CN106344929A - Reduction responding covalent organic polymer and preparation method and application thereof - Google Patents
Reduction responding covalent organic polymer and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a reduction responding covalent organic polymer and a preparation method and application thereof. The polymer provided by the invention is obtained by mixing and reacting carboxyl terminated polyethylene glycol, a compound with a structure shown in formula (I) and carboxylic cis-platinum prodrug, wherein the compound is obtained by respectively connecting 5,10,15,20-tetra(4-hydroxyphenyl) porphyrin with cis-platinum prodrug and polyethylene glycol, thus having good water solubility and biocompatibility; the obtained nano particles not only can produce singlet oxygen under laser radiation, but also can generate dissociation under the condition with high reducibility of cancer cells to release cis-platinum drugs, and has certain application in combined treatment of tumor; furthermore, the compound can also be directly used as a drug delivery system without a carrier, thus effectively avoiding use of additional carriers.
Description
Technical field
The present invention relates to drug world, more particularly, to a kind of reduction covalent organic polymer of response and preparation method thereof and
Application.
Background technology
Cancer is one of principal disease of harm human health, with scientific and technical development, Nano medication delivery system
Oncotherapy is gradually shown up prominently.Common drug delivery system includes liposome, polymer micelle, albumin nano
Grain etc. has been enter into clinical research in nanometer translation medicine.However, due to the restriction of drug loading, most Conventional nano
Drug delivery system is frequently accompanied by a large amount of uses of carrier material, and then inevitably improves Metabolic stress and cause opposite
The toxic and side effects of reason tissue, for example conventional polyesters drug delivery system acid degradation products that metabolism produces in vivo can draw
Play the inflammatory reaction of local, and albumin delivery system then can cause organism immune response to produce adverse consequencess etc., thus pole
The earth limits application in terms of clinical conversion for the Nano medication.
Photodynamic therapy (photodynamic therapy, pdt) is a kind of emerging tumor therapeuticing method, and traditional
Chemotherapy, radiotherapy and surgical operation therapy are compared, photodynamic therapy have safer, few intercurrent disease, organism is damaged little
Advantage, thus receive more and more attention.Optical dynamic therapy excites the light in tumor locus enrichment by the light of specific wavelength
Sensitive molecule, produces and has cytotoxic active oxygen, causes tumor impaired and dead by damaging tumor cell gene structure, reaches
To therapeutic purposes.
In recent years, the Nano medication delivery system of new carrier-free strategy is built by MIN use inert material
Gradually cause research interest.The system brought by carrier material can be prevented effectively from using carrier-free Nano medication delivery system
The added burden that toxicity causes to patient.
Covalently organic polymer (covalent organic polymer, cop) is the new of extensive concern in recent years
Polymeric material, by the organic material constructing various organo units in the form of covalent linkage.It has specific surface area
Greatly, heat stability is good, distinctive nano aperture can be used in structure-controllable and polyfunctional advantage, and its frame structure
Load other functions guest molecule, thus have potential using value.But, currently with cop material as carrier-free
Nano medication delivery system is still rare, and covalent organic polymer is applied to the light power of cancer as drug conveying carrier
Even more do not appeared in the newspapers with chemotherapy combined treatment.
Content of the invention
In view of this, the technical problem to be solved be to provide covalent organic polymer and preparation method thereof and
Application, the covalent organic polymer that the present invention provides as the medicine of optical dynamic therapy and chemotherapy combined treatment, and can have
The ability of higher suppression tumor cell proliferation.
Present invention also offers a kind of reduction covalent organic polymer of response, by the Polyethylene Glycol of carboxy blocking, formula (i)
The compound of structure and carboxylated cisplatin prodrug hybrid reaction obtain；
Wherein, r1、r2、r3And r4Independent selected from amino or hydroxyl.
Preferably, the compound of described formula (i) structure and the mol ratio of described cisplatin prodrug are (1～1.5): 1.
Preferably, the compound of described formula (i) structure and the mol ratio of described cisplatin prodrug are (1.1～1.3): 1.
Preferably, the Polyethylene Glycol of described carboxy blocking and the mol ratio of described cisplatin prodrug are (1.5～2): 1.
Preferably, the molecular weight of the Polyethylene Glycol of described carboxy blocking is 1kda～10kda.
Preferably, described cisplatin prodrug is formula (pt-1) or formula (pt-2)
Preferably, the particle diameter of the described reduction covalent organic polymer of response is 50～200 nanometers.
Present invention also offers a kind of preparation method of the reduction covalent organic polymer of response, comprising: by carboxy blocking
Polyethylene Glycol, the compound of formula (i) structure and carboxylated cisplatin prodrug hybrid reaction obtain reducing response covalently organic poly-
Compound；
Wherein, r1、r2、r3And r4Independent selected from amino or hydroxyl.
Preferably, the catalyst of described reaction is carbodicyclo hexylimide and 4- dimethylamino pyridine.
Present invention also offers a kind of reduction covalent organic polymer of response of the present invention is controlled preparing light power
Treat and the application in the medicine of chemotherapy combined treatment.
Compared with prior art, the invention provides a kind of reduce the covalent organic polymer of response, by carboxy blocking
Polyethylene Glycol, the compound of formula (i) structure and carboxylated cisplatin prodrug hybrid reaction obtain；Wherein, this compound is by making 5,
10,15,20- tetra- (4- hydroxyphenyl) porphyrin is connected by ester bond with cisplatin prodrug and Polyethylene Glycol respectively and obtains；And this reduction rings
The covalent organic polymer of answering property (thpp-pt-peg) has extraordinary water solublity and biocompatibility, in water and physiological condition
Under all there is good dispersibility；Still there is after lyophilization good redissolution ability；The nano-particle obtaining is not only
Laser can produce singlet oxygen under irradiating, and under conditions of the high reproducibility of cancer cell, nano-particle can dissociate, and releases
Release cisplatin medicine, there is in the therapeutic alliance of tumor certain application；And this compound be also used as DNAcarrier free
Drug delivery system directly uses, thus effectively prevent due to carrier introduce thus lead to inclusion normal tissue poison
Side effect, the Metabolic stress that kidney and other organs are caused and the local inflammation that caused due to vector degradation etc. a series of bad after
Really.Test result indicate that, by response covalent organic polymer thpp-pt-peg nano-particle will be reduced, tail is passed through to mice
Intravenous injection, and by Imaging-PAM, it is monitored；Find that nano-particle can have at the position of tumor very high
Enrichment, then carries out optical dynamic therapy with laser, notable in conjunction with chemotherapy effect, and can improve the weary oxygen situation of tumor locus,
Other positions will not be caused damage, control difficulty in relapse after healing；It can be seen that, the reduction response that the present invention provides is covalently organic poly-
Compound can be used as the medicine of optical dynamic therapy and chemotherapy combined treatment, and this polymer is also used as chemotherapeutics conveying
Carrier, it is to avoid chemotherapeutics use extra carrier.
Brief description
The dynamic laser grain size distribution of the thpp-pt-peg that Fig. 1 prepares for embodiment 1；
The transmission electron microscope photo figure of the thpp-pt-peg that Fig. 2 prepares for embodiment 1；
Fig. 3 is the relative intensity of fluorescence figure of thpp-pt-peg sosg under the irradiation of 660nm laser of embodiment 1 preparation；
Fig. 4 is the cumulative release in the buffer containing Glutathione (gsh) for the thpp-pt-peg of embodiment 1 preparation
Curve chart；
Fig. 5 is the change of size in the buffer containing Glutathione (gsh) for the thpp-pt-peg of embodiment 1 preparation
Curve chart；
It is thin with what mouse mastopathy cell (4t1 cell) co-cultured that Fig. 6 prepares thpp-pt-peg and cisplatin for embodiment 1
Born of the same parents' survival rate figure；
Fig. 7 is the thpp-pt-peg and the thpp- without cisplatin crosslinking of embodiment 1 preparation under 660nm laser irradiates
The cell survival rate figure that peg and mouse mastopathy cell (4t1 cell) co-culture；
Fig. 8 is the fluorescence photo that thpp-pt-peg prepared by embodiment 1 improves tumor locus weary oxygen situation；
Fig. 9 is the fluorescence statistical data that thpp-pt-peg prepared by embodiment 1 improves tumor locus weary oxygen situation；
The fluorescence photo that the thpp-pt-peg that Figure 10 provides for embodiment 1 is distributed in major organs；
The data that the thpp-pt-peg that Figure 11 provides for embodiment 1 is distributed in major organs；
Figure 12 is the variation diagram of gross tumor volume；
Figure 13 is Mouse Weight variation diagram.
Specific embodiment
The invention provides a kind of reduction covalent organic polymer of response, by the Polyethylene Glycol of carboxy blocking, formula (i) knot
The compound of structure and carboxylated cisplatin prodrug hybrid reaction obtain；
Wherein, r1、r2、r3And r4Independent selected from amino or hydroxyl.
According to the present invention, in the covalent organic polymer of described reduction response, the Polyethylene Glycol of described carboxy blocking is single
The Polyethylene Glycol of carboxy blocking, that is,The molecular weight of the Polyethylene Glycol of described carboxy blocking is preferably
1kda～10kda, more preferably 3kda～8kda.
According to the present invention, in the covalent organic polymer of described reduction response, described carboxylated cisplatin prodrug preferably has
Formula (pt-1) or formula (pt-2)
According to the present invention, in the covalent organic polymer of described reduction response, the compound of described formula (i) structure with described
The mol ratio of cisplatin prodrug is preferably (1～1.5): 1, more preferably 1.1～1.3): 1；The Polyethylene Glycol of described carboxy blocking with
The mol ratio of described cisplatin prodrug is preferably (1.5～2): 1, more preferably (1.6～1.8): 1；Described reduction response is covalent
The particle diameter of organic polymer is 50～200 nanometers, more preferably 60～150nm, most preferably 80～120nm；Additionally, described go back
In the covalent organic polymer of former response, described 5,10,15,20- tetra- (4- hydroxyphenyl) porphyrin respectively with cisplatin prodrug and poly- second
Glycol is connected by ester bond.
Present invention also offers a kind of preparation method of the reduction covalent organic polymer of response, comprising: by carboxy blocking
Polyethylene Glycol, the compound of formula (i) structure and carboxylated cisplatin prodrug hybrid reaction obtain reducing response covalently organic poly-
Compound；
Wherein, r1、r2、r3And r4Independent selected from amino or hydroxyl.
According to the present invention, the present invention is by before the Polyethylene Glycol of carboxy blocking, the compound of formula (i) structure and carboxylated cisplatin
Medicine hybrid reaction obtains reducing the covalent organic polymer of response；Wherein, the Polyethylene Glycol of described carboxy blocking seals for mono carboxylic
The Polyethylene Glycol at end, that is,The molecular weight of the Polyethylene Glycol of described carboxy blocking preferably 1kda～
10kda, more preferably 3kda～8kda；Described carboxylated cisplatin prodrug preferably there is formula (pt-1) or formula (pt-2)
In the present invention, the compound of described formula (i) structure is preferably (1～1.5) with the mol ratio of described cisplatin prodrug: 1,
More preferably 1.1～1.3): 1；The mol ratio of the Polyethylene Glycol of described carboxy blocking and described cisplatin prodrug be preferably (1.5～
2): 1, more preferably (1.6～1.8): 1；The present invention does not have particular/special requirement to the catalyst of described reaction, well known in the art can
For the catalyst of esterification, preferably carbodicyclo hexylimide and 4- dimethylamino pyridine；Wherein, described cisplatin prodrug
It is preferably 1 with the mol ratio of described carbodicyclo hexylimide: (3～5), more preferably 1: 4；Described cisplatin prodrug and described 4- bis-
The mol ratio of picolilamine is preferably 1: (3～5), more preferably 1: 4.
In the present invention, described reaction is preferably carried out under nitrogen atmosphere；The temperature of described reaction is preferably 30～45 DEG C, more
It is preferably 35～40 DEG C；Preferably 24～72 hours time of described reaction, more preferably 48～60 hours；In the present invention, it is
Reaction is enable more smoothly to carry out, the present invention is preferably first by the compound of formula (i) structure and carboxylated cisplatin prodrug
After hybrid reaction 24～26h, add the Polyethylene Glycol reaction of carboxy blocking, obtain reducing the covalent organic polymer of response.
Present invention also offers a kind of reduction covalent organic polymer of response of the present invention is controlled preparing light power
Treat and the application in the medicine of chemotherapy combined treatment.
The reduction response covalent organic polymer that the present invention provides, by the Polyethylene Glycol of carboxy blocking, formula (i) structure
Compound and carboxylated cisplatin prodrug hybrid reaction obtain；Wherein, this compound is by making 5,10,15,20- tetra- (4- hydroxyphenyl)
Porphyrin is connected by ester bond with cisplatin prodrug and Polyethylene Glycol respectively and obtains；And this covalent organic polymer of reduction response
(thpp-pt-peg) there is extraordinary water solublity and biocompatibility, all there is under water and physiological condition good dispersion
Property；Still there is after lyophilization good redissolution ability；The nano-particle obtaining can produce list under the irradiation of not only laser
Line state oxygen, and under conditions of the high reproducibility of cancer cell, nano-particle can dissociate, and discharges cisplatin medicine, in tumor
Therapeutic alliance in there is certain application；And this compound is also used as DNAcarrier free drug delivery system and directly makes
With thus effectively prevent the introducing due to carrier thus lead to includes the toxic and side effects of normal tissue, to devices such as kidneys
A series of adverse consequencess such as Metabolic stress that official causes and the local inflammation that caused due to vector degradation.Test result indicate that,
By response covalent organic polymer thpp-pt-peg nano-particle will be reduced, tail vein injection is passed through to mice, and by glimmering
Photoimaging technology is monitored to it；Find that nano-particle can have very high enrichment at the position of tumor, then use laser
Carry out optical dynamic therapy, notable in conjunction with chemotherapy effect, and the weary oxygen situation of tumor locus can be improved, will not be to other positions
Cause damage, control difficulty in relapse after healing；It can be seen that, the covalent organic polymer of reduction response that the present invention provides can move as light
The medicine of power treatment and chemotherapy combined treatment, and this polymer is also used as the carrier of chemotherapeutics conveying, it is to avoid change
Treat medicine and use extra carrier.
Technical scheme below in conjunction with the embodiment of the present invention is clearly and completely described the enforcement it is clear that described
Example is only a part of embodiment of the present invention, rather than whole embodiments.Based on the embodiment in the present invention, this area is common
The every other embodiment that technical staff is obtained under the premise of not making creative work, broadly falls into the model of present invention protection
Enclose.
Embodiment 1
The preparation reduction covalent organic polymer of response (thpp-pt-peg)
With 5,10,15,20- tetra- (4- hydroxyphenyl) porphyrin, carboxylated cisplatin prodrug and Polyethylene Glycol as reaction raw materials,
By esterification, preparation reduction response covalent organic polymer thpp-pt-peg.Specifically include following steps:
By the 5 of 27.2mg, 10,15,20- tetra- (4- hydroxyphenyl) porphyrin, 32.1mg carboxylated cisplatin prodrug, 49.4mg n,
The 4- dimethylamino pyridine of n '-dicyclohexylcarbodiimide and 29.3mg is dissolved in dried oxolane, in 35 DEG C of nitrogen
Atmosphere encloses lower stirring reaction 24 hours；
Then the mono- end of 100mg is added to be the Polyethylene Glycol of carboxyl, the n of 12.4mg, n '-dicyclohexyl carbon two in system
The 4- dimethylamino pyridine of imines and 7.3mg, continues stirring reaction 24 hours under 35 DEG C of nitrogen atmospheres.Resulting solution is dense
It is added dropwise to after contracting in ice ether and obtains crude product and be further dissolved in 2ml methanol, dialyse in pure water and reduced for 48 hours
The covalent organic polymer of response.
Using known 5,10,15,20- tetra- (4- hydroxyphenyl) porphyrins of standard curve method configuration series and platinum concentration of element
After standard curve, tested respectively by ultraviolet-visible spectrum (uv-vis) and inductivity coupled plasma mass spectrometry (icp-ms)
The 5 of sample, 10,15,20- tetra- (4- hydroxyphenyl) porphyrin contents and platinum content, calculate wherein 5,10,15,20- tetra- (4-
Hydroxyphenyl) porphyrin content be 8.2wt%, Determination of cisplatin be 2.1wt%, 5,10,15,20- tetra- (4- hydroxyphenyl) porphyrin respectively with
The amount of the material of cisplatin prodrug and Polyethylene Glycol is 1.1: 1: 1.8.
By (dynamic light scattering, transmission electron microscope, single line are characterized to the covalent organic polymer of reduction response obtaining
State oxygen produces ability), result is as follows:
The dynamic laser grain size distribution of the thpp-pt-peg that Fig. 1 prepares for embodiment 1, it can be seen that
The nano-particle diameter that thpp-pt-peg is formed is about 60nm, and assumes single dispersing；Fig. 2 prepares for embodiment 1
The transmission electron microscope photo figure of thpp-pt-peg, because transmissioning electric mirror test is drying regime, peg part is difficult to be photographed, figure
The particle diameter of middle hydrophobic inner core part is about 45nm, and size is homogeneous.Warp is verified by the fluorescence intensity detecting sosg
After 660nm laser irradiates, thpp-pt-peg produces the ability of singlet oxygen, and result is shown in Fig. 3, and Fig. 3 is embodiment 1 preparation
The relative intensity of fluorescence figure of thpp-pt-peg sosg under the irradiation of 660nm laser；It can be seen that thpp-pt-peg tool
There is the ability of good generation singlet oxygen, be a kind of good optical dynamic therapy reagent.
Degradation property test in the buffer containing gsh for the thpp-pt-peg of embodiment 2 embodiment 1 preparation
Because thpp-pt-peg passes through the crosslinking of cisplatin prodrug, can dissociate under reductive condition, discharge further
Porphyrin Molecule, inside tumor contains the Glutathione (gsh) of high level, presents certain reproducibility.In order to grind further
Study carefully degraded under reductive condition for the thpp-pt-peg, we test the porphyrin in the pbs buffer having or not gsh respectively
Release conditions and the change of size of nano-particle.
Fig. 4 is the cumulative release in the buffer containing Glutathione (gsh) for the thpp-pt-peg of embodiment 1 preparation
Curve chart, it can be seen that prolongation over time, in the medium containing gsh, porphyrin accumulation release rate is far more than
Without the preparation in the medium of gsh；
Fig. 5 is the change of size in the buffer containing Glutathione (gsh) for the thpp-pt-peg of embodiment 1 preparation
Curve chart, it can be seen that prolongation over time, in the medium containing gsh, the particle diameter generation of nano-particle is larger
Change, after showing that nano-particle dissociates, hydrophobic part is assembled, and as shown in the transmission electron microscope of in figure, and is not containing
In the medium of gsh, the particle diameter of nano-particle is held essentially constant.Prove that thpp-pt-peg nano-particle has obvious reduction
Response.
Embodiment 3: the killing capacity experimental to tumor cell for the thpp-pt-peg of embodiment 1 preparation
As a control group, additional condition is for selection cisplatin active compound and the covalent organic polymer thpp-peg without cisplatin
660nm laser irradiates, and chooses the 4t1 cell checking killing ability to tumor cell for the thpp-pt-peg.
The irradiation co-cultivation of 660nm laser is being had or not with thpp-pt-peg and cisplatin by mtt test verification 4t1 cell
The cumulative survival rate of 48 hours, result is shown in Fig. 6, and Fig. 6 is embodiment 1 preparation thpp-pt-peg and cisplatin is thin with mouse breast cancer
The cell survival rate figure that born of the same parents' (4t1 cell) co-culture, it can be seen that thpp-pt-peg have compared with cisplatin higher
Lethality, and irradiate through laser, lethality greatly enhances it was demonstrated that compared with single chemotherapy, chemotherapy and photodynamic therapy
Combine the ability with higher suppression tumor cell proliferation.
The irradiation of 660nm laser is being had or not altogether with thpp-pt-peg and thpp-peg by mtt test verification 4t1 cell
The culture cumulative survival rate of 48 hours, result is shown in the thpp-pt- that Fig. 7, Fig. 7 are embodiment 1 preparation under 660nm laser irradiates
Peg and the cell survival rate figure co-culturing with mouse mastopathy cell (4t1 cell) without the crosslinked thpp-peg of cisplatin, from figure
In as can be seen that thpp-pt-peg there is compared with thpp-peg higher lethality, and through laser irradiate, lethality
Greatly enhance it was demonstrated that compared with single photodynamic therapy, chemotherapy is combined with photodynamic therapy and had higher suppression tumor cell
The ability of propagation.Further illustrate, therapeutic alliance more advantage compared with monotherapy.
Embodiment 4: the thpp-pt-peg of embodiment 1 preparation improves tumor locus weary oxygen situation
After thpp-pt-peg is passed through tail vein injection 24 hours in mice body, experiment mice sacrifice, glimmering by immunity
Light staining observes the improvement ability to tumor locus weary oxygen situation for the thpp-pt-peg.Result is shown in Fig. 8～Fig. 9；Fig. 8 is to implement
The thpp-pt-peg of example 1 preparation improves the fluorescence photo of tumor locus weary oxygen situation；Fig. 9 is the thpp-pt- of embodiment 1 preparation
Peg improves the fluorescence statistical data of tumor locus weary oxygen situation；From figure 8, it is seen that with compareing of not injecting thpp-pt-peg
Group is compared, and the fluorescence intensity in the weary oxygen region of thpp-pt-peg treatment group substantially weakens, and shows that its weary oxygen situation is changed
Kind.The statistical data to the fluorescence in tumor hypoxia region from Fig. 9, can substantially find the tumor through injecting thpp-pt-peg
The fluorescence statistical value in region is significantly lower than the fluorescence statistical value of the matched group without thpp-pt-peg injection, shows thpp-pt-
Peg can be effectively improved the weary oxygen situation of tumor locus.
Embodiment 5: the thpp-pt-peg of embodiment 1 preparation distribution experiments in vivo
Thpp-pt-peg is passed through tail vein injection in mice body, after 24 hours, experiment mice sacrifice, takes out important
Organ be placed in surface plate, in small animal imaging system photographs fluorescence photo, observe each organ and tumor locus thpp-
The enriching quantity of pt-peg.
The fluorescence photo that the thpp-pt-peg that Figure 10 provides for embodiment 1 is distributed in major organs, result shows, 24
After hour, tumor locus have stronger fluorescence, show that thpp-pt-peg is higher in the enriching quantity of tumor locus, due in kidney
Enriching quantity also very high, illustrate that thpp-pt-peg can go out from mice internal metabolism,
Each for mice organ is shredded and after extraction after homogenate, tests distribution in each organ for the thpp-pt-peg, result is shown in figure
The data that 11, Figure 11 thpp-pt-peg providing for embodiment 1 are distributed in major organs, it can be seen that this result
It is consistent with the fluorescence imaging result of organ, further illustrate distribution in mice body for the thpp-pt-peg.
Embodiment six: the thpp-pt-peg of embodiment 1 preparation is in chemotherapy and the photodynamic therapy therapeutic alliance of live body level
Experiment
Choose 5 backs and carry the mice of 4t1 tumor as experimental group, from tail vein injection thpp-pt-peg, through 24
After hour, thpp-pt-peg reaches maximum in the enriching quantity of tumor locus, then tumor locus is exposed to 660 nanometer lasers
Lower irradiation 45min, laser power is 2w/cm2.The mice (every group 5) that other four groups of backs carry tumor is tried as matched group
Test, be (1) respectively not through the healthy mice of any process；(2) only has laser irradiation group；(3) inject same cisplatin dose
Cisplatin a bulk solution；(4) the additional laser of thpp-peg injecting same porphyrin concentration irradiates.When processed every group of mice it
Afterwards, the gross tumor volume of mouse back measured once every two days.
Figure 12 is the variation diagram of gross tumor volume, and as shown in figure 12, the tumor of experimental mice is after therapeutic alliance
Growth is significantly suppressed, and and other matched group tumor grows continuous, show therapeutic alliance compared with single therapy,
There is the ability of more excellent suppression tumour growth.
Figure 13 is Mouse Weight variation diagram, and as shown in figure 13, the body weight of experimental mice is not decreased obviously, and shows
Thpp-pt-peg has good biocompatibility, has potential using value.
The explanation of above example is only intended to help and understands the method for the present invention and its core concept.It should be pointed out that it is right
For those skilled in the art, under the premise without departing from the principles of the invention, the present invention can also be carried out
Some improvement and modification, these improve and modify and also fall in the protection domain of the claims in the present invention.
Claims (10)
1. a kind of reduction covalent organic polymer of response, by the Polyethylene Glycol of carboxy blocking, the compound of formula (i) structure and carboxylic
Base cisplatin prodrug hybrid reaction obtains；
Wherein, r1、r2、r3And r4Independent selected from amino or hydroxyl.
2. covalent organic polymer according to claim 1 is it is characterised in that the compound of described formula (i) structure and institute
The mol ratio stating cisplatin prodrug is (1～1.5): 1.
3. covalent organic polymer according to claim 1 is it is characterised in that the compound of described formula (i) structure and institute
The mol ratio stating cisplatin prodrug is (1.1～1.3): 1.
4. covalent organic polymer according to claim 1 is it is characterised in that the Polyethylene Glycol of described carboxy blocking and institute
The mol ratio stating cisplatin prodrug is (1.5～2): 1.
5. covalent organic polymer according to claim 1 it is characterised in that the Polyethylene Glycol of described carboxy blocking point
Son is measured as 1kda～10kda.
6. covalent organic polymer according to claim 1 is it is characterised in that described cisplatin prodrug is formula (pt-1) or formula
(pt-2)
7. covalent organic polymer according to claim 1 is it is characterised in that the covalent organic polymer of described reduction response
The particle diameter of thing is 50～200 nanometers.
8. a kind of preparation method of the reduction covalent organic polymer of response, comprising: by the Polyethylene Glycol of carboxy blocking, formula (i)
The compound of structure and carboxylated cisplatin prodrug hybrid reaction obtain reducing the covalent organic polymer of response；
Wherein, r1、r2、r3And r4Independent selected from amino or hydroxyl.
9. preparation method according to claim 8 is it is characterised in that the catalyst of described reaction is carbodicyclo hexylimide
With 4- dimethylamino pyridine.
10. the reduction covalent organic polymer of response and claim 8～9 times described in a kind of claim 1～7 any one
The covalent organic polymer of reduction response that preparation method described in meaning one prepares is preparing optical dynamic therapy and chemotherapy
Application in the medicine of therapeutic alliance.
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| CN108653288A (en) * | 2018-05-29 | 2018-10-16 | 福建医科大学孟超肝胆医院 | A kind of weary oxygen responsive polymer nanoparticle and its application |
| CN108904804A (en) * | 2018-08-02 | 2018-11-30 | 苏州大学 | A kind of covalent organic polymer of fluorination and its preparation method and application loading perfluorocarbon |
| CN109161022A (en) * | 2018-07-26 | 2019-01-08 | 安徽大学 | Tetravalence platinum complex-ortho esters polymeric prodrugs, its micella and preparation method and application |
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Cited By (5)
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| CN108046276A (en) * | 2017-12-26 | 2018-05-18 | 湖北工业大学 | A kind of polyethyleneglycol modified preparation of mesoporous silica nano-particle of carboxy blocking and application thereof |
| CN108046276B (en) * | 2017-12-26 | 2019-10-11 | 湖北工业大学 | A kind of polyethyleneglycol modified preparation of mesoporous silica nano-particle of carboxy blocking and application thereof |
| CN108653288A (en) * | 2018-05-29 | 2018-10-16 | 福建医科大学孟超肝胆医院 | A kind of weary oxygen responsive polymer nanoparticle and its application |
| CN109161022A (en) * | 2018-07-26 | 2019-01-08 | 安徽大学 | Tetravalence platinum complex-ortho esters polymeric prodrugs, its micella and preparation method and application |
| CN108904804A (en) * | 2018-08-02 | 2018-11-30 | 苏州大学 | A kind of covalent organic polymer of fluorination and its preparation method and application loading perfluorocarbon |
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