CN105327348B - A kind of nanometer of photo-thermal therapy reagent and preparation method thereof - Google Patents
A kind of nanometer of photo-thermal therapy reagent and preparation method thereof Download PDFInfo
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- CN105327348B CN105327348B CN201510757257.6A CN201510757257A CN105327348B CN 105327348 B CN105327348 B CN 105327348B CN 201510757257 A CN201510757257 A CN 201510757257A CN 105327348 B CN105327348 B CN 105327348B
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Abstract
The present invention provides a kind of nanometer of photo-thermal therapy reagent and preparation method thereof, the nano particle that the polymer to be covalently keyed by mPEG-PLGA and/or PEG-PLGA and porphyrins is formed, and the preferably described nanoparticle size is 50~1000nm；The preparation method includes the polymer for first preparing modified porphyrin, then is prepared into nano particle.This nanometer of photo-thermal therapy reagent has certain application potential in photo-thermal therapy reagent.
Description
Technical field
The invention belongs to nano biological field of medicaments, and in particular to a kind of nanometer of photo-thermal therapy reagent and preparation method thereof.
Background technique
Thermotherapy is that a kind of method of tumour is treated in the way of heating.Compared with traditional cancer treatment method, cancer
Thermotherapy have many advantages.The method of most of thermotherapies is all non-intrusion type, small to patient's damage, and operating method is simple
It is easy, and it is suitable for the vitals internal tumours of some unsuitable operations.It is using special photo-thermal therapy agent to close red
The absorption of outer light, and heat is converted by the luminous energy of absorption, increase tumor locus temperature, to induce cell apoptosis or to thin
Born of the same parents generate direct lethal effect.Compared with traditional operation treatment method, whole body system toxicity, therefore photo-thermal therapy are greatly reduced
It is counted as one of the technology of the treatment tumour of very potential substitution operation.
According to the difference of the raised degree of irradiated site temperature, photo-thermal therapy can be generally divided into hyperthermia
(Hyperthermia) and photo-thermal ablation two kinds of (Photothermal ablation, PTA).Hyperthermia refers to the temperature of tissue
Degree is increased between 42~46 DEG C, and the ablation of irreversible photo-thermal can then lead to the necrosis of tissue, and group is woven in 54 DEG C of temperature
240min under the conditions of 43 DEG C is equivalent in lower 1s.Photo-thermal therapy is usually to pass through laser irradiation to heat to tumor tissues, generally
Irradiation time is a few minutes to dozens of minutes, increases tumor tissues temperature.At such temperatures, since tumour cell is to warm
Tolerance it is lower, tumour cell is selectively destroyed.The heat that photo-thermal therapy generates often makes tumour cell generation can not
Inverse damage is mainly shown as mitochondria swelling, protein inactivation, the loss of birefringence, oedema and tissue necrosis, cell membrane
Loose and denaturation of memebrane protein etc..When temperature reaches 55~95 DEG C, several minutes of inner tissue will occur significantly to change.
In the prior art, photo-thermal therapy reagent mainly include gold nanorods, gold nanometer cage, graphene, carbon nanotube or
Copper sulfide etc. is nondegradable inorganic material, often causes people to its longer-term persistence genotoxic potential in vivo
Worry, greatly limits their extensive use.Therefore, attention is gradually transferred to exploitation new bio is compatible has by people
Come above machine photo-thermal therapy agent.Since the exploitation of organic photo-thermal therapy agent is currently in the starting stage, organic photo-thermal for developing
Therapeutic categories are also fewer, mainly include organic nir dye, porphyrin liposome and high molecular polymer three classes.Although close
IR dyes have the potentiality applied to photo-thermal therapy, and simple nir dye still has some defects: firstly, most of
Nir dye is in water phase and unstable, and the aggregation of concentration dependent can be presented；Secondly under the irradiation of near infrared light,
The photobleaching effect of dye molecule cannot be guaranteed its photo and thermal stability；And some dye molecules are during photo-thermal therapy
Due to lower in tumor locus enrichment degree, the effect for causing tumor photo-thermal to melt is substantially reduced.Porphyrin lipid self assembly, to close
Infrared light has stronger absorption and good biocompatibility.However, porphyrin liposome is unstable, during biologic applications
Its structure often changes, and especially photothermal processes more can cause liposome stability to reduce, so as to cause photo-thermal effect
Rate reduces.High molecular polymer, as Nano particles of polyaniline shows good colloidal stability, near-infrared in aqueous solution
Absorption peak changes with the variation of intracellular ph value and oxide content.Therefore, Nano particles of polyaniline can be used as
Potential photo-thermal therapy agent is used for the treatment of cancer.However, making it in most of feelings due to the charge characteristic on polyaniline surface
It is positive charge that condition lower electrically charged, can significantly affect its biocompatibility, which limits its further applying in human body.
Summary of the invention
In view of the deficiencies of the prior art, the purpose of the present invention is to provide a kind of nanometer of photo-thermal therapy reagent and its preparation sides
Method.
Realize that the object of the invention technical solution is as follows:
A kind of nanometer of photo-thermal therapy reagent, for by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer
(mPEG-PLGA) and/or polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) and porphyrins it is covalent
The nano particle that the polymer of key connection is formed.Preferably, the nanoparticle size is 50~1000nm.Further preferably
Ground, the nanoparticle size are 50nm~300nm.
The present invention also provides the preparation methods of above-mentioned nanometer photo-thermal therapy reagent comprising following steps:
By mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or polyethylene glycol
Lactic acid-ethanol block copolymer (PEG-PLGA) is dissolved in organic solvent, obtains polymer solution；
The porphyrins that can be reacted with hydroxyl on polymer are added into the polymer solution；Or it is additionally added
Catalyst is stirred to react, and obtains the polymer of modified porphyrin；
The polymer of the modified porphyrin is prepared into nano particle；Preferably, the nanoparticle size be 50~
1000nm。
Nanometer photo-thermal therapy reagent provided by the invention, porphyrin pass through the degradable polymer being covalently keyed, Bu Hui
It is discharged in cyclic process, for nanometer photo-thermal therapy reagent by emulsification-solidification method preparation, it is long to stablize the time, and nano particle can be with
Drug is contained in forming process, and there is certain application potential in photo-thermal therapy reagent.
Detailed description of the invention
Fig. 1 shows the transmission electron microscope pictures of the nanometer photo-thermal therapy reagent in embodiment 1.
Fig. 2 indicates the grain size distribution of the nanometer photo-thermal therapy reagent in embodiment 1.
Fig. 3 indicates the fluorescence spectra of nanometer photo-thermal therapy reagent and protoporphyrin in embodiment 1.
Fig. 4 indicates nanometer photo-thermal therapy reagent, chlorin e 6 and PBS buffer solution in embodiment 2 in 680nm laser
Irradiate the change curve of lower irradiation time and temperature.
Fig. 5 indicates the abosrption spectrogram of nanometer photo-thermal therapy reagent and modified porphyrin polymer in embodiment 1.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to the accompanying drawings and embodiments, right
The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and
It is not used in the restriction present invention.
The present invention provides a kind of nanometer of photo-thermal therapy reagent, is embedding by mono methoxy polyethylene glycol-polylactic acid-glycollic acid
Section copolymer (mPEG-PLGA) and/or polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) and porphyrin
Close the nano particle that the polymer that object is covalently keyed is formed.Preferably, the nanoparticle size is 50~1000nm.Into one
Preferably, the nanoparticle size is 50nm~300nm to step.
Preferably, the weight average molecular weight of PEG (polyethylene glycol) section of the mPEG-PLGA or PEG-PLGA be 1000~
10000。
Preferably, PLGA (polylactic acid-glycollic acid block copolymer) the section weight average molecular weight is 5000~50000；Into
Preferably, the lactide of the PLGA and the molar ratio of glycolide are 50:50~90:10 to one step.
Preferably, the polymer that the mPEG-PLGA and/or PEG-PLGA and porphyrins are covalently keyed be by
What the hydroxyl on mPEG-PLGA and/or PEG-PLGA and the porphyrins containing carboxyl were prepared.
Preferably, the porphyrins are the porphyrin containing carboxyl, preferably protoporphyrin, haematoporphyrin, chlorin
One or more of e6 etc..
The embodiment of the present invention also provides the preparation method of above-mentioned nanometer photo-thermal therapy reagent comprising following steps:
S01: by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer (mPEG-PLGA) and/or poly- second two
Alcohol-polylactic acid-glycollic acid block copolymer (PEG-PLGA) is dissolved in organic solvent, obtains polymer solution；
S02: the porphyrins that can be reacted with hydroxyl on polymer are added into the polymer solution；Or also
Catalyst is added, is stirred to react, obtains the polymer of modified porphyrin；
S03: the polymer of the modified porphyrin is prepared into nano particle；Preferably, the nanoparticle size is 50
~1000nm.
In above-mentioned preparation method:
In step S01, the organic solvent can be the organic solvent that can dissolve mPEG-PLGA or PEG-PLGA；It is excellent
It is selected as one or more of methylene chloride, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate etc..
In step S02, the hydroxyl of mPEG-PLGA or PEG-PLGA are reacted with porphyrins, are formed covalent
The polymer of key connection.The porphyrins can be the porphyrin compound for being activated carboxyl, be also possible to pass through
The carboxyl porphyrin compound of activation of catalyst is added；I.e. catalyst by after the activated carboxylic of the porphyrins again with
The hydroxyl of mPEG-PLGA or PEG-PLGA reacts.
Preferably, the catalyst is 1- (3- dimethylaminopropyl) -3- ethyl carbodiimide, 4- (dimethylamino) pyrrole
One or more of pyridine, n-hydroxysuccinimide, dicyclohexylcarbodiimide etc..
It is further preferred that in step S02, the hydroxyl of mPEG-PLGA or PEG-PLGA and the porphyrins
Organic base is added when being reacted as acid binding agent, to improve reaction efficiency.The acid binding agent is preferably triethylamine, N, and N- bis- is different
One or more of propylethylamine etc..
Preferably, the molar ratio of the mPEG-PLGA or PEG-PLGA and porphyrins is 1:10~10:1, institute
The molar ratio for stating catalyst and mPEG-PLGA or PEG-PLGA is 5:1~1:5.
Preferably, the time that the hydroxyl of mPEG-PLGA or PEG-PLGA is reacted with the porphyrins is logical
Often greater than 6h, to improve reaction efficiency.
Preferably, the hydroxyl of the mPEG-PLGA or PEG-PLGA passed through after being reacted with porphyrins
The Methods For Purification of filter and dialysis, and the polymer of modified porphyrin is obtained by freeze-drying.
In step S03, by the polymer of the modified porphyrin be prepared into nano particle method can for emulsification-solidification method,
The prior arts conventional method such as nanoprecipitation method, emulsion solvent evaporation technique；Preferably, emulsion solvent evaporation technique preparation is selected,
The nanoparticle structure obtained in this way is more fine and close and stablizes, and photo-thermal effect is more preferable.
The technical scheme of the invention is further explained by means of specific implementation.Those skilled in the art should be bright
, the described embodiments are merely helpful in understanding the present invention, should not be regarded as a specific limitation of the invention.
Dynamic light scattering (Zetasizer is carried out to nanometer photo-thermal therapy reagent obtained in following embodiment
NanoZS), transmission electron microscope (U.S. FEI, Tecnai G2 20 S-TWIN, 200kV), light transmittance (U.S. Perkin Elmer,
950 UV-spectrophotometer of Lambda), fluorescence analysis (U.S. Perkin Elmer, LS-55) and photo-thermal effect
Measurement.
Embodiment 1
A kind of nanometer of photo-thermal therapy reagent, for by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer
(mPEG-PLGA) nano particle that the polymer being covalently keyed with porphyrins is formed.
The preparation method of this nanometer of photo-thermal therapy reagent includes:
1) mPEG-PLGA of 100nmol is dissolved in 10mL anhydrous methylene chloride, obtains polymer solution；
2) protoporphyrin of 50nmol, the 1- (3- dimethylaminopropyl)-of 50nmol are added into resulting polymers solution
The N of 3- ethyl carbodiimide, 4- (dimethylamino) pyridine of 25nmol and 50 μ L, N- diisopropylethylamine room under protection of argon gas
Temperature reaction 48h；For 24 hours by products therefrom filtering, dialysis, freeze-drying obtains mPEG-PLGA- porphyrin；
3) gained mPEG-PLGA- porphyrin is dissolved in methylene chloride, mPEG-PLGA- porphyrin concentration is 20mg/mL, ultrasound
15min is to being completely dissolved；0.2mL deionized water and the mPEG-PLGA- porphyrin solution of 1.0mL are taken, with cell ultrasonication machine cream
Change 3min, obtains Water-In-Oil colostrum；Colostrum is added in PVA (polyvinyl alcohol) aqueous solution of 3mL, the concussion that is vortexed is uniformly mixed,
Then ultrasonic emulsification 5min obtains W/O/W emulsion；It is evaporated under reduced pressure using Rotary Evaporators, the dichloromethane in removing solution
Alkane obtains the nanometer photo-thermal therapy reagent.
Embodiment 2
A kind of nanometer of photo-thermal therapy reagent, for by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer
(mPEG-PLGA) nano particle that the polymer being covalently keyed with porphyrins is formed.
The preparation method of this nanometer of photo-thermal therapy reagent includes:
100nmol of mPEG-PLGA, 100nmol chlorin e 6,50nmol 1- (3- dimethylaminopropyl) -3-
Ethyl carbodiimide, 25nmol 4- (dimethylamino) pyridine and 50 μ L triethylamines mix in 10mL anhydrous methylene chloride, argon gas
Protection is lower to react at room temperature 48h, and product dialysis 48h is freeze-dried, obtains mPEG-PLGA- chlorin e 6.
7.5mg mPEG-PLGA- chlorin e 6 is dissolved in 1.5mL acetone, ultrasonic 15min is to being completely dissolved.In magnetic
Above-mentioned solution is added drop-wise in the deionized water of 10mL with the speed of 30 μ L/min under power stirring.Continue to stir 30min, solidification is received
Rice grain.It is evaporated under reduced pressure using Rotary Evaporators, the organic solvent in removing solution, obtains the nanometer photo-thermal therapy reagent.
Embodiment 3:
A kind of nanometer of photo-thermal therapy reagent, for by polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA)
The nano particle formed with the polymer that porphyrins are covalently keyed.
The preparation method of this nanometer of photo-thermal therapy reagent includes:
100nmol of PEG-PLGA, 100nmol haematoporphyrin, 300nmol n-hydroxysuccinimide, 300nmol bis-
Carbodicyclo hexylimide reacts at room temperature 48h, crosses filtered product dialysis 48h, and freeze-drying obtains PEG-PLGA- porphyrin.
20mg PEG-PLGA- porphyrin is dissolved in 1mL methylene chloride, ultrasonic 15min is to being completely dissolved.10mLPVA is added
(1%) solution, the concussion that is vortexed are uniformly mixed it, emulsify 5min using high-speed shearing machine, emulsify power 6,000rmp, obtain water
Packet oil emulsion.It is evaporated under reduced pressure using Rotary Evaporators, the organic solvent in removing solution, obtains the nanometer photo-thermal therapy examination
Agent.
Embodiment 4
A kind of nanometer of photo-thermal therapy reagent, for by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer
(mPEG-PLGA) nano particle that the polymer being covalently keyed with porphyrins is formed.
The preparation method of this nanometer of photo-thermal therapy reagent includes:
100nmol of mPEG-PLGA, 50nmol protoporphyrin, 50nmol 1- (3- dimethylaminopropyl) -3- ethyl
Carbodiimide, 25nmol 4- (dimethylamino) pyridine and 50 μ L N, N- diisopropylethylamine mix in 10mL anhydrous methylene chloride
It closes, argon gas protection is lower to react at room temperature 48h, and product is dialysed for 24 hours, and freeze-drying obtains mPEG-PLGA- porphyrin.
MPEG-PLGA- porphyrin is dissolved in methylene chloride, concentration 20mg/mL, ultrasonic 15min are to being completely dissolved.It takes
0.2mL deionized water and 1.0mLmPEG-PLGA- porphyrin solution emulsify 3min with cell ultrasonication machine, obtain Water-In-Oil colostrum.
Colostrum is added in 3mLPVA aqueous solution, the concussion that is vortexed is uniformly mixed, and then it is multiple to obtain W/O/W by ultrasonic emulsification 5min
Cream.It is evaporated under reduced pressure using Rotary Evaporators, the methylene chloride in removing solution, obtains the nanometer photo-thermal therapy reagent.
Embodiment 5
A kind of nanometer of photo-thermal therapy reagent, for by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer
(mPEG-PLGA) connect with polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) with porphyrins covalent bond
The nano particle that the polymer connect is formed.
The preparation method of this nanometer of photo-thermal therapy reagent includes:
1) mPEG-PLGA of 120nmol and PEG-PLGA are dissolved in 15mL anhydrous methylene chloride, obtain polymer solution；
Wherein, the ratio of mPEG-PLGA and PEG-PLGA is 1: 1；
2) protoporphyrin of 60nmol, the 1- (3- dimethylaminopropyl)-of 60nmol are added into resulting polymers solution
The N of 3- ethyl carbodiimide, 4- (dimethylamino) pyridine of 30nmol and 60 μ L, N- diisopropylethylamine room under protection of argon gas
Temperature reaction 48h；For 24 hours by products therefrom filtering, dialysis, freeze-drying obtains mPEG-PLGA- porphyrin and PEG-PLGA- porphyrin；
3) gained mPEG-PLGA- porphyrin and PEG-PLGA- porphyrin are dissolved in methylene chloride, mPEG-PLGA- porphyrin and
PEG-PLGA- porphyrin concentration is respectively 12mg/mL, and ultrasonic 15min is to being completely dissolved；Take 0.2mL deionized water and 1.0mL
MPEG-PLGA- porphyrin and PEG-PLGA- porphyrin solution emulsify 3min with cell ultrasonication machine, obtain Water-In-Oil colostrum；It will be first
Cream is added in PVA (polyvinyl alcohol) aqueous solution of 3mL, and the concussion that is vortexed is uniformly mixed, and then ultrasonic emulsification 5min obtains water packet
Water-In-Oil emulsion；It is evaporated under reduced pressure using Rotary Evaporators, the methylene chloride in removing solution, obtains the nanometer photo-thermal therapy examination
Agent.
Embodiment 6
A kind of nanometer of photo-thermal therapy reagent, for by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer
(mPEG-PLGA) connect with polyethylene glycol-polylactic acid-glycolic block copolymer (PEG-PLGA) with porphyrins covalent bond
The nano particle that the polymer connect is formed.
The preparation method of this nanometer of photo-thermal therapy reagent includes:
1) mPEG-PLGA of 120nmol and PEG-PLGA are dissolved in 15mL anhydrous methylene chloride, obtain polymer solution；
Wherein, the ratio of mPEG-PLGA and PEG-PLGA is 1: 1；
2) chlorin e 6 of 60nmol, 1- (the 3- dimethylamino third of 60nmol are added into resulting polymers solution
Base) -3- ethyl carbodiimide, 4- (dimethylamino) pyridine of 30nmol and 60 μ L N, N- diisopropylethylamine argon gas protect
Lower room temperature reaction 48h；For 24 hours by products therefrom filtering, dialysis, freeze-drying obtains mPEG-PLGA- porphyrin and PEG-PLGA- porphin
Quinoline；
3) gained mPEG-PLGA- porphyrin and PEG-PLGA- porphyrin are dissolved in methylene chloride, mPEG-PLGA- porphyrin and
PEG-PLGA- porphyrin concentration is respectively 12mg/mL, and ultrasonic 15min is to being completely dissolved；Take 0.2mL deionized water and 1.0mL
MPEG-PLGA- porphyrin and PEG-PLGA- porphyrin solution emulsify 3min with cell ultrasonication machine, obtain Water-In-Oil colostrum；It will be first
Cream is added in the mixed aqueous solution of PVA (polyvinyl alcohol) and F68 (polyoxyethylene poly-oxygen propylene aether block copolymer) of 3mL,
The concussion that is vortexed is uniformly mixed, and then ultrasonic emulsification 5min obtains W/O/W emulsion；It is evaporated under reduced pressure, removed using Rotary Evaporators
The methylene chloride in solution is removed, the nanometer photo-thermal therapy reagent is obtained.
Experimental example 1
Fig. 1 is the transmission electron microscope picture of nanometer photo-thermal therapy reagent prepared by embodiment 1, as can be seen that receiving from electron microscope
The size of rice grain is in 100nm or so, almost spherical.The nanometer photo-thermal therapy obtained using laser particle analyzer measurement embodiment 1
The particle diameter distribution of reagent also further confirms the nanometer light as shown in Fig. 2, the average grain diameter of nano particle is 150nm or so
Heat cure reagent has good dispersibility.The nanometer photo-thermal therapy reagent and simple protoporphyrin obtain to embodiment 1 carries out
Fluorescence analysis, such as Fig. 3, nanometer photo-thermal therapy reagent fluorescent quenching is very serious as the result is shown, illustrates protoporphyrin in nanometer photo-thermal
High aggregation in therapeutic reagent, this is also that it has the reason of good light thermal property.
In addition, the nanometer photo-thermal therapy reagent and chlorin e 6 and PBS buffer solution to the preparation of embodiment 2 carry out light
Fuel factor measurement, under the laser (radium will prestige, Beijing) of 680nm, utilizes 1W/cm2Laser it is irradiated, and using heat at
As instrument (Ti27, Fluke) progress temperature assessment, as the result is shown as shown in figure 4, nanometer photo-thermal therapy examination as shown in Figure 4
Agent has good light thermal property.The nanometer photo-thermal therapy reagent that embodiment 1 is obtained using ultraviolet specrophotometer and modification
The polymer of porphyrin carries out spectral scan, as a result as shown in figure 5, nanometer photo-thermal therapy reagent is sent out compared to the polymer of modified porphyrin
Raw red shift, therefore, the nanometer photo-thermal therapy reagent can effectively absorb near infrared light for photo-thermal therapy.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, fall within the scope of the claimed invention without departing from theon the basis of the spirit of the present invention.
Claims (8)
1. a kind of nanometer of photo-thermal therapy reagent, which is characterized in that it is embedding by mono methoxy polyethylene glycol-polylactic acid-glycollic acid
The polymer that section copolymer and/or polyethylene glycol-polylactic acid-glycolic block copolymer and porphyrins are covalently keyed
The nano particle of formation；The nanoparticle size is 50~1000nm；The porphyrins are the porphyrin containing carboxyl,
Selected from one or more of protoporphyrin, haematoporphyrin, chlorin e 6；Mono methoxy polyethylene glycol-the polylactic acid-glycollic acid
The weight average molecular weight of block copolymer or polyethylene glycol-polylactic acid-glycolic block copolymer polyethylene glycol section be 1000~
10000；The weight average molecular weight of the polylactic acid-glycollic acid block copolymer section is 5000~50000；Polylactic acid-the ethyl alcohol
The molar ratio of sour block copolymer section lactide and glycolide is 50:50~90:10；
The preparation method of the nanometer photo-thermal therapy reagent, includes the following steps:
S01: by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-glycolic
Block copolymer is dissolved in organic solvent, obtains polymer solution；
S02: the porphyrins that can be reacted with hydroxyl on polymer are added into the polymer solution；Catalysis is added
Agent, and organic base is added as acid binding agent, it is stirred to react, obtains the polymer of modified porphyrin；The catalyst is 1- (3- dimethyl
Aminopropyl) -3- ethyl carbodiimide, 4- (dimethylamino) pyridine, n-hydroxysuccinimide, in dicyclohexylcarbodiimide
One or more；The acid binding agent is triethylamine, N, one or more of N- diisopropylethylamine；
Alternatively, the porphyrins that can be reacted with hydroxyl on polymer are added into the polymer solution, it is added organic
Alkali is stirred to react as acid binding agent, obtains the polymer of modified porphyrin；The porphyrins are the porphins for being activated carboxyl
Quinoline compound；The acid binding agent is triethylamine, N, one or more of N- diisopropylethylamine；
S03: the polymer of the modified porphyrin is prepared into nano particle.
2. according to claim 1 nanometer of photo-thermal therapy reagent, which is characterized in that the nanoparticle size be 50nm~
300nm。
3. the preparation method of as claimed in claim 1 or 2 nanometer of photo-thermal therapy reagent, which comprises the steps of:
S01: by mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer and/or polyethylene glycol-polylactic acid-glycolic
Block copolymer is dissolved in organic solvent, obtains polymer solution；
S02: the porphyrins that can be reacted with hydroxyl on polymer are added into the polymer solution；Or it is additionally added
Catalyst is stirred to react, and obtains the polymer of modified porphyrin；
S03: the polymer of the modified porphyrin is prepared into nano particle.
4. preparation method according to claim 3, which is characterized in that in step S01, the organic solvent is that can dissolve list
Methoxy polyethylene glycol-polylactic acid-glycolic block copolymer or polyethylene glycol-polylactic acid-glycolic block copolymer
Organic solvent.
5. the preparation method according to claim 4, which is characterized in that in step S01, the organic solvent is dichloromethane
One or more of alkane, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate.
6. preparation method according to claim 3, which is characterized in that in step S03, by the polymer of the modified porphyrin
The method of nano particle is prepared into as any one in emulsification-solidification method, nanoprecipitation method, emulsion solvent evaporation technique.
7. according to the described in any item preparation methods of claim 3-6, which is characterized in that the mono methoxy polyethylene glycol-is poly-
Lactic acid-ethanol block copolymer or polyethylene glycol-polylactic acid-glycolic block copolymer and porphyrins mole
Than for 1:10~10:1, the catalyst and mono methoxy polyethylene glycol-polylactic acid-glycollic acid block copolymer or poly- second two
Alcohol-polylactic acid-glycollic acid block copolymer molar ratio is 5:1~1:5.
8. as claimed in claim 1 or 2 nanometer of photo-thermal therapy reagent is preparing the application in photo-thermal therapy reagent.
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| "Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles";Hai Wang等;《Biomaterials》;20110731(第32期);第8281-8290页 |
| "Nanoscopic micelle delivery improves the photophysical properties and efficacy of photodynamic therapy of protoporphyrin IX";Huiying Ding等;《Journal of Controlled Release》;20110110(第151期);第272页左栏第3-6段 |
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