CN105106954B - One kind targeting photo-thermal therapy water-soluble compound and preparation method and application - Google Patents
One kind targeting photo-thermal therapy water-soluble compound and preparation method and application Download PDFInfo
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- CN105106954B CN105106954B CN201510376833.2A CN201510376833A CN105106954B CN 105106954 B CN105106954 B CN 105106954B CN 201510376833 A CN201510376833 A CN 201510376833A CN 105106954 B CN105106954 B CN 105106954B
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Abstract
The present invention discloses a kind of targeting photo-thermal therapy water-soluble compound, is the nano material for poly- (N phenylglycines) the polyethylene glycol hyaluronic acid triplicity being made up of amino-end peg with amido link at both ends respectively in connection with poly- (N phenylglycines) and hyaluronic acid.Its preparation method carries out the polymerization of N phenylglycines using chemical oxidization method first, obtains poly- (N phenylglycines) PGNP, then synthesizes PGNP PEG NH using acid amides synthetic method2, PGNP PEG HA are finally synthesized using acid amides synthetic method.The complex solution has good photo-thermal effect, and cancer cell effectively can be targetedly killed under Infrared irradiation, smaller to normal cellular damage, and compound no cytotoxicity itself, good water solubility and stabilized aqueous solution.
Description
【Technical field】
The present invention relates to photo-thermal therapy agent, belongs to biology medical material technical field, and in particular to one kind targeting photo-thermal is controlled
Treatment water-soluble compound and preparation method and application.The present invention with N-phenylglycine, amino-end peg and thoroughly
Bright matter acid is material, using amidation process, prepares the compound of poly- (N-phenylglycine)-polyethylene glycol-hyaluronic acid
Material, products therefrom has water solubility, available for targetting photo-thermal therapy.
【Background technology】
Photo-thermal therapy is that the light of specific wavelength is absorbed using optothermal material, is converted the energy of absorption by non-radiative decay
Local ambient temperature rise is caused for thermal conductivity, and then realizes the treatment to diseased region.And over the course for the treatment of if can assign
Optothermal material targeting so that optothermal material can targetedly enter sick cell, further, have preferably by absorbing
Penetration into tissue and the near infrared light small to human injury sick cell is heated, then can not damage normal structure,
Improve the accuracy and controllability of photo-thermal therapy.Compared with the technologies such as traditional operation, radiation and chemotherapy, photo-thermal therapy had
Journey is easy, noninvasive or minimally invasive, few intercurrent disease, recovers fast, the advantage such as the hospital stays is short, thus can effective reduction of patient slight illness, carry
High patient outcomes.
Polyaniline is conducted electricity very well, unique mechanism of doping effect is widely used in anticorrosive paint, electromagnetic screen due to its overcast
Cover, secondary cell, electrochromic material, cell propagation etc..Recently research have indicated that polyaniline can by acid, lewis acid,
Transition metal and alkali metal ion etc. are adulterated, and polyaniline salt form is converted into from the benzene-benzene structure (EB) of polyphenyl amine base form
Benzene-quinone structure (ES), so as to cause high conductivity and strong near infrared absorption, it can be used as photo-thermal therapy reagent (Yang, J.；Choi,
J.；Bang,D.；Ki m,E.；Lim,E.K.；Park,H.；Suh,J.S.；Lee,K.；Yoo,K.H.；Ki m,E.K.；Huh,
Y.M.；Haam,S.Angew.Chem.,Int.Ed.2011,50,441–444).But polyaniline is a kind of firm with aniline long-chain
Property structure condensate, water-soluble poor, this greatly limits application of the polyaniline in biomedical material.For photo-thermal
Treatment should meet good aqueous solubility, biocompatibility etc..At present, pegylated fatty acids, poly- (N- vinyl pyrroles are passed through
Alkanone) and PLA doping or modification, polyaniline poorly water-soluble in photo-thermal therapy application process has been successfully overcome by, has been improved
Material near infrared light thermal conversion efficiency (Yang, J.；Choi,J.；Bang,D.；Ki m,E.；Lim,E.K.；Park,H.；
Suh,J.S.；Lee,K.；Yoo,K.H.；Ki m,E.K.；Huh,Y.M.；Haam,S.Angew.Chem.,Int.Ed.2011,
50,441–444；Ibarra,L.E.；Yslas,E.I.；Molina,M.A.；Rivarola,C.R.；Romanini,S.；
Barbero,C.A.；Rivarola,V.A.；Bertuzzi,M.L.Laser Physics,2013,23:066004；Zhou,J.；
Lu,Z.；Zhu,X.；Wang,X.；Liao,Y.；Ma,Z.；Li,F.Biomaterials,2013,34:9584-9592.).So
And the functionalization of these polyaniline composite nanoparticles is relatively simple, therapeutic effect how is further improved, reduces photo-thermal examination
The toxicity of agent needs to solve.Therefore, design and development function are more, and biocompatibility is high, the good polyaniline base material of targeting
Material, it is noticeable.
【The content of the invention】
The defects of during in order to overcome polyaniline composite nanoparticle to be used as photo-thermal therapy, therapeutic effect is improved, reduce photo-thermal
The toxicity of reagent, design and development function are more, and biocompatibility is high, the good polyaniline material of targeting, the present invention seeks to
On the basis of above-mentioned prior art, there is provided one kind targeting photo-thermal therapy water-soluble compound.
The targeting photo-thermal therapy water-soluble compound of the present invention, is at both ends by amino-end peg with amido link
Poly- (N-phenylglycine)-polyethylene glycol-hyalomitome formed respectively in connection with poly- (N-phenylglycine) and hyaluronic acid
The nano material of sour triplicity.
Poly- (N-phenylglycine) (PGNP) is the aniline analogs of N- substituted acetic acids, is the conduction of the backbone of phenyl ring
Macromolecule.Nabid et al. is used as the template sweet ammonia of ammonium persulfate chemical oxidising polymerisation N- phenyl by the use of sulfonated polystyrene (SPS)
Acid, form water-soluble poly N-phenylglycine (Nabid, M.R.；Taheri,S.S.；Sedghi,R.；Entezami,
A.A.Iranian Polymer Journal,2008,17(5):1-7.).Its yield and electrical conductivity are sweet with SPS and N- phenyl
What propylhomoserin monomer ratio increased and reduced.SPS possesses benzene-quinone knot of polyaniline as the poly- N-phenylglycine of templated synthesis
Structure, its ultraviolet characterizes find that poly- (N-phenylglycine) of synthesis has absorption near infrared region.Benzoquinones knot based on polyaniline
Structure has the property that near infrared absorption is converted to heat, then whether poly- (N-phenylglycine) can answer there is also light thermal property
Treated for biomedicine, there is no relevant report so far.And good water solubility is needed to have as photo-thermal therapy reagent, biology
Internal stability is good, hypotoxicity, the condition such as rapid photothermal deformation.Poly- (N-phenylglycine) of existing Template synthesis,
Template can not reach fully erased, may influence biological stability and toxicity.
The carboxylic group or Pi-conjugated systems that poly- (N-phenylglycine) (PGNP) has can provide modifiable position
Point, the functional materials that can be functioned are combined, form multifunctional structures.Contain carboxyl on PGNP side chains, can with it is a lot
Group reacts, and can utilize and solve its water solubility problems containing hydrophilic molecule modification PGNP.
The hydrophily and biocompatibility that polyethylene glycol (PEG) has had, are widely used in receiving for modified biological medical use
In terms of rice material.The aggregation of nano-particle can be prevented, hinder non-specific material and cell interaction (Elsabahy,
M.；Wooley,K.L.Chemical Society Reviews,2012,41(7):2545-2561；Cheng,L.；Yang,K.；
Chen,Q.；Liu,Z..ACS Nano,2012,6(6):5605-5613.).The present invention is reacted double-end amino using acid amides
Polyethylene glycol NH2-PEG-NH2Modify on PGNP, form composite PGNP-PEG-NH2, it is simultaneous to improve its water-soluble and biology
Capacitive.
The band for the wire that hyaluronic acid (HA) is made up of two dissacharide units D-Glucose aldehydic acid and N-acetyl-glucosamine
There is the acidic polysaccharose of negative electrical charge, inner side produces strongly hydrophilic due to substantial amounts of hydroxyl be present, is dissolved in water, insoluble in organic molten
Agent.With good biocompatibility, biodegradability, water solubility, nontoxicity etc., in the propagation of cell and transfer etc.
Play important use.(typically there are B16, HCT- in the hyaluronic acid receptor CD44 that most tumor cell surface has overexpression
116, MCF-7, Hela cell), and by the effect with CD44, its can be bonded with effective as selective cell (Culty M,
Nguyen HA,Underhill C B.J Cell Biol.1992,116(4):1055–1062).Therefore, hyaluronic acid can be with
As the carrier of anti-malignant tumor medicine, targeted therapy purpose (Hyukjin L, Kyuri L, Tae G is realized
P.Bioconjugate Chem.2008,19,1319-1325)。
The targeting photo-thermal therapy water-soluble compound of the present invention is poly- (N-phenylglycine)-polyethylene glycol-hyalomitome
The composite of sour (PGNP-PEG-HA) triplicity, the photothermal deformation of poly- (N-phenylglycine) is imitated using polyethylene glycol
Targeting characteristic that should be with the good aqueous solubility of hyaluronic acid and to cancer cell, combines, solves poly- (N-phenylglycine)
Water solubility, improve targeting photo-thermal therapy effect.
In the compound system of the targeting photo-thermal therapy water-soluble compound of the present invention, on the one hand, poly- (the sweet ammonia of N- phenyl
Acid) as photo-thermal therapy agent participation disease treatment；On the other hand, hyaluronic acid had both improved the water solubility of polyaniline, and it is certainly
Body also has the effect of target cancer cell.Experiment confirms that the PGNP-PEG-HA complex solutions have good photo-thermal effect,
Cancer cell effectively can be targetedly killed under Infrared irradiation, it is smaller to normal cellular damage, and also compound is in itself
No cytotoxicity.In addition the present invention gained targeting photo-thermal therapy water-soluble compound can in aqueous systems it is dispersed simultaneously
It is more than the moon to be stabilized at least one.
Second object of the present invention is to provide a kind of method for preparing above-mentioned targeting photo-thermal therapy water-soluble compound.
The preparation method of photo-thermal therapy water-soluble compound is targetted, is comprised the steps：
(1) N-phenylglycine is dissolved in H2SO4In, stirring makes fully to dissolve, and continues stirring at 0~5 DEG C and keeps 20~60
Minute；
(2) ammonium persulfate with N-phenylglycine equimolar amounts is dissolved in H2SO4In, it is added drop-wise in the solution of (1), 0~
5 DEG C are reacted 5~12 hours, then natural reaction 16~30 hours；Filter out washing after liquid, dry, obtain that poly- (N- phenyl is sweet
Propylhomoserin) it is PGNP；
(3) it will be added to after the PGNP grindings obtained by (2) in dimethyl sulfoxide (DMSO), ultrasound 20~30 minutes, add 5 times of PGNP
The 1- ethyls of upper carboxyl amount-(3- dimethylaminopropyls) phosphinylidyne Diimmonium salt hydrochlorate, after being well mixed, 10~20min of ultrasound, then
The N- carboxyl succimides of carboxyl amount on 5 times of PGNP are added, continue ultrasound 10~20 minutes, stir 2~6h at room temperature；
(4) then add 10 times of PGNP amounts amino-end peg NH2-PEG-NH2, continue stirring reaction at room temperature
After 20~30h, it is evaporated under reduced pressure, the solution after vacuum distillation is filtered, and be washed with water, blue filtrate is obtained, by blue filtrate
Dialysed, the molecule interception M=1000Da of bag filter, dialysed 4~5 days, dialysis finishes, and is freeze-dried, and obtains water
Dissolubility PGNP-PEG-NH2；
(5) hyaluronic acid HA is dissolved in PBS solution, adds 1- ethyls-(the 3- dimethylaminopropyls) with HA equimolar amounts
Phosphinylidyne Diimmonium salt hydrochlorate and N- carboxyls succimide are activated to the carboxyl on HA, and PGNP-PEG- is added after 2~6h
NH2The aqueous solution, continue 16~30h of stirring reaction, dialysed with the bag filter of molecular cut off M=8000~14000, dialyse
5~7 days, dialysis finished, and was freeze-dried.Obtain water-soluble PGNP-PEG-HA composites, as target product targeting light
Heat cure water-soluble compound.
Further, it is in step (2) the ammonium persulfate solution rate of addition：1~2mL/min.
Carried out in described reacted at 0~5 DEG C in ice-water bath of step (2).
Step (2) described drying for vacuum drying, vacuum drying temperature be 40~60 DEG C, vacuum drying time be 24~
48 hours.
What it is in step (4) and (5) described dialysis is ultra-pure water with water.
The present invention carries out the polymerization of N-phenylglycine using chemical oxidization method, obtains poly- (N-phenylglycine) PGNP.
Then, PGNP carboxyl and NH are utilized2-PEG-NH2The amino of (amino-end peg), synthesized using acid amides synthetic method
PGNP-PEG-NH2.Finally, PGNP-PEG-NH is utilized2Amino and HA carboxyl, using acid amides synthetic method synthesize PGNP-PEG-
HA。
" natural reaction " in step (2) refers to cancel above after the condition (0~5 DEG C) of process, give free rein to after
Continuous reaction.During being somebody's turn to do, reaction temperature is slowly warming up to room temperature naturally from initial temperature (some temperature between 0~5 DEG C),
Then continue to react at room temperature.
" the 10 times of PGNP amounts " in " carboxyl amount on 5 times of PGNP " and step (4) in step (3) refers to mole
Ratio.
The present invention also provides a kind of pharmaceutical composition.Said composition includes at least one pharmaceutically acceptable carrier and upper
State described targeting photo-thermal therapy water-soluble compound.
The present invention also provides targeting photo-thermal therapy water-soluble compound described above and the above-mentioned drug regimen
Thing is preparing the application of antineoplastic.
The formulation of antineoplastic includes injection, oral agents, externally-applied liniment and other pharmaceutically defined and suitable
Using the formulation of photo-thermal therapy.
The tumour includes typical melanoma, cervical carcinoma, breast cancer and colon cancer.Also other suitable uses are included
The solid tumor of photo-thermal therapy.
【Embodiment】
The principle and feature of the present invention are described with reference to embodiments, the given examples are served only to explain the present invention,
It is not intended to limit the scope of the present invention.
Prepare embodiment
Prepare water-soluble PGNP-PEG-HA compounds
(1) 7mmol N-phenylglycines (PG) are dissolved in 50mL H2SO4Stirring 10min, is fully dissolved in (0.1M),
This process keeps ice-water bath.
(2) 7mmol ammonium persulfates (APS) are dissolved in 50mL H2SO4It is added drop-wise in above-mentioned solution, is added dropwise about in (0.1M)
0.5h, ice-water bath 5h is kept, then stir lower natural reaction 24h, washed after filtering out liquid, be dried in vacuo 24h, obtain poly- (N-
Phenylglycine) (PGNP).
(3) 4mmol PGNP are added in 200mL dimethyl sulfoxide (DMSO)s (DMSO) (solution is in navy blue) after being ground into fine powder,
Ultrasound 20 minutes.20mmol 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne Diimmonium salt hydrochlorate is added into above-mentioned solution
(EDC) after, being well mixed, ultrasonic 10min.20mmol N- carboxyls succimides (NHS) are added, continue ultrasonic 10min,
Ultrasound is finished, and stirs 2h at room temperature, and the carboxyl on PGNP is activated.
(4) and then 40mmol amino-end pegs NH is added2-PEG-NH2, continue stirring reaction 24h at room temperature, obtain
Blue solution containing a small amount of sediment.Above-mentioned solution decompression is distilled, removes most of DMSO, treats solution about 10mL in flask
When, stop being evaporated under reduced pressure.Solution after vacuum distillation is filtered, and is washed with water, obtains blue filtrate.Blue filtrate is carried out
Dialysis, the molecule interception M=1000Da of bag filter, dialyse four days.Dialysis finishes, and is freeze-dried, and obtains water solubility
PGNP-PEG-NH2。
(5) 0.56mmol HA are dissolved in 30mL PBS solutions, are stirred to molten.Take 0.56mmol EDC and 0.56mmol
NHS is added in above-mentioned solution, and the carboxyl on HA is activated.Activate 4h.Addition concentration is 6g L-1PGNP-PEG-NH2
Aqueous solution 10mL.Continue stirring reaction 24h.After reaction, dialysed with the bag filter of molecular cut off M=8000~14000,
Dialysis 5 days.Solution (solution is green) is freeze-dried.Obtain water-soluble PGNP-PEG-HA composites, as target
Product targets photo-thermal therapy water-soluble compound.
Test case 1
Experimental method is as follows：
Prepare containing the PGNP-PEG-NH that PGNP is 75ug/mL2And the PGNP-PEG-HA aqueous solution, the 1mL solution is taken, is used
Infrared laser 808nm (0.3W cm-2) irradiation irradiation 5min, using the temperature of thermal infrared imager recording solution with light application time
Change.
With the increase of light application time, PGNP-PEG-NH2And the temperature of PGNP-PEG-HA complex solutions also significantly rises
Height, and the PGNP-PEG-NH in 10 minutes215 DEG C are increased, PGNP-PEG-HA increases 22 DEG C, and pure water shines in same light
Under the conditions of only raise 0.2 DEG C.Experiment confirms that PGNP-PEG-HA complex solutions have good photo-thermal effect.
Application Example 1
Vitro cytotoxicity method of testing is as follows：
It is respectively final concentration of 0,50,100,200, the 400 μ g mL containing PGNP that a series of concentration, which are respectively configured,-1PGNP-
PEG-NH2With PGNP-PEG-HA solution.In 96 orifice plates (per hole 104Individual cell) 180 μ L Murine melanoma B16 cells of middle addition
And the suspension of l cell L929 cells, cultivated.After diel, the PGNP- of prepared series concentration is added
PEG-NH2With the μ L of PGNP-PEG-HA solution 20, it is further cultured for 24 hours.Cell inhibitory rate (inhibiting rate is surveyed with MTT method
(%)=(1- test holes OD values/control wells OD values) × 100%).
Under non-illuminated conditions, PGNP-PEG-NH2The equal unrestraint of two kinds of cells is made with PGNP-PEG-HA composites
With that is, material is non-toxic material, can be applied to the treatment of cell.
Application Example 2
Cell in vitro targeting method of testing is as follows：
It is respectively final concentration of 0,50,100,200, the 400 μ g mL containing PGNP that a series of concentration, which are respectively configured,-1PGNP-
PEG-NH2With PGNP-PEG-HA solution.In 96 orifice plates (per hole 104Individual cell) 180 μ L Murine melanoma B16 cells of middle addition
And the suspension of l cell L929 cells, cultivated.After diel, the PGNP- of prepared series concentration is added
PEG-NH2With the μ L of PGNP-PEG-HA solution 20, it is further cultured for 24 hours.808nm (0.3W cm are used respectively-2) irradiation irradiation 5min.
It is further cultured for 24 hours, cell inhibitory rate (inhibiting rate (%)=(1- test holes OD values/control wells OD values) is surveyed with MTT method
× 100%).
PGNP-PEG-NH is detected using Laser Scanning Confocal Microscope (Carl Zeiss LSM 710)2With PGNP-PEG-HA pairs
B16, L929 targeting photo-thermal therapy effect.By B16, L929 cells with 0.25% Trypsin Induced into cell suspending liquid,
24 orifice plate 1mL cell suspensions are added with 5000~10000 cells/wells, are put into 37 DEG C, 5%CO2Cell culture incubator culture 24
Hour.By PGNP-PEG-NH2Added with PGNP-PEG-HA fresh culture in each hole, make it finally containing the dense of PGNP
Spend for 400 μ g mL-1, and using be not added with medicine as control, continue culture 24 hours.Old culture medium is changed, adds 1mL's
PBS rinses 3 times, remove the PGNP-PEG-NH for being introduced into cell2And PGNP-PEG-HA.Add 1mL fresh cultures.Use ripple
A length of 808nm (0.3W cm-2) near-infrared laser under, irradiate 10min/ holes.1.6%Calcein-AM is used before and after illumination
Life or death cell is dyed with 2%PI.With copolymerization, Jiao is taken pictures.
Under 808nm laser irradiation conditions, experiment shows PGNP-PEG-HA to the kill rate of B16 cells up to 85%；And
80% is all higher than to L929 normal cell survival rates.PGNP-PEG-NH2To B16 and L929 cells without effect.Co-focusing imaging
It is more compared with the mediation PGNP-PEG-HA entrance of L929 normal cells to demonstrate B16 cancer cells, Apoptosis imaging is obvious；It is and right
PGNP-PEG-NH2Enter without mediation.Experiment confirms that PGNP-PEG-HA compound combination photo-thermal therapies have overexpression to surface
Hyaluronic acid receptor CD44 B16 cells have good targeting.
Application Example 3
Internal nude mice method of testing is as follows：
PGNP-PEG-NH has been investigated in experiment2With PGNP-PEG-HA as killing tumor effect in photo-thermal therapy agent body.
The right side back of female athymic nude mice carries out the tincture of iodine/ethanol disinfection, subcutaneous transplantation 0.1ml 1-2 × 107B16 cell physiologicals
Saline suspension, until the volume growth of tumour is close to 500mm3Afterwards, nude mice is randomly divided into 6 groups, respectively physiological saline group,
PGNP-PEG-NH2Group, PGNP-PEG-HA groups, physiological saline+laser irradiation group, PGNP-PEG-NH2+ laser irradiation group, PGNP-
PEG-HA+ laser irradiation groups, every group 5, weigh and carry out mark.Corresponding group inject respectively 200 μ L physiological saline,
PGNP-PEG-NH2(being 0.8mg/mL containing PGNP) and PGNP-PEG-HA (being 0.8mg/mL containing PGNP).Inject the same day of medicine
It is designated as the 0th day.Laser irradiation group mouse uses 808nm (0.3W cm after every 24 hours-2) laser irradiation 5min, and in During Illumination
It is middle to shoot laser irradiation group mouse thermograph with thermal camera.During photo-thermal therapy daily measurement mouse tumor major diameter a and
Minor axis b and mouse weight change.After the photo-thermal therapy of 14 days, all mouse are euthanized, and take out tumor tissues
Carry out contrast tumor size.
During photo-thermal therapy, the change of mouse tumor spot temperature is detected using thermal imaging system.PNPG-PEG-
HA has reached the effect of targeting aggregation photo-thermal heating in Mice Body.Because photo-thermal therapy makes actual shrinkage, body in mouse treatment
Weight is rapid to be reduced, after curing tumour, state that mouse restore normal growth, this demonstrate that PNPG-PEG-HA is not bright in vivo
Aobvious toxic action.Using the detection to gross tumor volume, photo-thermal therapy effect is evaluated, experiment finds that PGNP-PEG-HA+ laser shines
Penetrating group can effectively eliminate cancer cell, and other groups can not eliminate cell.Confirm that PGNP-PEG-HA compounds can be effectively in contact element
Melanoma cells.
According to the method for Application Example 2, checking PGNP-PEG-HA compound combination photo-thermal therapies cervical carcinoma, breast cancer
And colon cancer cell also has good targeting.
According to the method for Application Example 3, PGNP-PEG-NH has been investigated2With PGNP-PEG-HA as photo-thermal therapy agent body
The effect of interior killing cervical carcinoma, breast cancer and colon cancer, shows the effect same with Application Example 3.
The foregoing is only presently preferred embodiments of the present invention, be not intended to limit the invention, it is all the present invention spirit and
Within principle, any modification, equivalent substitution and improvements made etc., it should be included in the scope of the protection.
Claims (10)
1. one kind targeting photo-thermal therapy water-soluble compound, is tied respectively at both ends with amido link by amino-end peg
Poly- (N-phenylglycine)-polyethylene glycol-hyaluronic acid three for closing poly- (N-phenylglycine) and hyaluronic acid and forming
With reference to nano material.
2. the preparation method of the targeting photo-thermal therapy water-soluble compound described in claim 1, it is characterised in that：Including following
Step：
(1) N-phenylglycine is dissolved in H2SO4In, stirring makes fully to dissolve, and continues stirring at 0~5 DEG C and is kept for 20~60 points
Clock；
(2) ammonium persulfate with N-phenylglycine equimolar amounts is dissolved in H2SO4In, it is added drop-wise in the solution of (1), at 0~5 DEG C
Reaction 5~12 hours, then react 16~30 hours；Filter out washing after liquid, dry, obtain poly- (N-phenylglycine), i.e.,
PGNP；
(3) it will be added to after the PGNP grindings obtained by (2) in dimethyl sulfoxide (DMSO), ultrasound 20~30 minutes, add carboxylic on 5 times of PGNP
The 1- ethyls of base mole-(3- dimethylaminopropyls) phosphinylidyne Diimmonium salt hydrochlorate, after being well mixed, 10~20min of ultrasound, then
The N- hydroxysuccinimides of carboxyl mole on 5 times of PGNP are added, continue ultrasound 10~20 minutes, stir 2~6h at room temperature；
(4) then add 10 times of PGNP moles amino-end peg NH2-PEG-NH2, continue stirring reaction at room temperature
After 20~30h, it is evaporated under reduced pressure, the solution after vacuum distillation is filtered, and be washed with water, blue filtrate is obtained, by blue filtrate
Dialysed, the molecule interception M=1000Da of bag filter, dialysed 4~5 days, dialysis finishes, and is freeze-dried, and obtains water
Dissolubility PGNP-PEG-NH2；
(5) hyaluronic acid HA is dissolved in PBS solution, adds 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne with HA equimolar amounts
Diimmonium salt hydrochlorate and N- hydroxysuccinimides are activated to the carboxyl on HA, and PGNP-PEG-NH is added after 2~6h2Water
Solution, continue stirring reaction 24h, dialysed with the bag filter of molecular cut off M=8000~14000, dialyse 5~7 days, thoroughly
Analysis is finished, and is freeze-dried, and obtains water-soluble PGNP-PEG-HA composites, and as target product targeting photo-thermal therapy is used
Water-soluble compound.
3. preparation method according to claim 2, it is characterised in that：Speed is added dropwise in step (2) ammonium persulfate solution
Spend and be：1~2mL/min.
4. preparation method according to claim 2, it is characterised in that：Described in step (2) frozen water is being reacted at 0~5 DEG C
Carried out in bath.
5. preparation method according to claim 2, it is characterised in that：In step (2) described drying to be dried in vacuo, vacuum
Drying temperature is 40~60 DEG C, and vacuum drying time is 24~48 hours.
6. preparation method according to claim 2, it is characterised in that：It is super in step (4) and the water of using of (5) described dialysis
Pure water.
7. a kind of pharmaceutical composition, include the targeting photo-thermal described at least one pharmaceutically acceptable carrier and claim 1
Treatment water-soluble compound.
8. the pharmaceutical composition described in targeting photo-thermal therapy water-soluble compound and claim 7 described in claim 1 exists
Prepare the application of antineoplastic.
9. application according to claim 8, it is characterised in that：The formulation of antineoplastic include injection, oral agents,
Externally-applied liniment and other suitable dosage forms pharmaceutically.
10. application according to claim 8, it is characterised in that：The tumour includes：Melanoma, cervical carcinoma, mammary gland
Cancer and colon cancer.
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| CN108047462B (en) * | 2017-12-30 | 2020-12-29 | 广西师范大学 | Preparation method and application of hydrogel based on poly N-phenylglycine-polyethylene glycol |
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| "Chemical Synthesis and Characterization of Watersoluble，Conducting Poly(N-phenylglycine)";Mohammad Reza Nabid等;《Iranian Polymer Journal》;20080407;第17卷(第5期);第365-371页 * |
| "聚苯胺微/纳米结构及其应用";朱英等;《高分子通报》;20111031(第10期);第15-32页 * |
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