cellular uptake situation
Result figure.
Specific embodiment
Embodiment 1: tetravalence platinum complex-ortho esters polymeric prodrugs preparation
(1) it is suitable that two carboxyl end groups that 0.350g (0.65mmol) molecular weight is 534.05 are added into 25mL dry reaction bottle
Platinum, 0.314g (1.64mmol) molecular weight be 191.7 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride,
The anhydrous N of 3mL, N- dimethyl methyl is added in the n-hydroxysuccinimide that 0.189g (1.64mmol) molecular weight is 115.09 later
Amide and 0.2mL anhydrous triethylamine, room temperature, which is protected from light, is stirred to react 5h；
(2) 0.202g (1.64mmol) is added is with the molecular weight of the anhydrous N,N-dimethylformamide dissolution of 0.5mL in advance
The 4 of 308.328,4 '-two-two-(2- amino ethoxy -1,3- dioxolanes) of methylene oxygroup, are protected from light stirring 3 under nitrogen protection
It, is transferred to molecular cut off for reaction product, with water dialysis 12h, to be freeze-dried, obtaining in the bag filter of 1000D later
0.468g tetravalence platinum complex-ortho esters polymeric prodrugs P (OE DS-CP), yield 84.78%.1H NMR (400MHz,
DMSO-d6, δ, ppm): 2.82-2.89 (t, 4H, H2-NH2),3.51-3.74(m,8H,NH-CH2-CH2,CH2-O-CH2),
3.77-4.19(m,4H,CH-O-CH2),4.29-4.50(m,2H,CH2-CH-CH2),5.85-5.87(d,2H,CH-(O)3),
6.48(s,6H,-NH3),2.15-2.43(m,-CH2-CH2), see Fig. 1.The position at all nuclear-magnetism peaks and area integral ratio are just
Really, show that the polymer is correctly synthesized.
Embodiment 2: the preparation of prodrug micelle
The prodrug for taking 20mg embodiment 1 to prepare, is 500D's with molecular cut off is transferred to after 2mL dmso solution
Bag filter obtains prodrug micelle OCM with the 2h that dialyses in water.
The particle diameter distribution of micella prepared by the present embodiment 2 is detected by photon correlation spectroscopy (DLS), as a result as shown in Figure 2.
Figure it is seen that prepared micella particle, partial size is in 100-200nm or so.
The pattern of the micella of the preparation of the present embodiment 2 is detected by transmission electron microscope, as a result as shown in Figure 3.It can from Fig. 3
Out, prepared micella particle, the form spherical shape uniform and regular in size.
Embodiment 3: the measurement of prodrug micelle critical micelle concentration
Utilize the critical micelle concentration of prodrug micelle OCM prepared by Nile Red Assay measurement embodiment 2, critical micell
Curve is as shown in Figure 4.From fig. 4, it can be seen that micella OCM prepared by embodiment 2, critical micelle concentration is 1.12 × 10-5mg/
ml。
It is as follows using the specific detection process of Nile Red Assay:
(1) it is 1.0 × 10 that 20 μ L concentration are separately added into 8 brown bottles-4The acetone soln of mol/L Nile red；
(2) molten with the phosphoric acid buffer of pH=7.4 after being freeze-dried the polymeric prodrugs micella OCM prepared in embodiment 2
It is 1 × 10 that liquid is configured to concentration respectively-8、1×10-7、1×10-6、1×10-5、1×10-4、1×10-3、1×10-2、1×10- 1The gradient OCM solution of mg/m L；
(3) after the acetone in brown bottle volatilizees completely, each gradient solution of 2mL is taken to be added in each brown bottle respectively, room
It is protected from light under the conditions of temperature and is incubated for 12h；
(4) using the emission spectrum of Nile red in each solution of fluorescent spectrophotometer assay；
(5) wavelength corresponding to maximum fluorescence intensity is found out in launching light spectrogram at various concentrations, it is bent makees concentration-wavelength
Line chart, then the corresponding concentration of curve catastrophe point is the critical micelle concentration value of OCM.
Embodiment 4: the preparation of carrier micelle
The prodrug and 8mg adriamycin for taking 80mg embodiment 1 to prepare are divided with retention is transferred to after 5mL dmso solution
The bag filter that son amount is 500D obtains carrier micelle OCM/D with the 2h that dialyses in water.
Embodiment 5: release detection of the DOX of the Pt and its carrier micelle OCM/D of prodrug micelle OCM under condition of different pH
The load medicine that prodrug micelle OCM and the 1mL doxorubicin concentration that 1mLPt concentration is 500 μ g/ml is 500 μ g/ml is taken respectively
Micella OCM/D is transferred in two bag filter water that molecular cut off is 8kD-14kD, is put into the pH difference containing 5mL
In EP pipe for 5,6.5,7.4 buffer, if 3 repetitions are vibrated under the conditions of 100rpm at 37 DEG C, respectively 30min, 1,
2, buffer is taken out after 3,4,5,6,7,8,9,10,11,12,24,36,48,72 hours, and new buffer is added.Then lead to
It crosses the burst size of ICP-MS detection platinum and the doxorubicin concentration in buffer is detected by microplate reader, calculate the release of adriamycin
Amount, releasing result such as Fig. 5.As shown in Figure 5: OCM and OCM/D is relatively stable in a neutral environment, substantially without drug release；pH
Smaller, drug release is more.Thus illustrate that prodrug micelle and carrier micelle all have sensitivity to acid.
Embodiment 6: release in the presence of DTT under Pt the and DOX condition of different pH of carrier micelle OCM/D
Take the dialysis that the carrier micelle OCM/D that 1mL doxorubicin concentration is 500 μ g/ml is 8kD-14kD in molecular cut off
In bag, it is put into the EP pipe of the 20mMDDT buffer of the PH=5 containing 5mL, 6.5,7.4, if 3 repetitions, at 37 DEG C,
It is vibrated under the conditions of 100rpm, takes out buffer behind 30min, 1,2,3,4,5,6,7,8,9,10,11,12,24 hour respectively, and
New buffer is added.The burst size of platinum is detected by ICP-MS and the doxorubicin concentration in buffer is detected by microplate reader,
Then the burst size of adriamycin, releasing result such as Fig. 6 are calculated.As shown in Figure 6: OCM and OCM/D drug under DDT existence condition
Rate of release ratio is very fast without discharging in the presence of DDT, illustrates that micella has reduction-sensitive.
Embodiment 7: toxicity detection of the prodrug micelle OCM and carrier micelle OCM/D to HepG2 cell
(1) human liver cancer cell (HepG2) is added into 96 orifice plates, guarantees that the cell concentration in every hole at 4,000 or so, pastes
After wall culture for 24 hours, culture medium is removed, the fresh culture of 180 μ l is added；
(2) 96 orifice plates in a step (1) are taken, the cisplatin aqueous solution (CP) of 20 μ l is separately added into every hole, makes every hole
In cis-platinum final concentration be respectively 0.5,1,2,4,8,16 μ g/mL, obtain experimental group 1；
96 orifice plates in a step (1) are taken, 20 μ l prodrug micelle OCM are separately added into every hole, make the cis-platinum in every hole
Final concentration is respectively 0.5,1,2,4,8,16 μ g/mL, obtains experimental group 2；
96 orifice plates in a step (1) are taken, 20 μ l cis-platinums and adriamycin mixed aqueous solution (CP+ are separately added into every hole
DOX), making the cis-platinum final concentration in every hole is respectively 0.5,1,2,4,8,16 μ g/mL, obtains experimental group 3；
96 orifice plates in a step (1) are taken, 20 μ l carrier micelle OCM/D are separately added into every hole, are made suitable in every hole
Platinum final concentration is respectively 0.5,1,2,4,8,16 μ g/mL, obtains experimental group 4；
(3) experimental group 1-4 is co-cultured respectively for 24 hours and after 48h, removes culture medium；Then the fresh culture of 180 μ l is added
After co-culturing 4h with 20 μ l MTT (5mg/mL), culture medium is removed；The DMSO of 150 μ l is added later, after shaking 10min,
Detected under 570nm wavelength, as a result such as Fig. 7 and 8, wherein Fig. 7 is CP and OCM group cytotoxicity result, Fig. 8 be CP+DOX with
OCM/D group cytotoxicity result.
From Fig. 7 and 8: OCM and OCM/D shows dosage and time dependence toxicity, and OCM group toxicity is greater than CP
Group, OCM/D group toxicity are greater than CP+DOX group, and OCM/D cytotoxicity is most strong.
Embodiment 8: toxicity detection of the prodrug micelle OCM and carrier micelle OCM/D to H22 cell
(1) murine hepatocarcinoma cell (H22) is added into 96 orifice plates, guarantees that the cell concentration in every hole at 4,000 or so, is mended
Fresh culture is filled to 180 μ l；
(2) 96 orifice plates in a step (1) are taken, the cisplatin aqueous solution (CP) of 20 μ l is separately added into every hole, makes every hole
In cis-platinum final concentration be respectively 0.5,1,2,4,8,16 μ g/mL, obtain experimental group 1；
96 orifice plates in a step (1) are taken, 20 μ l prodrug micelle OCM are separately added into every hole, make the cis-platinum in every hole
Final concentration is respectively 0.5,1,2,4,8,16 μ g/mL, obtains experimental group 2；
96 orifice plates in a step (1) are taken, 20 μ l cis-platinums and adriamycin mixed aqueous solution (CP+ are separately added into every hole
DOX), making the cis-platinum final concentration in every hole is respectively 0.5,1,2,4,8,16 μ g/mL, obtains experimental group 3；
96 orifice plates in a step (1) are taken, 20 μ l carrier micelle OCM/D are separately added into every hole, are made suitable in every hole
Platinum final concentration is respectively 0.5,1,2,4,8,16 μ g/mL, obtains experimental group 4；
(3) experimental group 1-4 is co-cultured respectively for 24 hours and after 48h, and 20 μ l MTT (5mg/mL) are added and co-culture 4h；Then plus
Enter the three first a ceremonial jade-ladle, used in libation solution of 150 μ l, after shaking 10min, detected under 490nm wavelength, as a result such as Fig. 9 and 10, wherein Fig. 9 is
CP and OCM group cytotoxicity result, Figure 10 are CP+DOX and OCM/D group cytotoxicity result.
From Fig. 9 and 10: Toxic test results of the OCM and OCM/D to H22 cell and the toxicity knot to HepG2 cell
Fruit is similar.
Embodiment 9: qualitative detection of the carrier micelle OCM/D to HepG2 and H22 cellular uptake situation
The experiment of A group:
(1) guarantee that every hole cell concentration exists with human liver cancer cell (HepG2) is added in 12 orifice plates of coverslip to bottom
105 or so, after overnight incubation, culture medium is removed, 1.8mL fresh culture is added；
(2) 12 orifice plates in a step (1) are taken, free Ah mould of the final concentration of 8 μ g/mL of 0 adriamycin is added into every hole
Element obtains experimental group 1；
12 orifice plates in a step (1) are taken, the polymer supported of the final concentration of 8 μ g/mL of 0.2mL adriamycin is added into every hole
Medicine micella OCM/D, obtains experimental group 2；
(3) after experimental group 1-2 co-cultures 0.5h and 4h respectively, culture medium is removed, is first rinsed 2 times with PBS, then with more than 4%
Polyformaldehyde liquid fixes cell, is rinsed 2 times after 5min with PBS, then contaminates nucleus with dye core reagent, washed 2 times after 10min with PBS,
Cell is collected by centrifugation, is dispersed later with 0.5mLPBS, uses confocal laser scanning microscope.
The experiment of B group: the method tested using A group, the difference is that, the cell being added in the step (1) is mouse
Liver cancer cells (H22).
A group and the result of B group experiment are as shown in figure 11.As shown in Figure 11: OCM/D group and Free DOX group have in various degree
Red fluorescent, illustrate that carrier micelle can be successfully by cellular uptake.The no significant difference in 0.5h, incubation time increase
After being added to 4h, OCM/D group fluorescence intensity is apparently higher than Free DOX group.
Embodiment 10: quantitative detection of the carrier micelle OCM/D to HepG2 and H22 cellular uptake situation
The experiment of A group:
(1) human liver cancer cell (HepG2) is added into 6 orifice plates, guarantees that every hole cell concentration is 2.5 × 105A cell is left
The right side after overnight incubation, removes culture medium, 1.8mL fresh culture is added；
(2) 6 orifice plates in a step (1) are taken, free adriamycin are added into every hole, until the final concentration of 8 μ g/ of adriamycin
mL；
The 6 orifice plates in a step (1) are taken, carrier micelle OCM/D are added into every hole, until the final concentration of 8 μ g/ of adriamycin
mL；
(3) after experimental group 1-2 co-cultures 0.5h and 4h respectively, culture medium is removed, is first washed 2 times with PBS, then disappeared with pancreatin
Change, cell is collected by centrifugation later, and use flow cytomery after being dispersed with the PBS of 0.5mL.
The experiment of B group: the method tested using A group, the difference is that, the cell being added in the step (1) is mouse
Liver cancer cells (H22).
A group and the result of B group experiment are as shown in figure 12.As shown in Figure 12: OCM/D group is compared with Free DOX group intake
As a result result is consistent compared with fluorescence intensity in qualitative experiment, i.e. difference is unobvious when 0.5h, and OCM/D intake is greater than when 4h
Free DOX group.
Claims (10)
1. a kind of tetravalence platinum complex-ortho esters polymeric prodrugs, which is characterized in that have structure shown in formula (I):
Wherein, n indicates the degree of polymerization, value range n=10-40.
2. a kind of preparation method of tetravalence platinum complex-ortho esters polymeric prodrugs according to claim 1, feature exist
In steps are as follows:
(1) by tetravalence platinum complex monomer, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, carboxyl activator,
Anhydrous triethylamine, anhydrous N,N-dimethylformamide are according to 1:2.5:2.5:(0.5-1): after the molal volume of (3-6) is than mixing
Carry out priming reaction；
(2) diamido ortho-ester monomer is added into activation reaction product and anhydrous N,N-dimethylformamide polymerize instead
It answers, obtains polymeric prodrugs；
The ingredient proportion of the diamido ortho-ester monomer and anhydrous N,N-dimethylformamide is 1:2-5；
The molar ratio example of the tetravalence platinum complex monomer and diamido ortho-ester monomer is 1:1.
3. the preparation method of tetravalence platinum complex-ortho esters polymeric prodrugs according to claim 2, it is characterised in that:
The tetravalence platinum complex monomer is two carboxyl end group cis-platinums, and chemical formula is Pt (NH3)2Cl2(OOCCH2CH2CO2H)2, there is formula
(II) structure shown in:
The diamido ortho-ester monomer is 4,4 '-two-two-(2- amino ethoxy -1,3- dioxolanes) of methylene oxygroup.
4. the preparation method of tetravalence platinum complex-ortho esters polymeric prodrugs according to claim 2, it is characterised in that:
The carboxyl activator is selected from one of n-hydroxysuccinimide, EDC, NHS.
5. the preparation method of tetravalence platinum complex-ortho esters polymeric prodrugs according to claim 2, it is characterised in that:
The reaction process of the step (1) is in room temperature, drying, is protected from light, reacts 4-6h under stirring condition.
6. the preparation method of tetravalence platinum complex-ortho esters polymeric prodrugs according to claim 2, it is characterised in that:
The reaction process of the step (2) is to be protected from light, be stirred to react 2-4 days in a nitrogen environment.
7. a kind of tetravalence platinum complex-ortho esters polymeric prodrugs micella, by tetravalence platinum complex-original described in claim 1
Acid ester polymer prodrug or tetravalence platinum complex-ortho esters of the preparation of the preparation method as described in any one of claim 2-6
Polymeric prodrugs are prepared.
8. a kind of preparation method of tetravalence platinum complex according to claim 7-ortho esters polymeric prodrugs micella, special
Sign is: sufficiently dissolving polymeric prodrugs with dimethyl sulfoxide, carries out dialysis treatment later, obtains tetravalence platinum complex-ortho acid
Ester polymer prodrug micelle.
9. a kind of tetravalence platinum complex-ortho esters polymeric prodrugs according to claim 1 are being prepared as pharmaceutical carrier
Application in anti-tumor drug.
10. application according to claim 9, it is characterised in that: the application is achieved by the steps of: the cooperation of tetravalence platinum
Object-ortho esters polymeric prodrugs are mixed by the mass ratio of 8-12:1 with pharmaceutical carrier and are placed in dimethyl sulfoxide, to sufficiently dissolve
It is placed in bag filter and dialyses, obtain tetravalence platinum complex-ortho esters polymer medicament carrying micelle；
The pharmaceutical carrier is one of camptothecine, taxol, adriamycin, 5 FU 5 fluorouracil.
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| CN112546236A (en) * | 2020-12-16 | 2021-03-26 | 安徽大学 | PH-sensitive double-drug-framework polymer prodrug and preparation method and application thereof |
| CN112807441A (en) * | 2020-12-31 | 2021-05-18 | 安徽大学 | Crosslinked polymer prodrug with reduction and pH hypersensitiveness as well as preparation method and application thereof |
| CN112961188A (en) * | 2021-02-07 | 2021-06-15 | 山东省第二人民医院(山东省耳鼻喉医院、山东省耳鼻喉研究所) | Tetravalent platinum prodrug platinum benzydate, preparation thereof, preparation method and application |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109796445A (en) * | 2019-02-19 | 2019-05-24 | 安徽大学 | A kind of Indomethacin dimer prodrug and its preparation method and application |
| CN109796445B (en) * | 2019-02-19 | 2020-07-14 | 安徽大学 | Indometacin dimer prodrug and preparation method and application thereof |
| CN112546236A (en) * | 2020-12-16 | 2021-03-26 | 安徽大学 | PH-sensitive double-drug-framework polymer prodrug and preparation method and application thereof |
| CN112546236B (en) * | 2020-12-16 | 2023-06-20 | 安徽大学 | PH-sensitive double-drug-skeleton polymer prodrug, and preparation method and application thereof |
| CN112807441A (en) * | 2020-12-31 | 2021-05-18 | 安徽大学 | Crosslinked polymer prodrug with reduction and pH hypersensitiveness as well as preparation method and application thereof |
| CN112807441B (en) * | 2020-12-31 | 2023-06-27 | 安徽大学 | Crosslinked polymer prodrugs that are reduced and pH hypersensitive, methods of making and using same |
| CN112961188A (en) * | 2021-02-07 | 2021-06-15 | 山东省第二人民医院(山东省耳鼻喉医院、山东省耳鼻喉研究所) | Tetravalent platinum prodrug platinum benzydate, preparation thereof, preparation method and application |
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