CN106344921A - Preparation method of porphyrin nanometer carrier for photodynamic therapy - Google Patents
Preparation method of porphyrin nanometer carrier for photodynamic therapy Download PDFInfo
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- CN106344921A CN106344921A CN201610808816.6A CN201610808816A CN106344921A CN 106344921 A CN106344921 A CN 106344921A CN 201610808816 A CN201610808816 A CN 201610808816A CN 106344921 A CN106344921 A CN 106344921A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0061—5-aminolevulinic acid-based PDT: 5-ALA-PDT involving porphyrins or precursors of protoporphyrins generated in vivo from 5-ALA
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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Abstract
The invention discloses a preparation method of a porphyrin nanometer carrier for photodynamic therapy and belongs to the field of functional materials. The preparation method includes that porphyrin with photodynamic effect is selected as a functional group, chitosan molecules (CS) with positive charge and sulfonic acid phenyl porphyrin (TPPS) with negative charge are alternatively deposited on surfaces of silica nanoparticles through electrostatic interaction by an electrostatic layer-by-layer assembly method, and the nanometer carrier with silicon dioxide as a nucleus and chitosan and porphyrin-based photosensitizer as a multilayer film is prepared. The nanometer carrier can produce singlet oxygen under fluorescence emission spectrum detection and can be used for the photodynamic therapy; the nanometer carrier is good in biocompatibility and has good stability in a PBS (poly butylenes succinate) buffer solution 7.4 in pH (potential of hydrogen) value; the nanometer carrier prepared has wide application prospect in biomedical fields.
Description
Technical field
The present invention relates to the design of porphyryl nano-carrier and preparation, belong to field of functional materials.
Background technology
Photodynamic therapy is a kind of emerging cancer immunotherapies in recent years, and photosensitive drug enters internal, is enriched in focus
Afterwards, under the laser action of coupling absorbing wavelength, photosensitizer molecule absorbs the energy jump of photon to excited state, the light being stimulated
The quick dose of oxygen transferring energy to surrounding, thus produce strong oxidizing property singlet oxygen (1o2), cause the apoptosis of tumor cell, bad
Extremely, as shown in Figure 1.Porphyrin-Based Sensitizer has good spectral characteristic and higher singlet oxygen yield, and in vivo
It is widely present, metabolic pathway is distinct, good biocompatibility, widely studied as photosensitizer.But because porphyrin is photosensitive
Agent belongs to organic molecule mostly, is easily identified by immune system in vivo in cyclic process, and exclusion is external.Thus, can be by means of
There is the macromole nano-carrier of good biocompatibility, to extend medicine circulation time in vivo, the poison reducing medicine is secondary
Effect, simultaneously because the dimensional effect of nano-particle, can be good at coordinating high-permeability and the retention effect of solid tumor, makes light
Quick agent molecule preferably enters tumor cell.
Shitosan is a kind of polysaccharide derivates with biocompatibility and biodegradability, by glucosamine and n-
The repetitives composition of acetyl group glucose.Amphipathic nature polyalcohol nano-particle based on shitosan can as pharmaceutical carrier,
It is used widely in optical dynamic therapy.Photosensitizer can be directly wrapped in the kernel of nano-particle of shitosan formation,
Photosensitizer can be modified on shitosan macromolecular chain, then self assembly obtains nano-particle.Further, since shitosan contain rich
Rich amino group, carries positive charge after protonating under sour environment, has substantial amounts of report that shitosan is negatively charged with other
Polyelectrolyte nano-carrier is self-assembled into by electrostatic interaction, for medicament transport.Thus, shitosan is preferable macromole
Nano-carrier, is expected to be implemented in combination with effective optical dynamic therapy effect with Porphyrin-Based Sensitizer.
The present invention selects electrostatic layer-by-layer, by positively charged shitosan macromole and electronegative sulfonic group
Phenyl porphyrin (tpps) passes through electrostatic interaction alternating deposit on the surface of nano silicon, and preparation one kind is with silica nanometer
Granule is core, and shitosan and Porphyrin-Based Sensitizer are the nano-carrier of multilayer film.Tpps has good spectral characteristic and higher
Singlet oxygen yield, the load factor of tpps is controlled by the number of plies controlling electrostatic self-assembled, thus controlling singlet oxygen
Yield.The porphyryl nano-carrier that the present invention prepares has good biocompatibility, can stable circulation in vivo, energy
The high-permeability of enough solid tumors of cooperation well and retention effect, make photosensitizer molecule preferably enter tumor cell, are tumor
Treatment provides theoretical foundation and actual application value.
Content of the invention
It is contemplated that with silicon dioxide as core, using electrolyte between electrostatic interaction preparation to tumor cell, there is light
The nano-carrier with biocompatibility of dynamic therapy effect.
Technical scheme: a kind of preparation method of the porphyryl nano-carrier for photodynamic therapy, (1)
Nano SiO 2 particle is prepared for raw material with tetraethyl orthosilicate, particle diameter is about 150nm, and with silane coupler 3- aminopropyl three
Ethoxysilane carries out amination modified to its surface;
(2), after the nano SiO 2 particle after will be amino modified is distributed in ultra-pure water, add tetrasulfonic acid in the solution
The aqueous solution of phenyl porphyrin, wherein sulfonate radical are 1:1~2:1 with the molar ratio of amino;Group reaction cartridge, after 24 hours, uses pure water
Wash away the unassembled tetrasulfonic acid phenyl porphyrin of particle surface, add the aqueous solution of shitosan, proceed group reaction cartridge 24 little
When, wherein unassembled sulfonate radical is 1:3~1:5 with the molar ratio of amino in shitosan;In succession assembling tetrasulfonic acid is repeated several times
The Nano microsphere of the non-multilayer film in surface is can get after phenyl porphyrin and shitosan;One layer, two-layer and multilamellar tetrasulfonic acid benzene will be loaded
The nano-particle of base porphyrin and shitosan is calculated separately as sio2/tpps-cs,sio2/(tpps-cs)2, sio2/(tpps-cs)n.
Beneficial effects of the present invention: the present invention selects electrostatic layer-by-layer, and positively charged shitosan is divided greatly
Sub and electronegative sulfonic group phenyl porphyrin (tpps) passes through electrostatic interaction alternating deposit on the surface of nano silicon, prepares
With nano silicon as core, shitosan and Porphyrin-Based Sensitizer are the nano-carrier of multilayer film to one kind.Tpps has good
Spectral characteristic and higher singlet oxygen yield, control the load factor of tpps by the number of plies controlling electrostatic self-assembled, thus
Control the yield of singlet oxygen.The porphyryl nano-carrier that the present invention prepares has good biocompatibility, Neng Gou
Internal stable circulation, can be good at coordinating high-permeability and the retention effect of solid tumor, so that photosensitizer molecule is preferably entered
Tumor cell, provides theoretical foundation and actual application value for oncotherapy.
Brief description
Fig. 1 sio2(a),sio2-nh2(b),sio2/tpps(c),sio2/(tpps-cs)2The transmission electron microscope photo of (d).
Fig. 2 sio2/ tpps (a), sio2/(tpps-cs)21,3 diphenyl isobenzofurans are added in (b) dispersion liquid
(a kind of dpbf: chemical substance highstrung to active oxygen, when active oxygen, dpbf occurs chemistry anti-with active oxygen at once
Should and oxidized, lose simultaneously absorbing light with transmitting fluorescence ability) after laser irradiate different time under fluorescent emission intensity
Change.
The schematic diagram of Fig. 3 optical dynamic therapy.
Specific embodiment
Embodiment 1, the preparation of nano SiO 2 particle
By 55ml dehydrated alcohol add 250ml there-necked flask in, sequentially add under 700rpm mechanical agitation 4ml ammonia and
4ml tetraethyl orthosilicate, reacts 4 hours, will be centrifuged 15min afterwards, pour out supernatant and obtain white under gained dispersion liquid 7500rpm
Nano-silicon dioxide particle, and with dehydrated alcohol centrifuge washing 3 times, be finally vacuum dried.
Embodiment 2, the preparation of amido modified nano-silicon dioxide particle
Carry out the process of raw material first, toluene adds a small amount of cah2And magnetic stirrer over night, afterwards toluene is carried out
Vacuum distillation, removes front-end volatiles water and other impurities, collects tails dry toluene and sealing preserve is stand-by.Weigh 1g previously to close
The snps sample dispersion becoming, in 100ml dry toluene, is slowly added dropwise 5ml silane coupled 3- aminopropyl three under quick magnetic agitation
Ethoxysilane (kh550), in 110 DEG C, n2Condensing reflux 12 hours under environment, pour out upper strata after standing a period of time afterwards clear
Liquid, washs lower floor's product 3 times, obtains amido modified nano-silicon dioxide particle with toluene and dehydrated alcohol alternating centrifugal, note
Make sio2-nh2, finally it is vacuum dried.
Embodiment 3, sio2Prepared by/tpps
Take certain mass amido modified after Nano particles of silicon dioxide be distributed in ultra-pure water, ultrasonic a period of time obtains
To sio2-nh2Dispersion liquid, then compound concentration is the tpps aqueous solution of 0.75mg/ml, and the ratio of wherein sulfonate radical and amino is
2:1, two solution mixing magnetic agitation, react 24h at normal temperatures.Centrifugation after reaction terminates obtains loading the silicon dioxide of tpps
Nano-particle, is denoted as snps/tpps, no longer has the uv absorption of tpps in filtrate with ultra-pure water centrifuge washing, finally cold
Lyophilizing is dry.
Embodiment 4, sio2The preparation of/tpps-cs
Take the sio that certain mass prepares2The dispersion liquid in the ultra-pure water for/tpps sample dispersion, takes certain matter simultaneously
The shitosan of amount, is dissolved in ultra-pure water, two kinds of solution mixing simultaneously magnetic agitation, reacts 24h at normal temperatures.Reaction terminates
Centrifugation obtains loading the sio of cs afterwards2/ tpps nano-particle, is denoted as sio2/ tpps-cs, with ultra-pure water centrifuge washing 3 times, finally
Lyophilization.
Claims (3)
1. a kind of preparation method of the porphyryl nano-carrier for photodynamic therapy, is characterized in that photosensitive from porphyrin
The shitosan of agent and good biocompatibility is primary raw material, prepares nano SiO 2 particle with tetraethyl orthosilicate for raw material,
With silane coupler 3- aminopropyl triethoxysilane, its surface is carried out again amino modified obtaining amination silica nanometer
Granule;Finally, by electrostatic layer-by-layer by the tetrasulfonic acid phenyl porphyrin with negative charge and with positive charge shell
Polysaccharide load to respectively amino modified after silica nanoparticle surface, obtain having receiving of optical dynamic treatment of tumor effect
Meter Zai Ti.
2. preparation method according to claim 1 is it is characterised in that the method for electrostatic layer-by-layer is as follows: by ammonia
After the modified nano SiO 2 particle of base is distributed in ultra-pure water, add the water-soluble of tetrasulfonic acid phenyl porphyrin in the solution
Liquid, wherein sulfonate radical are 1:1~2:1 with the molar ratio of amino;Group reaction cartridge, after 24 hours, washes away particle surface not with pure water
The tetrasulfonic acid phenyl porphyrin of assembling, adds the aqueous solution of shitosan, proceeds to organize reaction cartridge 24 hours, wherein unassembled sulphur
Acid group is 1:3~1:5 with the molar ratio of amino in shitosan;In succession assembling tetrasulfonic acid phenyl porphyrin and shitosan are repeated several times
Can get the Nano microsphere of the non-multilayer film in surface afterwards;By one layer of load, two-layer and multilamellar tetrasulfonic acid phenyl porphyrin and shitosan
Nano-particle is calculated separately as sio2/tpps-cs,sio2/(tpps-cs)2, sio2/(tpps-cs)n.
3. preparation method according to claim 1 is it is characterised in that tetrasulfonic acid phenyl porphyrin is negative in nano grain surface
Load rate can be controlled by controlling the number of plies of electrostatic self-assembled, and the number of plies is more, and load factor is higher, and load factor can be controlled in 1%
More than;The porphyryl nano-carrier that the present invention prepares has good biocompatibility, can stable circulation in vivo, join
Close high-permeability and the retention effect of solid tumor, make photosensitizer molecule preferably enter tumor cell, can be applicable to the light of tumor
Dynamic therapy.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110003888A (en) * | 2019-04-11 | 2019-07-12 | 苏州大学 | A kind of fluorescent nano probe and preparation method thereof |
CN111603436A (en) * | 2020-06-02 | 2020-09-01 | 徐州医科大学 | Photodynamic silica nanomaterial @ hydrogel composite drug loading system, and preparation method and application thereof |
CN117618583A (en) * | 2024-01-25 | 2024-03-01 | 深圳大学 | Photosensitizer for tumor photodynamic therapy based on wireless charging and combination system thereof |
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CN104857521A (en) * | 2015-05-15 | 2015-08-26 | 江南大学 | Preparation method of bio-based macromolecular vesicles with glucose response |
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CN102133208A (en) * | 2011-03-17 | 2011-07-27 | 北京化工大学 | Photosensitive microcapsule used for photodynamic therapy and preparation method thereof |
CN104857521A (en) * | 2015-05-15 | 2015-08-26 | 江南大学 | Preparation method of bio-based macromolecular vesicles with glucose response |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110003888A (en) * | 2019-04-11 | 2019-07-12 | 苏州大学 | A kind of fluorescent nano probe and preparation method thereof |
CN110003888B (en) * | 2019-04-11 | 2022-03-22 | 苏州大学 | Fluorescent nano probe and preparation method thereof |
CN111603436A (en) * | 2020-06-02 | 2020-09-01 | 徐州医科大学 | Photodynamic silica nanomaterial @ hydrogel composite drug loading system, and preparation method and application thereof |
CN111603436B (en) * | 2020-06-02 | 2022-12-27 | 徐州医科大学 | Photodynamic silica nanomaterial @ hydrogel composite drug loading system, and preparation method and application thereof |
CN117618583A (en) * | 2024-01-25 | 2024-03-01 | 深圳大学 | Photosensitizer for tumor photodynamic therapy based on wireless charging and combination system thereof |
CN117618583B (en) * | 2024-01-25 | 2024-06-04 | 深圳大学 | Photosensitizer for tumor photodynamic therapy based on wireless charging and combination system thereof |
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