CN102133208A - Photosensitive microcapsule used for photodynamic therapy and preparation method thereof - Google Patents
Photosensitive microcapsule used for photodynamic therapy and preparation method thereof Download PDFInfo
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- 239000003094 microcapsule Substances 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 238000002428 photodynamic therapy Methods 0.000 title claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 25
- 239000000463 material Substances 0.000 claims abstract description 22
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- 229920000867 polyelectrolyte Polymers 0.000 claims abstract description 12
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- 238000000034 method Methods 0.000 claims abstract description 10
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- Manufacturing Of Micro-Capsules (AREA)
Abstract
本发明公开了一种可用于光动力疗法的光敏微胶囊及其制备方法，属于光敏聚合物薄膜材料技术领域。首先，制备光敏剂分子接枝聚合物的光敏聚合物材料；然后采用层层自组装技术，在微球模板上组装带相反电荷的聚电解质材料，去核后制备出囊壁材料中含有以化学键直接接枝光敏剂的天然聚合物聚糖(CHI)或葡聚糖的多层囊壁自组装的中空胶囊。本发明的光敏微胶囊水分散性好，粒径均一；具有良好的生物相容性；固定了光敏分子，在特定波长光照下单线态氧量子产率高，能有效杀死肿瘤细胞，可潜在应用于PDT中，工艺简单，易于操作。The invention discloses a photosensitive microcapsule which can be used in photodynamic therapy and a preparation method thereof, belonging to the technical field of photosensitive polymer film materials. Firstly, prepare the photosensitive polymer material of photosensitizer molecular graft polymer; then use the layer-by-layer self-assembly technology to assemble the oppositely charged polyelectrolyte material on the microsphere template, and prepare the capsule wall material containing chemical bonds after enucleation. Self-assembled hollow capsules with multilayered walls of natural polymer polycan (CHI) or dextran directly grafted with photosensitizer. The photosensitive microcapsules of the present invention have good water dispersibility and uniform particle size; they have good biocompatibility; photosensitive molecules are immobilized, and the singlet oxygen quantum yield is high under light of a specific wavelength, which can effectively kill tumor cells and potentially Applied in PDT, the process is simple and easy to operate.
Description
Technical field
The invention belongs to photosensitive polymer thin-film material technical field, be specifically related to a kind of light-sensitive microcapsule that can be used for photodynamic therapy and preparation method thereof.
Background technology
Cancer is one of principal disease that threatens the human life.Control and Comprehensive Treatment cancer are the emphasis of various countries' health strategy at present, also are the research focuses of World Focusing.Traditional treatment of cancer means, i.e. kinds of tumors can be controlled, be cured to operation, radiation and chemotherapy through updating, but still the very big defective of existence, for example, operation meeting grievous injury patient's function or pattern, radiation and chemotherapy then has bigger toxic and side effects.
Rising in the photodynamic therapy (PDT) of the nineties in last century is a kind of photochemical reaction of Local treatment lesion tissue.In recent years, PDT is as a kind of effective ways for the treatment of the shallow-layer cancer, with its good targeting, safety to the specific tumors cell, and advantage such as local damage, become a kind of novel cancer method that paid attention to by the various countries scholar.Yet the many photosensitizer that are used for the PDT therapy have hydrophobicity, have limited the clinical practice of PDT.Be head it off, multiple hydrophilic carrier is introduced among the PDT, as gel, liposome, colloid etc.Wherein, the hydrophilic natural polyelectrolyte multiplayer microcapsule that utilizes layer-by-layer to construct has caused common concern, particularly it has the controllability of unique size, pattern, composition and permeability, has bigger inner-cavity structure in addition and coats the function micromolecule.Load the micromolecular light-sensitive microcapsule of photosensitive drug can be under specific wavelength illumination condition, make photosensitive molecular arrive excited state, by scurrying transition between being is triplet state, this part photosensitive molecular and ambient oxygen molecule shift by energy and react, generation can cause irreversible damage of cell or dead singlet oxygen, finishes the PDT therapeutic process.
At present, utilize the existing report of microcapsule of layer-by-layer preparation.As, international monopoly (wo9947252) is a template with melamino-formaldehyde (MF), and alternately absorption has opposite electrical polyphenyl enamine and kayexalate, and the last molten MF of going makes hollow microcapsule.Above-mentioned patent is to have adopted non-biodegradation and compatible wall material, can't put into practice at biomedicine field.International monopoly (wo2008028246) has been constructed the microcapsule of sodium alginate (ALG)/chitosan (CHI) the coated magnetic Fe3O4 nanoparticle with good biocompatibility, and its microcapsule particle diameter can't be realized drug delivery in the body greater than 100 μ m.It is capsule-core with fat-soluble medicines such as elemenes that domestic patent (CN101703490) discloses a kind of, and CHI or its quaternary ammonium salt/λ～carrageenin or ALG come the micro-nano medicine-carrying capsule of the polymer/inorganic nanometer particle hydridization of coated magnetic nanoparticle or photosensitive nanoparticle for the wall material.Other has people such as bibliographical information Li Jun cypress by direct dipping process, the light-sensitive microcapsule of micromolecule photosensitizer HB that prepared a kind of load, and this capsule is subjected to after the optical excitation tumor cell have been produced high toxicity.But in the above-mentioned report, the photosensitive particle of micromolecule is adsorbed on the cyst material at random or is enriched in capsule, and so photosensitive particle can be reunited along with the increasing of enrichment concentration, and then causes photosensitive decrease in efficiency or singlet oxygen productive rate to reduce.In addition, the photosensitive particle of the micromolecule of absorption is easy to be revealed by the cyst wall duct before arriving lesions position, reduces singlet oxygen output, and easily normal structure is caused toxic and side effects.Therefore, realize that in light-sensitive microcapsule pre-fixing of photosensitizer just seems particularly important.
Summary of the invention
The objective of the invention is to solve the problems of the prior art, a kind of have biocompatibility and the active light-sensitive microcapsule of efficiency light and preparation method thereof are provided, with direct grafting the natural polymer of micromolecule photosensitizer as the wall material, adopt layer-by-layer to prepare microcapsule.Light-sensitive microcapsule of the present invention has effectively pre-fixed photosensitizer molecule, and can quantitatively control photosensitizer content, singlet oxygen productive rate height, and microcapsule uniform particle diameter, performance are controlled.
A kind of light-sensitive microcapsule that can be used for photodynamic therapy of the present invention is characterized in that, is the hollow capsules that contains in the cyst material with the multilamellar cyst wall self assembly of the natural polymer polysaccharide (CHI) of the direct grafting photosensitizer of chemical bond or glucosan.
The above-mentioned light-sensitive microcapsule that can be used for photodynamic therapy that the present invention proposes, adopt following technical scheme:
1) preparation of photosensitive cyst material:
Polymer tegument polysaccharide (CHI) or glucosan are mixed with the polymer solution A that concentration is 1～50mg/mL, regulate pH to 4-9; Photosensitizer is made into the photosensitizer solution B that concentration is 1～50mg/mL; Solution A slowly is added drop-wise in the solution B, and hybrid reaction is also stirred simultaneously, and wherein the volume ratio of solution A and solution B is (1～40): 1, and mixing speed is 500～1000rpm, reacts 1～3 day under 25～80 ℃ of conditions; With above-mentioned reactant molecular cut off is 7000 bag filter dialysis 5～20 days, after washing/centrifugal 2～3 times, with the precipitate lyophilization that obtains 2～4 days, obtains Powdered photosensitive polymer product; Be dissolved in the deionized water, being mixed with concentration is the photosensitive polymer aqueous solution of 0.1～10mg/mL.
2) preparation of light-sensitive microcapsule
Adopt the method for self assembly layer by layer, having on the microsphere template of electric charge the polyelectrolyte that assembling has opposite charges, adsorption multi-layer alternately, number of assembling steps 1 then) in photosensitive polymer, obtain the light-sensitive microcapsule of hollow after the enucleation, be scattered in the deionized water solution and preserve.
Used solvent is the common solvent of solubilized respective substance when preparing solution A or B in the step 1), can be deionized water, alcohol, acetic acid, sodium hydrate aqueous solution etc.
The described adjusting of step 1) pH agents useful for same is sodium carbonate/bicarbonate buffer or 2-(N-morphine quinoline) ethyl sulfonic acid (MES) buffer.
Photosensitizer described in the step 1) be have can with the photoactive substance of the active group of corresponding polymer condensation reaction, active group is as amino, carboxyl, halogenic substituent etc., to realize pre-fixing of photoactive substance.Described photosensitizer is preferably rose-red, fluorescein or 9-chloromethyl anthracene, but is not limited to above-mentioned photosensitizer.
Step 2) described microsphere template is positively charged melamino-formaldehyde (MF) microsphere in surface, the electronegative polyphenyl alkene microgranule (PS) in surface, polylactic acid or with the SiO of polymine (PEI) or poly--4-vinylbenzenesulfonic acid sodium (PSS) processing
2Microsphere, CaCO
3, MnCO
3Deng mineral crystal.Described charged template can directly be adsorbed the polyelectrolyte material that has opposite charges with it, and those skilled in the art can prepare voluntarily according to existing document.
Step 2) described polyelectrolyte solution is respectively: electronegative polyelectrolyte is sodium alginate, dextran sulfate or sodium carboxymethyl cellulose, and its concentration of aqueous solution is 1mg/mL; Positively charged polyelectrolyte is chitosan, polylysine, and its concentration of aqueous solution is 1mg/mL, or set by step 1) the aqueous solution of photosensitive polymer of method preparation.
Step 2) described pitting method depends on the character of selected mould material, and wherein, the MF microsphere decomposes under the acid condition of pH＜1.6; The carbonate template can be removed with hydrochloric acid or chelating agent; The PS ball can dissolve in THF; SiO
2Microsphere available hydrogen fluoric acid removal etc.; Those skilled in the art can consult the removal template method voluntarily according to existing document.
Under specific wavelength illumination, the light-sensitive microcapsule response produces singlet oxygen: the deionized water dispersion liquid of 200L light-sensitive microcapsule is placed the electron paramagnetic resonance instrument, with 40 μ L concentration is 2 of 2.0M, 2,6, the 6-tetramethyl piperidine is the singlet oxygen trapping agent, under the irradiation of 550nm wavelength laser, detects the generation of singlet oxygen.
Compared with prior art, the present invention has following beneficial effect:
1) has the photosensitive molecular of high singlet oxygen quantum yield to natural polymer with the direct grafting of chemical bond, this photosensitive polymer is assembled light-sensitive microcapsule as a microcapsule wall material aqua, fixing photosensitizer molecule, and prevent its local reunion, efficient singlet oxygen quantum yield can be kept.The inventive method is simple, and the gained photopolymerizable material has higher surface charge, is easy to assemble capsule.
2) the prepared light-sensitive microcapsule water dispersible of the present invention is good, and uniform particle diameter has high singlet oxygen quantum yield under specific wavelength illumination, but the kill tumor cell can potentially be applied among the PDT.
3) material of preparation light-sensitive microcapsule provided by the present invention is natural polyelectrolyte, and safe and harmless, raw material is easy to get.Light-sensitive microcapsule size, composition, the permeability of preparation are easy to control, and technology is simple, and be repeatable strong.
Description of drawings
Among Fig. 1, Comparative Examples 1 and the embodiment 1 preparation pure chitosan CHI and grafting Fourier's infrared spectrum of photosensitizer chitosan cyst material RB-CHI.
The sem photograph of the light-sensitive microcapsule of preparation among Fig. 2, the embodiment 1.
The fluorescence co-focusing picture of the light-sensitive microcapsule of preparation among Fig. 3, the embodiment 1.
The blank microcapsule of preparation and the electron paramagnetic resonance spectrum (EPR) figure of light-sensitive microcapsule among Fig. 4, Comparative Examples 2 and the embodiment 1.
The invention will be further described below in conjunction with accompanying drawing and example.
The specific embodiment
Embodiment 1
The preparation of photosensitive cyst material:
A: the volume ratio that the CHI of 0.1g is added 25mL is in 1% acetic acid aqueous solution, stirring under the speed of agitator of 200～1000rpm more than the 12h, regulates pH=5～6 with the MES buffer;
B: the RB (rose-red) of 0.028g is dissolved in the 25mL absolute methanol solution, and low whipping speed is under 200～1000rpm, adds catalyst 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides/N-hydroxy-succinamide, the about 30min of activated carboxyl;
C: the CHI acetic acid solution of A step is slowly dripped in the RB absolute methanol solution of B step, and be that 500～1000rpm was stirred 1～3 day with mixing speed simultaneously, temperature is controlled at 25～60 ℃;
D: with the reactant molecular cut off of C step is 7000 bag filter dialysis 5～20 days, after washing/centrifugal 2～3 times, with the precipitate lyophilization that obtains 2～4 days, obtains the photosensitive polymer product RB-CHI of Powdered pale pink.
E: the RB-CHI of D step is dissolved in the deionized water, and being mixed with concentration is the RB-CHI solution of 1mg/mL;
The preparation of light-sensitive microcapsule:
A: the aqueous dispersions of getting the positively charged MF microsphere template in 1mL surface is put into centrifuge centrifugalize 3～10min in the centrifuge tube of 1.5mL, remove upper water solution;
B: electronegative electrolyte solution ALG (sodium alginate) absorption: in centrifuge tube, add 1.5mL and prepare the also ALG solution of filtering 1mg/mL, vibration shakes up, allow ball-type particle MF be dispersed in the polymer solution, static placement 1～2h, the centre also need vibrate and shake up 2～3 times, makes absorption carry out better more completely;
C: washing: centrifugalize 7～8min, remove upper strata liquid, add the vibration of 1.5mL deionized water and shake up centrifugalize then.Remove upper strata liquid then and add the 1.5mL deionized water again, repetitive vibrations shakes up step with centrifugal separation, carries out 2～3 washings altogether;
D: positively charged electrolyte solution CHI absorption: remove the upper strata liquid after the washing in the above-mentioned C step/centrifugal, add and prepare the also CHI solution 1.5mL of filtering 1mg/mL, vibration shakes up, allow the ball-type particle be dispersed in the polymer solution, static placement 1～2h, the centre also need vibrate and shake up 2～3 times, makes absorption carry out better more completely;
E: repeat B～D step, alternately adsorb 5 bilayers, in the end one deck uses the electropositive photosensitive polymer solution RB-CHI of above-mentioned preparation to form as cyst wall;
F: enucleation: adding 1mL concentration in assembling 10 layers microcapsule is the hydrochloric acid solution of 0.1M, and vibration shakes up, and places the suspension bleach of 20～60min in centrifuge tube, and upper strata liquid is removed in centrifugalize again; After the washing, vibration shakes up, and obtains the light-sensitive microcapsule of hollow, preserves in deionized water solution.
As Fig. 1, contrast pure chitosan CHI and grafting Fourier's infrared spectrum of chitosan RB-CHI of photosensitizer, before the graft reaction, 1655cm
-1And 1599cm
-1The peak at place is owing to the C=O on the CHI strand, N-H key.After CHI and the RB reaction, at 1643cm
～1And 1548cm
-1Tangible absworption peak has appearred in the place, belongs to C=O stretching vibration and N-H stretching vibration respectively, is the characteristic peak of amido link.With CHI at 1595cm
-1The free amino group absworption peak difference at place.In addition, at 1730cm
-1The place does not have new peak to occur, and prove does not have the generation of fat base, and this illustrates that also the N-H group on the CHI chain is main active reactive group, can with the carboxyl generation dehydration condensation of RB.
Above-mentioned testing result explanation is by condensation reaction, and micromolecular photosensitive molecular successfully has been grafted on the polymer shell polysaccharide.
As Fig. 2, at the photosensitive surface of microcapsule of the hollow of air drying many irregular folds appear, particle size distribution homogeneous, good dispersion.
As Fig. 3, the fluorescence co-focusing microscope picture of the light-sensitive microcapsule of preparation shows that the capsule periphery shows the red fluorescence ring of light among the embodiment 1, directly proved grafting the chitosan RB-CHI of photosensitizer be covered by on the capsule as cyst wall, effectively fix photosensitizer, and kept fluorescent characteristic.
As Fig. 4, the blank microcapsule (Comparative Examples 2) of photosensitive polymerization material and electron paramagnetic resonance (ESR) wave spectrogram of light-sensitive microcapsule are not adsorbed in contrast, for light-sensitive microcapsule, increase along with irradiation time, the ESR signal intensity increases sharply, and speed slows down subsequently, finally reaches a platform.And blank microcapsule does not produce the ESR signal of representing singlet oxygen.The light-sensitive microcapsule that the present invention's preparation is described can effectively produce singlet oxygen, can potentially be used for PDT.
Embodiment 2
The preparation of photosensitive cyst material:
A: the CHI of 0.5g is dissolved in 1% acetic acid solution of 50mL, regulates pH=5～6 with the sodium carbonate/bicarbonate buffer;
B: the fluorescein of 0.05g is dissolved in the 5mL absolute methanol solution, and mixing speed is 200～1000rpm;
C: the CHI acetic acid solution of A step is slowly dripped more than the slow middle reaction 48h of fluorescein absolute methanol solution of B step, and be 500～1000rpm with mixing speed simultaneously, obtain reactant under 60～80 ℃ of vacuum;
D: with the reactant molecular cut off of C step is 7000 bag filter dialysis 5～20 days, after washing/centrifugal 2～3 times, with the precipitate lyophilization that obtains 1～2 day, obtains Powdered photosensitive polymer product.
E: the Powdered photosensitive polymer product of D step is dissolved in the deionized water, and the photosensitive polymer aqueous solution that is mixed with concentration and is 1mg/mL is stand-by;
The preparation of light-sensitive microcapsule:
A: get PS particulate templates that the 1mL surface has negative charge in the centrifuge tube of 1.5mL, put into centrifuge centrifugalize 3～10min, remove upper water solution;
B: positively charged CHI aqueous solution absorption: in centrifuge tube, add 1.5mL and prepare the also CHI aqueous solution of filtering 1mg/mL.Vibration shakes up, and allows the PS particulate templates be dispersed in the polymer solution, static placement 1～2h, and the centre also need vibrate and shake up 2～3 times, makes absorption carry out better more completely;
C: washing: centrifugalize 7～8min, remove upper strata liquid, add the vibration of 1.5mL deionized water and shake up centrifugalize then.Remove upper strata liquid then and add the 1.5mL deionized water again, repetitive vibrations shakes up step with centrifugal separation, carries out 2～3 washings altogether;
D: electronegative dextran sulfate aqueous solution absorption: remove the upper strata liquid after the washing in the above-mentioned C step/centrifugal, add and prepare the also dextran sulfate aqueous solution 1.5mL of filtering 1mg/mL, vibration shakes up, allow the PS microgranule be dispersed in the polymer solution, static placement 1～2h, the centre also need vibrate and shake up 2～3 times, makes absorption carry out better more completely;
E: repeat B～D step, alternately adsorb 5 bilayers, the electropositive photosensitive polymer solution that re-uses above-mentioned preparation at the capsule outermost layer is formed as cyst wall;
F: enucleation: add the THF solution of 1mL in the light-sensitive microcapsule that assembles, vibration shakes up, and places the suspension bleach of 20～60min in centrifuge tube, and upper strata liquid is removed in centrifugalize again; After the washing, vibration shakes up, and obtains the light-sensitive microcapsule of hollow, preserves in deionized water solution.
Embodiment 3
A: the glucosan of 1g is dissolved in the NaOH aqueous solution of 40mL, regulates pH=5～6 with the MES buffer;
B: the 9-chloromethyl anthracene of 0.06g is dissolved in the 2mL toluene solution, and mixing speed is 500～1000rpm;
C: the dextran solution of A step is slowly dripped in the 9-chloromethyl anthracene solution of B step, and be that 100～600rpm was stirred 1-3 days with mixing speed simultaneously, at N
2Protection is controlled 40～80 ℃ of reactions of temperature down;
D: with the reactant molecular cut off of C step is 7000 bag filter dialysis 5～20 days, and after washing/centrifugal 2～3 times, the precipitate lyophilization that will obtain with the cyclohexane extraction extraction 1～2 day obtains pulverous photosensitive polymer product.
E: the photosensitive polymer aqueous solution that the photosensitive polymer of D step is mixed with 1mg/mL is stand-by;
The preparation of light-sensitive microcapsule:
A: get the CaCO that 1mL has handled with PSS
3The particle aqueous solution is put into centrifuge centrifugalize 3～10min in the centrifuge tube of 1.5mL, remove upper water solution;
B: positively charged polylysine solution absorbs: in centrifuge tube, add 1.5mL and prepare the also polylysine solution of filtering 1mg/mL.Vibration shakes up, and allows the CaCO3 particle be dispersed in the polymer solution, static placement 1～2h, and the centre also need vibrate and shake up 2～3 times, makes absorption carry out better more completely;
C: washing: centrifugalize 7～8min, remove upper strata liquid, add the vibration of 1.5mL deionized water and shake up centrifugalize then.Remove upper strata liquid then and add the 1.5mL deionized water again, repetitive vibrations shakes up step with centrifugal separation, carries out 2～3 washings altogether;
D: electronegative carboxymethylcellulose sodium solution absorption: remove the upper strata liquid after the washing in the above-mentioned C step, add and prepare and filtering 1mg/mL elecrtonegativity sodium carboxymethyl cellulose solution 1.5mL, vibration shakes up, allow the ball-type particle be dispersed in the polymer solution, static placement 1～2h, the centre also need vibrate and shake up 2～3 times, makes absorption carry out better more completely;
E: repeat B～D step, alternately adsorb 5 bilayers, the electropositive photosensitive polymer aqueous solution that re-uses above-mentioned preparation at outermost layer is formed as cyst wall;
F: enucleation: adding 1mL concentration in assembling 10 layers microcapsule centrifuge tube is the EDTA solution of 0.2M, and vibration shakes up, and places the suspension bleach of 20～60min in centrifuge tube, and upper strata liquid is removed in centrifugalize again; After the washing, vibration shakes up, and obtains the light-sensitive microcapsule of hollow, preserves in deionized water solution.
Embodiment 4
The preparation of photosensitive cyst material:
A: the volume ratio that the CHI of 0.2g is added 25mL is in 1% acetic acid aqueous solution, stirring under the speed of agitator of 200～1000rpm more than the 12h, regulates pH=5～6 with the MES buffer;
B: the RB (rose-red) of 0.028g is dissolved in the 25mL absolute methanol solution, and low whipping speed is under 200～1000rpm, adds catalyst 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides/N-hydroxy-succinamide, the about 30min of activated carboxyl;
C: the CHI acetic acid solution of A step is slowly dripped in the RB absolute methanol solution of B step, and be that 500～1000rpm was stirred 1～3 day with mixing speed simultaneously, temperature is controlled at 25～60 ℃;
D: with the reactant molecular cut off of C step is 7000 bag filter dialysis 5～20 days, after washing/centrifugal 2～3 times, with the precipitate lyophilization that obtains 2～4 days, obtains the photosensitive polymer product RB-CHI of Powdered pale pink.
E: the RB-CHI of D step is dissolved in the deionized water, and being mixed with concentration is the RB-CHI solution of 1mg/mL;
The preparation of light-sensitive microcapsule:
A: the aqueous dispersions of getting the positively charged MF microsphere template in 1mL surface is put into centrifuge centrifugalize 3～10min in the centrifuge tube of 1.5mL, remove upper water solution;
B: electronegative electrolyte solution ALG absorption: in centrifuge tube, add 1.5mL and prepare the also ALG solution of filtering 1mg/mL, vibration shakes up, allow ball-type particle MF be dispersed in the polymer solution, static placement 1～2h, the centre also need vibrate and shake up 2～3 times, makes absorption carry out better more completely;
C: washing: centrifugalize 7～8min, remove upper strata liquid, add the vibration of 1.5mL deionized water and shake up centrifugalize then.Remove upper strata liquid then and add the 1.5mL deionized water again, repetitive vibrations shakes up step with centrifugal separation, carries out 2～3 washings altogether;
D: positively charged electrolyte solution CHI absorption: remove the upper strata liquid after the washing in the above-mentioned C step/centrifugal, add and prepare the also CHI solution 1.5mL of filtering 1mg/mL, vibration shakes up, allow the ball-type particle be dispersed in the polymer solution, static placement 1～2h, the centre also need vibrate and shake up 2～3 times, makes absorption carry out better more completely;
E: repeat B～D step, alternately adsorb 2 bilayers, in the 3rd～5 bilayer, use the electropositive photosensitive polymer solution RB-CHI replaced C HI of above-mentioned preparation to form as cyst wall, same B～the D of step promptly forms the light-sensitive microcapsule (ALG/CHI) that contains three layers of photosensitizer layer
2(ALG/RB-CHI)
3
F: enucleation: adding 1mL concentration in assembling 10 layers microcapsule is the hydrochloric acid solution of 0.1M, and vibration shakes up, and places the suspension bleach of 20～60min in centrifuge tube, and upper strata liquid is removed in centrifugalize again; After the washing, vibration shakes up, and obtains the light-sensitive microcapsule of hollow, preserves in deionized water solution.
Comparative Examples 1
Described Comparative Examples 1 is natural polymer shell polysaccharide pressed powder.
Comparative Examples 2
Preparation process is identical with embodiment 2, is template with MF, alternately adsorbs 5 double-deck ALG/CHI, obtains first and third, five, seven, nine layer at last and is the ALG adsorption layer, and second, four, six, eight, ten layer is the hollow microcapsule of CHI adsorption layer.
Claims (5)
1. a light-sensitive microcapsule that can be used for photodynamic therapy is characterized in that, is the hollow capsules that contains in the cyst material with the multilamellar cyst wall self assembly of the natural polymer polysaccharide (CHI) of the direct grafting photosensitizer of chemical bond or glucosan.
2. according to the preparation method of the light-sensitive microcapsule that can be used for photodynamic therapy of claim 1, it is characterized in that, may further comprise the steps:
1) preparation of photosensitive cyst material:
Polymer tegument polysaccharide (CHI) or glucosan are mixed with the polymer solution A that concentration is 1～50mg/mL, regulate pH to 4-9; Photosensitizer is made into the photosensitizer solution B that concentration is 1～50mg/mL; Solution A slowly is added drop-wise in the solution B, and hybrid reaction is also stirred simultaneously, and wherein the volume ratio of solution A and solution B is (1～40): 1, and mixing speed is 500～1000rpm, reacts 1～3 day under 25～80 ℃ of conditions; With above-mentioned reactant molecular cut off is 7000 bag filter dialysis 5～20 days, after washing/centrifugal 2～3 times, with the precipitate lyophilization that obtains 2～4 days, obtains Powdered photosensitive polymer product; Be dissolved in the deionized water, being mixed with concentration is the photosensitive polymer aqueous solution of 0.1～10mg/mL;
2) preparation of light-sensitive microcapsule
Adopt the method for self assembly layer by layer, having on the microsphere template of electric charge the polyelectrolyte that assembling has opposite charges, adsorption multi-layer alternately, number of assembling steps 1 then) in photosensitive polymer, obtain the light-sensitive microcapsule of hollow after the enucleation;
The described adjusting of step 1) pH agents useful for same is sodium carbonate/bicarbonate buffer or 2-(N-morphine quinoline) ethyl sulfonic acid (MES) buffer;
Photosensitizer described in the step 1) be have can with the photoactive substance of the active group of corresponding polymer condensation reaction.
3. according to the preparation method of claim 2, it is characterized in that described photosensitizer is preferably rose-red, fluorescein or 9-chloromethyl anthracene.
4. according to the preparation method of claim 2, it is characterized in that, the microsphere template that has electric charge is positively charged melamino-formaldehyde (MF) microsphere in surface, polyphenyl alkene microgranule (PS), polylactic acid that the surface is electronegative or the SiO that handles with polymine (PEI) or poly--4-vinylbenzenesulfonic acid sodium (PSS)
2Microsphere, CaCO
3, MnCO
3
5. according to the preparation method of claim 2, it is characterized in that electrically charged polyelectrolyte solution is: electronegative polyelectrolyte is sodium alginate, dextran sulfate or sodium carboxymethyl cellulose, and its concentration of aqueous solution is 1mg/mL; Positively charged polyelectrolyte is chitosan, polylysine, and its concentration of aqueous solution is 1mg/mL, or set by step 1) the aqueous solution of photosensitive polymer of method preparation.
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