CN103301482A - Amphipathy tri-block polypeptide ICG (Indocyanine Green) loaded micelle and preparation method thereof - Google Patents
Amphipathy tri-block polypeptide ICG (Indocyanine Green) loaded micelle and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an amphipathy tri-block polypeptide ICG (Indocyanine Green) loaded micelle and a preparation method thereof. The amphipathy tri-block polypeptide ICG loaded micelle comprises a core, a middle layer and a shell, wherein the core is formed by polyleucine; the middle layer surrounds the core and is formed by polylysine; the shell is inserted into the middle layer and is formed by polyethylene glycol; and indocyanine green is dispersed in the core. By forming the core-shell structure to wrap the indocyanine green in polyethylene glycol-b-polylysine-b-polyleucine tri-block hybridized polypeptide, the indocyanine green is effectively prevented from being accumulated to decompose, so that the stability is enhanced. The prepared amphipathy tri-block polypeptide ICG loaded micelle has the characteristics of spatial stability, long circulation and the like, and has excellent fluorescence property, photothermal conversion capability as well as good passive targeting property, biocompatibility and degradability; optical imaging and photo-thermal treatment on tumor cells or tissues can be realized.
Description
[technical field]
The invention belongs to the technical field of nano material, particularly the poly-polypeptide of a kind of amphipathic three blocks carries ICG micelle and preparation method thereof.
[background technology]
Indocyanine green (ICG) is a kind of functional dye molecule, optical physics, photochemistry and photobiology characteristic with a series of uniquenesses, it is unique optical diagnostics factor with near-infrared characteristic of drugs approved by FDA, also be a kind of desirable light absorber simultaneously, can be used for carrying out the photo-thermal therapy of laser mediation.This near infrared dyestuff can be used as a kind of desirable contrast medium and is used for the difunctional targeted probes that development integrates optical imagery and photo-thermal therapy.At present, the application of indocyanine green is subject to great restriction, because the defective that itself has, comprises the gathering that concentration relies on, and relatively poor stability of molecule is with the non-specific binding of albumen and lack targeting specific.Therefore, the scientific research personnel improves its performance can carry out a large amount of research for fluorescent labeling.
Patent application 201010607708.5 discloses a kind of fluorescent nano probe and preparation method thereof "; by forming nucleocapsid structure indocyanine green is wrapped in the poly (glycolide-co-lactide); can effectively avoid indocyanine green to occur to assemble and decompose; the stability enhancing; but in default of targeting specific, limited its application in human body.(the Kirchherr A K such as Kirchherr, et al.Stabilization of Indocyanine Green by Encapsulation within MIicellar Systems[J] .Molecular pharmaceutics, 2009,6 (2): 480-491.) ICG is wrapped in prepared in the micelle volume in polar solvent lowly assemble, quantum yield is original 3 times ICG micelle; (the Cuifang Zheng such as Cuifang Zheng, et al.Indocyanine green-loaded biodegradable tumor targeting nanoprobes in vitro and in vivo imaging.Biomaterials, 2012,33:5603-5609) ICG is embedded in the poly (glycolide-co-lactide) phospholipid ball that has connect folate-targeted has prepared the nano-probe of particle diameter about 100nm, optical characteristics and the stability of solution of this nano-particle are improved, and have initiatively targeting; (the Mingbin Zheng such as Mingbin Zheng, et al.Single-Step Assembly of DOX/ICG Loaded Lipid_Polymer Nanoparticles for Highly Effective Chemo-photothermal Combination Therapy.ACS Nano, 2013,3,2056 – 2067) ICG and anticarcinogen amycin are wrapped in the lecithin granule of poly (lactic acid-glycolic acid), a kind of nanometer system that carries out the collaborative therapy of chemistry-photo-thermal of the interior fluorescence imaging of human body and tumor is provided.But, not yet have based on poly-polypeptide macromolecule polymer material natural or non-natural amino acids to be applied in report in the biodegradable micelle delivery system.
[summary of the invention]
Primary and foremost purpose of the present invention is to overcome the shortcoming and defect that prior art exists, and provides the poly-polypeptide of a kind of amphipathic three blocks to carry the ICG micelle.This micelle has good biocompatibility and biodegradable, and stable in properties can be applicable to optical imagery and photo-thermal therapy.
Another object of the present invention is to provide the described amphipathic three blocks preparation method that poly-polypeptide carries the ICG micelle.
Purpose of the present invention is achieved through the following technical solutions: the poly-polypeptide of a kind of amphipathic three blocks carries the ICG micelle, comprise kernel that poly-leucine forms, around the intermediate layer that is formed by polylysine of described kernel and partly be interspersed in the shell that is formed by Polyethylene Glycol in described intermediate layer, wherein, be dispersed with indocyanine green in the described kernel.
The diameter that the poly-polypeptide of described amphipathic three blocks carries the ICG micelle is preferably 100～160nm.
The preparation method that the poly-polypeptide of described amphipathic three blocks carries the ICG micelle, comprise the steps: the poly-polypeptide (PEG-PLL-PLLeu) of the poly-leucine three block hydridization of Polyethylene Glycol-b-polylysine-b-and indocyanine-green (ICG) 100:1～1:1 mix homogeneously in mass ratio, add organic solvent, the concentration that makes indocyanine-green is 0.01～10mg/mL, shake 3～5h in 20～25 ℃, 1000～1500rpm, obtain mixed solution; Mixed solution is dialysed, obtain the poly-polypeptide of amphipathic three blocks and carry the ICG micelle;
The mass ratio of the poly-polypeptide of the poly-leucine three block hydridization of described Polyethylene Glycol-b-polylysine-b-and indocyanine-green is preferably 5:1;
The poly-polypeptide (PEG-PLL-PLLeu) of the poly-leucine three block hydridization of described Polyethylene Glycol-b-polylysine-b-preferably adopts following methods to be prepared:
(1) MPEG-b-PZLL's is synthetic: with MPEG-NH
2With lysine anhydride 1:15～1:30, centrifugal behind 28～32 ℃ of stirring reaction 60～80h in molar ratio, get precipitation, vacuum drying obtains MPEG-b-PZLL; Synthetic equation is as follows:
MPEG-b-PZLL's is synthetic
(2) MPEG-b-PZLL-b-PLLeu's is synthetic: with the MPEG-b-PZLL of step (1) and leucine anhydride 1:20～1:40, centrifugal behind 28～32 ℃ of stirring reaction 60～80h in molar ratio, vacuum drying obtains MPEG-b-PZLL-b-PLLeu; Synthetic equation is as follows:
MPEG-b-PZLL-b-PLLeu's is synthetic
(3) the Z group deprotection of MPEG-b-PZLL-b-PLLeu: the MPEG-b-PZLL-b-PLLeu adding of step (2) is contained in the ethanol of 33wt%HBr, add trifluoroacetic acid, in 20～25 ℃ of reaction 2～4h, obtain the poly-polypeptide of the poly-leucine three block hydridization of Polyethylene Glycol-b-polylysine-b-; Add 0.4～0.6 milligram of MPEG-b-PZLL-b-PLLeu in the ethanol that every milliliter contains 33wt%HBr, trifluoroacetic acid is 1:5000～1:10 with the volume ratio that contains the ethanol of 33wt%HBr
4Synthetic equation is as follows:
The Z group deprotection of MPEG-b-PZLL-b-PLLeu
In the step (1):
Described reaction is preferably at dimethyl formamide (DMF) and N
2In carry out;
Described reaction is preferably carried out under the oil bath heating;
Described centrifugal preferred employing absolute ether carries out centrifugal;
Described vacuum drying is preferably room temperature (25 ℃) vacuum drying 24h;
(Lys (Z)-NCA) preferably adopts following methods to synthesize and obtains: Lys (Z) (10g, 33.56mmol) is dissolved in the 100mL oxolane, and oil bath is heated to 50 ℃ to described lysine anhydride; Triphosgene (4.6g, 97.71mmol) joins in the constant pressure funnel after being dissolved in the 20mL oxolane fully, after the question response solution temperature is stable, splashes into (1 drops/sec) triphosgene solution; Continue to be filled with N in the course of reaction
2, reaction 3h continues reaction 30min again after reactant liquor becomes the slightly yellow solution of clarification fully, so that react completely and discharge the by-products such as unnecessary phosgene, HCl; Behind the stopped reaction, reactant liquor is concentrated into 20mL, pours in the normal hexane of 200mL and precipitate, vacuum filtration obtains the solid white crude product; The gained crude product is at 65 ℃, V
THF: V
Normal hexaneRecrystallization is 2 times in the solution of=1:3, and room temperature vacuum drying 24h obtains the lysine anhydride (Lys (Z)-NCA) of white plates crystal form.
In the step (2):
Described reaction is preferably at dimethyl formamide (DMF) and N
2In carry out;
Described reaction is preferably carried out under the oil bath heating;
Described centrifugal preferred employing absolute ether carries out centrifugal;
Described leucine anhydride (Leu-NCA) preferably adopts following methods to synthesize and obtains: with Leu (10g, 76.23mmol) be dissolved in the 100mL oxolane, oil bath is heated to 50 ℃, triphosgene (11.66g, 39.29mmol) join in the constant pressure funnel after being dissolved in the oxolane of 20mL fully, after the question response solution temperature is stable, splash into (1 drops/sec) triphosgene solution; Continue to be filled with N in the course of reaction
2, reaction 3h continues reaction 30min again after reactant liquor becomes the slightly yellow solution of clarification fully, so that react completely and discharge the by-products such as unnecessary phosgene, HCl; Behind the stopped reaction, reactant liquor is concentrated into 10mL, pours in the 200mL normal hexane and precipitate, vacuum filtration obtains the solid white crude product; The gained crude product is at 65 ℃, V
THF: V
Normal hexaneRecrystallization is 2 times in the solution of=1:10, and room temperature vacuum drying 24h obtains the leucine anhydride (Leu-NCA) of white particulate.
The condition optimization of the reaction described in the step (3) is in 25 ℃ of reaction 2h.
Described organic solvent is a kind of or at least two kinds of mixture in dimethyl sulfoxide, oxolane, chloroform, normal hexane, methanol, ethanol, isopropyl alcohol, n-butyl alcohol and the acetone, is preferably dimethyl sulfoxide;
The concentration of described indocyanine-green is preferably 0.5～5mg/mL;
Described dialysis preferably adopts following methods to carry out: mixed solution is placed bag filter, and room temperature dialysis 48～72h in ultra-pure water, per 6～10h changes water one time, obtains the poly-polypeptide of amphipathic three blocks and carries the ICG micelle;
It is 3500 bag filter that described bag filter is preferably molecular cut off;
Described room temperature refers to 25 ℃.
The present invention has following advantage and beneficial effect with respect to prior art:
(1) the present invention adopts ICG and three amphipathic blocks to gather polypeptide, by forming nucleocapsid structure indocyanine green (ICG) is wrapped in the poly-polypeptide of poly-leucine (PEG-PLL-PLLeu) the three block hydridization of Polyethylene Glycol-b-polylysine-b-, can effectively avoid the ICG generation to assemble and decompose, stability strengthens, the ICG of parcel has the near-infrared fluorescent characteristic, the background fluorescence of penetrate tissue is less, can be applied to comparatively accurately biological fluorescent labelling.Because ICG and the amphipathic poly-polypeptide of three blocks all have hydrophilic and lipophilic double grading, non-covalent mutually combining can occur by hydrophobic interaction and Van der Waals force in both, form a kind of nanostructured of high-sequential, the poly-polypeptide of amphipathic three blocks that prepare carry the ICG micelle with hydrophilic PEG as shell, hydrophobic PLLeu as kernel, and ICG is wrapped in the hydrophobic kernel.The hydrophilic structure that Polyethylene Glycol is surrounded on the formation of polylysine surface can make probe avoid immune identification, strengthens probe in the half-life of system's internal recycle; The PEG shell can be so that granule possesses the characteristics such as spatial stability, electrostatic stabilization and long circulation; Poly-leucine and polylysine and Polyethylene Glycol PEG all have good biocompatibility, and be biodegradable and absorb or excrete by normal physiological pathway, little to the organism injury.
(2) the poly-polypeptide of amphipathic three blocks of the present invention carries the ICG micelle and possesses the characteristics such as spatial stability and long circulation, have outstanding fluorescence property, photo-thermal transfer capability and good passive targeting, biocompatibility and degradability, can realize tumor cell or tissue are carried out optical imagery and photo-thermal therapy.
[description of drawings]
Fig. 1 is the structural representation that the poly-polypeptide of amphipathic three blocks carries the ICG micelle.
Fig. 2 is the transmission electron microscope picture that the poly-polypeptide of amphipathic three blocks of embodiment 11 carries the ICG micelle.
Fig. 3 is the particle size distribution figure that the poly-polypeptide of amphipathic three blocks of embodiment 11 carries the ICG micelle.
Fig. 4 is the fluorescence spectrum figure that the poly-polypeptide of amphipathic three blocks of embodiment 11 carries the ICG micelle.
Fig. 5 is the photo-thermal intensification figure that the poly-polypeptide of amphipathic three blocks of embodiment 11 carries the ICG micelle.
[specific embodiment]
Below in conjunction with the drawings and specific embodiments the present invention is described in further detail.
(1) aminoacid anhydride (NCA) is synthetic, synthetic comprising lysine anhydride Lys (Z)-NCA and leucine anhydride Leu-NCA:
Lys (Z)-NCA's is synthetic: add Lys (Z) (10g in the dry reaction bottle, 33.56mmol) and the 100mL tetrahydrofuran THF, stir, oil bath is heated to 50 ℃, triphosgene (4.6g, 97.71mmol) join in the constant pressure funnel after being dissolved in the THF of 20mL fully, behind the temperature stabilization of question response solution, dropwise splash into (1 drops/sec) triphosgene solution, reactant becomes gel immediately, and can not stir splashing into along with triphosgene solution behind the 30min this moment, gel slowly dissolves, and begin slowly to stir with frequency 100rpm this moment.In the course of reaction, continue to be filled with N
2Reaction 3h, after becoming the slightly yellow solution of clarification fully, continues again reactant liquor reaction 30min, react completely and discharge the by-products such as unnecessary phosgene, HCl to allow, behind the stopped reaction, be spin-dried for reactant liquor to 20mL at 25 ℃, pour in the 200mL normal hexane and precipitate, then vacuum filtration obtains the solid white crude product; With the gained crude product at 65 ℃, V
THF: V
Normal hexaneBe recrystallization in the solution of 1:3 2 times, room temperature vacuum drying 24h obtains white plates crystal form product 8.05g, is Lys (Z)-NCA, productive rate 73.8%.
Leu-NCA's is synthetic: and the building-up process of Lys (Z)-NCA is similar.In the dry reaction bottle, add Leu (10g, 76.23mmol) and 100mL THF, be heated to 50 ℃, triphosgene (11.66g, 39.29mmol) join in the constant pressure funnel after being dissolved in the THF of 20mL fully, behind Leu reaction solution temperature stabilization, dropwise splash into (1 drops/sec) triphosgene solution, reactant becomes thick immediately, along with splashing into of triphosgene solution, reactant liquor becomes clarification by muddiness gradually, reaction 3h, and be filled with continuously N
2, after reactant liquor becomes the slightly yellow solution of clarification fully, continue again reaction 30min, to allow sufficient reacting and the by-products such as the unnecessary phosgene of discharge, HCl; Behind the stopped reaction, be spin-dried for reactant liquor to 10mL at 25 ℃, add in the 200mL normal hexane and precipitate, stir fully rear sucking filtration, obtain the solid white crude product; With the gained crude product at 65 ℃, V
THF: V
Normal hexaneBe recrystallization in the solution of 1:10 2 times, room temperature vacuum drying 24h obtains white particulate product 8.67g, is Leu-NCA, productive rate 72.4%.
(2) MPEG-b-PZLL's is synthetic: by PEG(MPEG-NH that will band amino
2) and lysine anhydride Lys (Z)-NCA in molar ratio 1:15 react and obtain MPEG-b-PZLL
15: first with MPEG-NH
2(0.33g, 0.16mmol) is dissolved among the DMF of 10mL drying and is used as macromole evocating agent, obtains reactant liquor A; Get the Lys (Z) of step (1)-NCA (0.75g, 2.4mmol) and be dissolved among the DMF of 10mL, obtain reactant liquor B; Then reactant liquor A and reactant liquor B are mixed, at N
2Lower, the oil bath heating is stirred with the frequency of 300rpm, 28 ℃ of reaction 80h, and reactant liquor becomes the water white transparency thick liquid; Finish after the reaction product dropwise to be dripped in the 100mL absolute ether that stirs with 400rpm, obtain white precipitate, in centrifugal 10 minutes of 25 ℃, 5000rpm, obtain crude product, again crude product is dissolved in 50mL DMF, with 100mL absolute ether precipitation, in centrifugal 10 minutes of 25 ℃, 5000rpm, in 25 ℃ of vacuum dryings, obtain product MPEG-b-PZLL
15
(3) MPEG-b-PZLL
15-b-PLLeu
20Synthetic: building-up process and MPEG-b-PZLL's is synthetic similar, by with MPEG-b-PZLL
15With Leu-NCA in molar ratio 1:20 react and make: first with the MPEG-b-PZLL of step (2)
15(0.70g, 0.15mmol) is dissolved among the DMF of 5mL drying and is used as macromole evocating agent, obtains reaction liquid C; The Leu-NCA (0.48g, 3.02mmol) that gets step (1) is dissolved among the DMF of 10mL, obtains reactant liquor D; Then reaction liquid C and reactant liquor D are mixed, at N
2Lower, the oil bath heated and stirred, 28 ℃ of reaction 80h, reactant liquor becomes the water white transparency thick liquid; After reaction finishes product is dropwise dripped in the 100mL absolute ether that stirs with 400rpm, obtain white precipitate, in centrifugal 10 minutes of 25 ℃, 5000rpm, obtain crude product, again crude product is dissolved in 50mL DMF, with 100mL absolute ether precipitation, in centrifugal 10 minutes of 25 ℃, 5000rpm, in 25 ℃ of vacuum dryings, obtain product MPEG-b-PZLL
15-b-PLLeu
20
(4) MPEG-b-PZLL
15-b-PLLeu
20Z group deprotection: by sloughing MPEG-b-PZLL
15-b-PLLeu
20The Z group obtain PEG-PLL
15-PLLeu
20Triblock copolymer, concrete experimentation is: 40 milligrams of MPEG-b-PZLL that get step (3)
15-b-PLLeu
20Be dissolved in 10 microlitre CF fully
3In the COOH solvent, under ice bath stirs, add 100 milliliters 33%HBr/AcOH solution, in the 100mL absolute ether, precipitate the centrifugal yellow crude product that obtains behind the reaction 2h; Again crude product is joined among the 5mL DMSO and dissolve, directly be encased in dialysis (the bag filter molecular cut off is 3500Da) in the bag filter, dialysis is transferred to the 24h that dialyses in the ammonia of 5 liters of pH9.0 behind the 24h in 5 liters of deionized waters, then 24h dialyses in the HCl of 5 liters of pH5.0 solution, in 5 liters of deionized waters, dialyse 24h (in the above-mentioned dialysis procedure at last, change extracellular fluid dialysis one time every 8h), in-30 ℃ of lyophilization 48h, obtain the poly-polypeptide PEG-PLL of the poly-leucine three block hydridization of Polyethylene Glycol-b-polylysine-b-
15-PLLeu
20
(1) aminoacid anhydride (NCA) is synthetic, synthetic comprising lysine anhydride Lys (Z)-NCA and leucine anhydride Leu-NCA: with (1) of embodiment 1.
(2) MPEG-b-PZLL
20Synthetic: by PEG(MPEG-NH that will band amino
2) and lysine anhydride Lys (Z)-NCA in molar ratio 1:20 react and obtain MPEG-b-PZLL
20: first with MPEG-NH
2(0.33g, 0.16mmol) is dissolved among the DMF of 10mL drying and is used as macromole evocating agent, obtains reactant liquor A; Get the Lys (Z) of step (1)-NCA (1g, 3.2mmol) and be dissolved among the DMF of 10mL, obtain reactant liquor B; Then reactant liquor A and reactant liquor B are mixed, at N
2Lower, the oil bath heating is stirred with the speed of 300rpm, 30 ℃ of reaction 72h, and reactant liquor becomes the water white transparency thick liquid; Finish after the reaction product dropwise to be splashed in the 100mL absolute ether that stirs with 400rpm, obtain white precipitate, in centrifugal 10 minutes of 25 ℃, 5000rpm, obtain crude product, again crude product is dissolved in 50mL DMF, with 100mL absolute ether precipitation, in centrifugal 10 minutes of 25 ℃, 5000rpm, in 25 ℃ of vacuum dryings, obtain product MPEG-b-PZLL
20
(3) MPEG-b-PZLL
20-b-PLLeu
30Synthetic: building-up process and MPEG-b-PZLL's is synthetic similar, by with MPEG-b-PZLL
20With Leu-NCA in molar ratio 1:30 react and make: first with MPEG-b-PZLL
20(0.7g, 0.15mmol) is dissolved in and is used as macromole evocating agent among the DMF of 5mL drying and obtains reaction liquid C; The Leu-NCA (0.72g, 4.52mmol) that gets step (1) is dissolved among the DMF of 10mL, obtains reactant liquor D; Then reaction liquid C and reactant liquor D are mixed, at N
2Lower, the oil bath heating is stirred with the speed of 300rpm, 30 ℃ of reaction 72h, and reactant liquor becomes the water white transparency thick liquid; After reaction finishes product is dropwise splashed in the 100mL absolute ether that stirs with 400rpm, obtain white precipitate, in centrifugal 10 minutes of 25 ℃, 5000rpm, obtain crude product, again crude product is dissolved in 50mLDMF, with 100mL absolute ether precipitation, in centrifugal 10 minutes of 25 ℃, 5000rpm, in 25 ℃ of vacuum dryings, obtain product MPEG-b-PZLL
20-b-PLLeu
30
(4) MPEG-b-PZLL
20-b-PLLeu
30Z group deprotection: by sloughing MPEG-b-PZLL
20-b-PLLeu
30The Z group obtain PEG-PLL
20-PLLeu
30Triblock copolymer, concrete experimentation is: 50 milligrams of MPEG-b-PZLL that get step (3)
20-b-PLLeu
30Be dissolved in 15 microlitre CF fully
3In the COOH solvent, under ice bath stirs, add 100 milliliters 33%HBr/AcOH solution, in the 100mL absolute ether, precipitate the centrifugal yellow crude product that obtains behind the reaction 2h.Again crude product is joined among the 5mL DMSO and dissolve, directly be encased in dialysis (the bag filter molecular cut off is 3500Da) in the bag filter, dialysis is transferred to the 24h that dialyses in the ammonia of 5 liters of pH9.0 behind the 24h in 5 liters of deionized waters, then 24h dialyses in the HCl of 5 liters of pH5.0 solution, in 5 liters of deionized waters, dialyse 24h (in the above-mentioned dialysis procedure at last, change extracellular fluid dialysis one time every 8h), in-30 ℃ of lyophilization 48h, obtain the poly-polypeptide PEG-PLL of the poly-leucine three block hydridization of Polyethylene Glycol-b-polylysine-b-
20-PLLeu
30
Embodiment 3
(1) aminoacid anhydride (NCA) is synthetic, synthetic comprising lysine anhydride Lys (Z)-NCA and leucine anhydride Leu-NCA: with (1) of embodiment 1.
(2) MPEG-b-PZLL
30Synthetic: by PEG(MPEG-NH that will band amino
2) and lysine anhydride Lys (Z)-NCA in molar ratio 1:30 react and obtain MPEG-b-PZLL
30: first with MPEG-NH
2(0.33g, 0.16mmol) is dissolved among the DMF of 10mL drying and is used as macromole evocating agent, obtains reactant liquor A; Get the Lys (Z) of step (1)-NCA (1.5g, 4.8mmol) and be dissolved among the DMF of 10mL, obtain reactant liquor B; Then reactant liquor A and reactant liquor B are mixed, at N
2Lower, the oil bath heating is stirred with the speed of 300rpm, 32 ℃ of reaction 60h, and reactant liquor becomes the water white transparency thick liquid; Finish after the reaction product dropwise to be splashed in the 100mL absolute ether that stirs with 400rpm, obtain white precipitate, in centrifugal 10 minutes of 25 ℃, 5000rpm, obtain crude product, again crude product is dissolved in 50mL DMF, with 100mL absolute ether precipitation, in centrifugal 10 minutes of 25 ℃, 5000rpm, in 25 ℃ of vacuum dryings, obtain product MPEG-b-PZLL
30
(3) MPEG-b-PZLL
30-b-PLLeu
40Synthetic: building-up process and MPEG-b-PZLL's is synthetic similar, by with MPEG-b-PZLL
30With Leu-NCA in molar ratio 1:40 react and make: first with MPEG-b-PZLL
30(0.80g, 0.15mmol) is dissolved in and is used as macromole evocating agent among the DMF of 5mL drying and obtains reaction liquid C; The Leu-NCA (0.96g, 6.04mmol) that gets step (1) is dissolved among the DMF of 10mL, obtains reactant liquor D; Then reaction liquid C and reactant liquor D are mixed, at N
2Lower, the oil bath heating is stirred with 300rpm, 32 ℃ of reaction 60h, and reactant liquor becomes the water white transparency thick liquid; After reaction finishes product is dropwise splashed in the 100mL absolute ether that stirs with 400rpm, obtain white precipitate, in centrifugal 10 minutes of 25 ℃, 5000rpm, obtain crude product, again crude product is dissolved in 50mL DMF, with 100mL absolute ether precipitation, in centrifugal 10 minutes of 25 ℃, 5000rpm, in 25 ℃ of vacuum dryings, obtain product MPEG-b-PZLL
30-b-PLLeu
40
(4) MPEG-b-PZLL
30-b-PLLeu
40Z group deprotection: by sloughing MPEG-b-PZLL
30-b-PLLeu
40The Z group obtain PEG-PLL
30-PLLeu
40Triblock copolymer, concrete experimentation is: 60 milligrams of MPEG-b-PZLL that get step (3)
30-b-PLLeu
40Be dissolved in 20 microlitre CF fully
3In the COOH solvent, under ice bath stirs, add 100 milliliters 33%HBr/AcOH solution, in the 100mL absolute ether, precipitate the centrifugal yellow crude product that obtains behind the reaction 2h.Again crude product is joined among the 5mL DMSO and dissolve, directly be encased in dialysis (the bag filter molecular cut off is 3500Da) in the bag filter, dialysis is transferred to the 24h that dialyses in the ammonia of 5 liters of pH9.0 behind the 24h in 5 liters of deionized waters, then 24h dialyses in the HCl of 5 liters of pH5.0 solution, in 5 liters of deionized waters, dialyse 24h (in the above-mentioned dialysis procedure at last, change extracellular fluid dialysis one time every 8h), in-30 ℃ of lyophilization 48h, obtain the poly-polypeptide PEG-PLL of the poly-leucine three block hydridization of Polyethylene Glycol-b-polylysine-b-
30-PLLeu
40
With the poly-polypeptide PEG-PLL of the poly-leucine three block hydridization of the Polyethylene Glycol of 4mg embodiment 1-b-polylysine-b-
15-PLLeu
20, 0.04mg indocyanine green ICG is dissolved among the dimethyl sulfoxide DMSO of 4mL, shakes 3h at 20 ℃, 1500rpm, makes PEG-PLL
15-PLLeu
20All fully be dissolved in DMSO with ICG, and make both abundant mix homogeneously, obtain mixed solution;
Then mixed solution is placed bag filter (molecular cut off is 3500), the 48h that in the lower ultra-pure water of room temperature (25 ℃), dialyses, every 6h changes water one time, and the poly-polypeptide of amphipathic three blocks that obtains mean diameter and be 145.8nm carries ICG micelle PEG-PLL
15-PLLeu
20/ ICG
100:1
With the poly-polypeptide PEG-PLL of the poly-leucine three block hydridization of the Polyethylene Glycol of 4mg embodiment 1-b-polylysine-b-
15-PLLeu
20, 0.8mg indocyanine green ICG is dissolved among the dimethyl sulfoxide DMSO of 4mL, shakes 3h at 20 ℃, 1500rpm, makes PEG-PLL
15-PLLeu
20All fully be dissolved in DMSO with ICG, and make both abundant mix homogeneously, obtain mixed solution;
Then mixed solution is placed bag filter (molecular cut off is 3500), the 60h that in the lower ultra-pure water of room temperature (25 ℃), dialyses, every 8h changes water one time, and the poly-polypeptide of amphipathic three blocks that obtains mean diameter and be 155nm carries ICG micelle PEG-PLL
15-PLLeu
20/ ICG
5:1
Embodiment 6
With the poly-polypeptide PEG-PLL of the poly-leucine three block hydridization of the Polyethylene Glycol of 4mg embodiment 1-b-polylysine-b-
15-PLLeu
20, 4mg indocyanine green ICG is dissolved among the dimethyl sulfoxide DMSO of 4mL, shakes 3h at 20 ℃, 1500rpm, makes PEG-PLL
15-PLLeu
20All fully be dissolved in DMSO with ICG, and make both abundant mix homogeneously, obtain mixed solution;
Then mixed solution is placed bag filter (molecular cut off is 3500), the 72h that in the lower ultra-pure water of room temperature (25 ℃), dialyses, every 10h changes water one time, and the poly-polypeptide of amphipathic three blocks that obtains mean diameter and be 158.7nm carries ICG micelle PEG-PLL
15-PLLeu
20/ ICG
1:1
Embodiment 7
With the poly-polypeptide PEG-PLL of the poly-leucine three block hydridization of the Polyethylene Glycol of 4mg embodiment 2-b-polylysine-b-
20-PLLeu
30, 0.04mg indocyanine green ICG is dissolved among the dimethyl sulfoxide DMSO of 4mL, shakes 4h at 23 ℃, 1200rpm, makes PEG-PLL
20-PLLeu
30All fully be dissolved in DMSO with ICG, and make both abundant mix homogeneously, obtain mixed solution;
Then mixed solution is placed bag filter (molecular cut off is 3500), the 48h that in the lower ultra-pure water of room temperature (25 ℃), dialyses, every 6h changes water one time, and the poly-polypeptide of amphipathic three blocks that obtains mean diameter and be 152.7nm carries ICG micelle PEG-PLL
20-PLLeu
30/ ICG
100:1
Embodiment 8
Get the poly-polypeptide PEG-PLL of the poly-leucine three block hydridization of the Polyethylene Glycol of 4mg embodiment 2-b-polylysine-b-
20-PLLeu
30, 0.8mg indocyanine green ICG is dissolved among the dimethyl sulfoxide DMSO of 4mL, shakes 4h at 23 ℃, 1200rpm, makes PEG-PLL
20-PLLeu
30All fully be dissolved in DMSO with ICG, and make both abundant mix homogeneously, obtain mixed solution;
Then mixed solution is placed bag filter (molecular cut off is 3500), the 60h that in the lower ultra-pure water of room temperature (25 ℃), dialyses, every 8h changes water one time, and the poly-polypeptide of amphipathic three blocks that obtains mean diameter and be 154nm carries ICG micelle PEG-PLL
20-PLLeu
30/ ICG
5:1
Embodiment 9
Get the poly-polypeptide PEG-PLL of the poly-leucine three block hydridization of the Polyethylene Glycol of 4mg embodiment 2-b-polylysine-b-
20-PLLeu
30, 4mg indocyanine green ICG is dissolved among the dimethyl sulfoxide DMSO of 4mL, shakes 4h at 23 ℃, 1200rpm, makes PEG-PLL
20-PLLeu
30All fully be dissolved in DMSO with ICG, and make both abundant mix homogeneously, obtain mixed solution;
Then mixed solution is placed bag filter (molecular cut off is 3500), the 72h that in the lower ultra-pure water of room temperature (25 ℃), dialyses, every 10h changes water one time, and the poly-polypeptide of amphipathic three blocks that obtains mean diameter and be 155.2nm carries ICG micelle PEG-PLL
20-PLLeu
30/ ICG
1:1
Get the poly-polypeptide PEG-PLL of the poly-leucine three block hydridization of the Polyethylene Glycol of 4mg embodiment 3-b-polylysine-b-
30-PLLeu
40, 0.04mg indocyanine green ICG is dissolved among the dimethyl sulfoxide DMSO of 4mL, shakes 5h at 25 ℃, 1000rpm, makes PEG-PLL
30-PLLeu
40All fully be dissolved in DMSO with ICG, and make both abundant mix homogeneously, obtain mixed solution;
Then mixed solution is placed bag filter (molecular cut off is 3500), the 48h that in the lower ultra-pure water of room temperature (25 ℃), dialyses, every 6h changes water one time, and the poly-polypeptide of amphipathic three blocks that obtains mean diameter and be 155nm carries ICG micelle PEG-PLL
30-PLLeu
40/ ICG
100:1
Embodiment 11
Get the poly-polypeptide PEG-PLL of the poly-leucine three block hydridization of the Polyethylene Glycol of 4mg embodiment 3-b-polylysine-b-
30-PLLeu
40, 0.8mg indocyanine green ICG is dissolved among the dimethyl sulfoxide DMSO of 4mL, shakes 5h at 25 ℃, 1000rpm, makes PEG-PLL
30-PLLeu
40All fully be dissolved in DMSO with ICG, and make both abundant mix homogeneously, obtain mixed solution;
Then mixed solution is placed bag filter (molecular cut off is 3500), the 60h that in the lower ultra-pure water of room temperature (25 ℃), dialyses, every 8h changes water one time, and the poly-polypeptide of amphipathic three blocks that obtains mean diameter and be 159nm carries ICG micelle PEG-PLL
30-PLLeu
40/ ICG
5:1
The transmission electron microscope picture that the poly-polypeptide of these amphipathic three blocks carries the ICG micelle as shown in Figure 2; As can be seen from Figure 2, poly-polypeptide carries the ICG micelle and is monodispersed even spherical particle, and particle size distribution is at 150nm.
The particle size distribution figure that the poly-polypeptide of these amphipathic three blocks carries the ICG micelle as shown in Figure 3; As can be seen from Figure 3, the poly-polypeptide of three blocks carries the ICG micelle and has narrower particle size distribution at 150nm, has shown the monodispersity that it is good, is consistent with transmission electron microscope results.
The fluorescence spectrum figure that the poly-polypeptide of these amphipathic three blocks carries the ICG micelle as shown in Figure 4; As can be seen from Figure 4, near the near-infrared region (800nm) that the poly-polypeptide of these amphipathic three blocks carries the ICG micelle has characteristic absorption peak, substantially conform to simple ICG fluorescent spectrum curve, therefore, the poly-polypeptide of these amphipathic three blocks carries the ICG micelle and can be used as near infrared fluorescent dye, is applied to the biological fluorescent labelling field.
The photo-thermal intensification figure that the poly-polypeptide of these amphipathic three blocks carries the ICG micelle as shown in Figure 5; Wherein, 5A is with the infrared temperature recording photograph of the different time points of thermal imaging system record under the irradiation of near-infrared NIR laser; 5B is carrier micelle PEG-PLL
30-PLLeu
40/ ICG
5:1(comprising 20 μ g/mL ICG) is at power 1W/cm
2The NIR laser irradiation under in time intensification figure; As can be seen from Figure 5, in irradiation 5min, PEG-PLL
30-PLLeu
40/ ICG
5:1Solution has been warmed up to 50 ℃ from 20 ℃, and all keeps stable in rear 5min, has shown outstanding photo-thermal conversion performance, has proved that the poly-polypeptide of this amphipathic three blocks carries the ICG micelle for the probability of photo-thermal therapy.
Get the poly-polypeptide PEG-PLL of the poly-leucine three block hydridization of the Polyethylene Glycol of 4mg embodiment 3-b-polylysine-b-
30-PLLeu
40, 4mg indocyanine green ICG is dissolved among the 4mL dimethyl sulfoxide DMSO, shakes 5h at 25 ℃, 1000rpm, makes PEG-PLL
30-PLLeu
40All fully be dissolved in DMSO with ICG, and make both abundant mix homogeneously, obtain mixed solution;
Then mixed solution is placed bag filter (molecular cut off is 3500), the 72h that in the lower ultra-pure water of room temperature (25 ℃), dialyses, every 10h changes water one time, and the poly-polypeptide of amphipathic three blocks that obtains mean diameter and be 160nm carries ICG micelle PEG-PLL
30-PLLeu
40/ ICG
1:1
The above the specific embodiment of the present invention does not consist of the restriction to protection domain of the present invention.Various other corresponding changes and distortion that any technical conceive according to the present invention has been done all should be included in the protection domain of claim of the present invention.
Claims (10)
1. the poly-polypeptide of amphipathic three blocks carries the ICG micelle, it is characterized in that, comprise kernel that poly-leucine forms, around the intermediate layer that is formed by polylysine of described kernel and partly be interspersed in the shell that is formed by Polyethylene Glycol in described intermediate layer, wherein, be dispersed with indocyanine green in the described kernel.
2. the poly-polypeptide of amphipathic three blocks according to claim 1 carries the ICG micelle, it is characterized in that, the diameter that the poly-polypeptide of described amphipathic three blocks carries the ICG micelle is 100～160nm.
3. claim 1 or 2 described amphipathic three blocks gather the preparation method that polypeptide carries the ICG micelle, it is characterized in that, comprise the steps: the poly-polypeptide of the poly-leucine three block hydridization of Polyethylene Glycol-b-polylysine-b-and indocyanine-green 100:1～1:1 mix homogeneously in mass ratio, add organic solvent, the concentration that makes indocyanine-green is 0.01～10mg/mL, shake 3～5h in 20～25 ℃, 1000～1500rpm, obtain mixed solution; Mixed solution is dialysed, obtain the poly-polypeptide of amphipathic three blocks and carry the ICG micelle.
4. amphipathic three blocks according to claim 3 gather the preparation method that polypeptide carries the ICG micelle, it is characterized in that, described organic solvent is a kind of or at least two kinds of mixture in dimethyl sulfoxide, oxolane, chloroform, normal hexane, methanol, ethanol, isopropyl alcohol, n-butyl alcohol and the acetone.
5. amphipathic three blocks according to claim 3 gather the preparation method that polypeptide carries the ICG micelle, it is characterized in that, the poly-polypeptide of the poly-leucine three block hydridization of described Polyethylene Glycol-b-polylysine-b-adopts following methods to be prepared:
(1) MPEG-b-PZLL's is synthetic: with MPEG-NH
2With lysine anhydride 1:15～1:30, centrifugal behind 28～32 ℃ of stirring reaction 60～80h in molar ratio, get precipitation, vacuum drying obtains MPEG-b-PZLL;
(2) MPEG-b-PZLL-b-PLLeu's is synthetic: with the MPEG-b-PZLL of step (1) and leucine anhydride 1:20～1:40, centrifugal behind 28～32 ℃ of stirring reaction 60～80h in molar ratio, vacuum drying obtains MPEG-b-PZLL-b-PLLeu;
(3) the Z group deprotection of MPEG-b-PZLL-b-PLLeu: the MPEG-b-PZLL-b-PLLeu adding of step (2) is contained in the ethanol of 33wt%HBr, add trifluoroacetic acid, in 20～25 ℃ of reaction 2～4h, obtain the poly-polypeptide of the poly-leucine three block hydridization of Polyethylene Glycol-b-polylysine-b-; Add 0.4～0.6 milligram of MPEG-b-PZLL-b-PLLeu in the ethanol that every milliliter contains 33wt%HBr, trifluoroacetic acid is 1:5000～1:10 with the volume ratio that contains the ethanol of 33wt%HBr
4
6. amphipathic three blocks according to claim 4 gather the preparation method that polypeptide carries the ICG micelle, it is characterized in that, described organic solvent is dimethyl sulfoxide.
7. amphipathic three blocks according to claim 3 gather the preparation method that polypeptide carries the ICG micelle, it is characterized in that, the mass ratio of the poly-polypeptide of the poly-leucine three block hydridization of described Polyethylene Glycol-b-polylysine-b-and indocyanine-green is 5:1.
8. amphipathic three blocks according to claim 3 gather the preparation method that polypeptide carries the ICG micelle, it is characterized in that, the concentration of described indocyanine-green is 0.5～5mg/mL.
9. amphipathic three blocks according to claim 3 gather the preparation method that polypeptide carries the ICG micelle, it is characterized in that, described dialysis preferably adopts following methods to carry out: mixed solution is placed bag filter, room temperature dialysis 48～72h in ultra-pure water, per 6～10h changes water one time, obtains the poly-polypeptide of amphipathic three blocks and carries the ICG micelle.
10. amphipathic three blocks according to claim 5 gather the preparation method that polypeptide carries the ICG micelle, it is characterized in that, the reaction described in step (1) and the step (2) is at dimethyl formamide and N
2In carry out.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102533248A (en) * | 2010-12-27 | 2012-07-04 | 中国科学院深圳先进技术研究院 | Fluorescence nanometer probe and preparation method thereof |
| CN102920649A (en) * | 2012-08-24 | 2013-02-13 | 中国科学院深圳先进技术研究院 | Drug-loading nano-micelles, and preparation method and application thereof |
-
2013
- 2013-06-27 CN CN201310263389.4A patent/CN103301482B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102533248A (en) * | 2010-12-27 | 2012-07-04 | 中国科学院深圳先进技术研究院 | Fluorescence nanometer probe and preparation method thereof |
| CN102920649A (en) * | 2012-08-24 | 2013-02-13 | 中国科学院深圳先进技术研究院 | Drug-loading nano-micelles, and preparation method and application thereof |
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| CN108721649A (en) * | 2018-06-26 | 2018-11-02 | 武汉凯德维斯生物技术有限公司 | A kind of design, synthesis and the application of cancer target near-infrared fluorescent developer |
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| CN113929740B (en) * | 2020-06-29 | 2024-01-16 | 中国科学技术大学 | Amphiphilic polypeptide and preparation method and application thereof |
| WO2022194733A2 (en) | 2021-03-17 | 2022-09-22 | Provepharm Life Solutions | Stable formulations of indocyanine green |
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