CN109966491A - A kind of antimicrobial nano micella and its preparation method and application discharging photosensitizer - Google Patents
A kind of antimicrobial nano micella and its preparation method and application discharging photosensitizer Download PDFInfo
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- CN109966491A CN109966491A CN201910263711.0A CN201910263711A CN109966491A CN 109966491 A CN109966491 A CN 109966491A CN 201910263711 A CN201910263711 A CN 201910263711A CN 109966491 A CN109966491 A CN 109966491A
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- photosensitizer
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- micella
- polyethylene glycol
- polycaprolactone
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- 229910021645 metal ion Inorganic materials 0.000 description 1
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- 239000000178 monomer Substances 0.000 description 1
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- 239000002114 nanocomposite Substances 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
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- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 235000003499 redwood Nutrition 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000001926 trapping method Methods 0.000 description 1
- 229960001572 vancomycin hydrochloride Drugs 0.000 description 1
- LCTORFDMHNKUSG-XTTLPDOESA-N vancomycin monohydrochloride Chemical compound Cl.O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 LCTORFDMHNKUSG-XTTLPDOESA-N 0.000 description 1
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Classifications
-
- 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
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Life Sciences & Earth Sciences (AREA)
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- Public Health (AREA)
- Medicinal Chemistry (AREA)
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- Animal Behavior & Ethology (AREA)
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- Epidemiology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
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- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of antimicrobial nano micellas and its preparation method and application for discharging photosensitizer, the nano-micelle forms antimicrobial nano micella by amphipathic three block copolymer embedding quinones hydrophobic photosensitizer, and amphipathic three block copolymer is the poly- beta-amino ester of mono methoxy polyethylene glycol-polycaprolactone-.Nano-micelle of the invention is a kind of with pH response, the antimicrobial nano micella of Targeting delivery photosensitizer, the nano-micelle is to pathogenetic bacteria, especially drug-fast bacteria, there is good smooth power antibacterial action, it is not likely to produce drug resistance, can be assembled at the bacterium position of lipase sensibility, and orientation kills anti-medicine bacterium under illumination condition.Nano-micelle targeting of the invention is good, has good biocompatibility and biodegradability, is easy to convert to clinical application direction, and the nano-micelle good water solubility, targeting and drug accumulation are high, and light dynamic pasteurization significant effect has a good application prospect.
Description
Technical field
The invention belongs to nano biological medical material field, be related to a kind of antimicrobial nano micella for discharging quinones photosensitizer and
Preparation method and application.
Background technique
The appearance of drug-resistant bacteria has resulted in serious health problem, and has millions of people's therefore death, generation every year
Boundary's health organization thinks that drug-fast bacteria has become one of chief threat of human health.Such as methicillin-resistant staphylococcus aureus
(methicillin-resistant Staphylococcus aureus, MRSA) etc. is continually to divide in patient body from hospital
The typical opportunist separated out.Since MRSA infection rate is high, Antibiotic Resistance is wide, and has had already appeared multidrug resistance, therefore, urgently
New antibacterial agent to be developed infects to treat MRSA.
Current various anti-biotic materials, such as metal ion, antibacterial peptide, carbon and inorganic nano material, cationic polymer and
Polymer nanoparticle drug carriers have been widely used in antibacterial research.However, these antibacterial agents may generate long-term poison to mammal
Property, and be easy to be degraded by enzymes in vivo.Meanwhile for many serious bacterium infections, these anti-biotic materials may need more
Big dosage and lasting multiple dosing can be only achieved ideal antibacterial effect.Wherein about the publication of anti-biotic material
Have: number of patent application: 201710091773.9 disclose the nano antibacterial agent of a kind of loading nano silvery simultaneously and curcumin and its
Preparation method and application, still, silver ion endures always dispute to the fullest extent, it has been reported that silver ion may have certain poison to mammal
Property.
Antibacterial photodynamic therapy (APDT) is more and more concerned, and APDT is a kind for the treatment of method of Noninvasive, to health
Tissue injury is small.The three elements of photodynamic therapy are as follows: oxygen, light source and photosensitizer (PS).It can be generated after irradiation sensitising agent
Active oxygen (ROS), including free radical, superoxides and singlet oxygen.ROS can destroy DNA of bacteria, cell membrane, and interfere
Cell metabolism.
Quinones photosensitizer, such as Elsinochrome element, are one of metabolites of fungi, have good antibacterial effect,
It is a kind of very promising antibacterial agent.However, some obvious disadvantages limit the antimicrobial efficiency of Elsinochrome element, such as water-soluble
Property is poor, is easy to assemble in physiological environment so as to cause Elsinochrome element, and significantly reduce ROS yield.In addition to this, scab capsule
Chamber rhzomorph lacks specificity in infected tissue as most of quinones photosensitizers.In order to overcome these disadvantages, exploitation is suitable
Delivery system is water-soluble to improve Elsinochrome element, enhances the targeting of tissue specificity and needle antagonistic drug bacterium, is to solve anti-medicine
The important means of bacterium infection.
In order to improve quinones photosensitizer, such as the water solubility and tissue specificity of Elsinochrome element class photosensitizer, have disclosed
Method be to be improved using the method for chemical modification and physically trapping.Wherein, physically trapping method is Elsinochrome element class in recent years
The emphasis of photosensitizer study on the modification.The data of Elsinochrome element: number of patent application is encapsulated about application material at present
20081024636.4323.5 a kind of preparation method of water-soluble cystolycin A silica dioxide nano particle is disclosed, selection
Encapsulating material is silica.(the synthesis and characterization of the cystolycin A analog derivative of aminobutyric acid modification such as hair favour.2015,
4:62-65) with aminobutyric acid modification Elsinochrome element, its water solubility is improved.
In common chemical modifier, polyethylene glycol (PEG) and its derivative are because of its amphipathic, biofacies
Capacitive, non-immunogenicity, the features such as having no toxic side effect, and become the chemical modifier being concerned.PCL is to have excellent performance, and is used
Extensive biodegradable material on the way, and can be degraded by Institute of Micro-biology, therefore the work of targeted delivery antibacterials can be played
With.(east Miao Rui, the degradation property of polycaprolactone and its influence to microorganism.Plastics industry, 2009,9:50-53;Lin Dongpo,
Polycaprolactone/polylactic acid/nano particle composite material structure and property 2011) therefore, in terms of drug delivery research, often will
Two kinds and two or more has the advantages that different polymer material as passing drug material.(the The impact of such as high Red Army
PEGylation patterns on the in vivo biodistribution of mixed shell
Micelles.2013,1:229-4246 the composite micelle PCL-b-PAE-c (RGDfK) of function synergic) is used) it is received as antitumor
The research of rice pharmaceutical carrier.Number of patent application: 201610924044.2 Huang Xiangxuan (2016) disclose a kind of grafting of cholesterol
PH responds the amphipathic copolymer preparation method and application of three block, which has synthesized PAE-PEG- using the pH responsiveness of PAE
PAE is for containing poorly water soluble drugs.Therefore good biocompatibility, degradable mPEG, PCL, PAE prepare nano-carrier
Ideal material, high red woods etc., (A charge adaptive nanosystem for prolonged and enhanced in
Vivo antibiotic delivery.Chem Commun (Camb) .2016,52:6265-6268) once use PEG-PCL-
PAE prepares nanoparticle for delivering vancomycin for treating dermatitis, but this method two-layer solvent emulsifies volatility process and loads ten thousand
Ancient mycin, encapsulation rate and carrying drug ratio are low, and respectively only 45.4% and 9.2%, low carrying drug ratio makes vancomycin be difficult to reach reason
Think drug effect.Also, with the appearance of drug-fast bacteria, vancomycin-resistant enterococcus, vancomycin resistance golden yellow grape are gradually appeared
The antibody-resistant bacterium such as coccus, this is restricted the application of vancomycin.It is had no in file disclosed above by amphipathic three block
The poly- beta-amino ester embedding photosensitizer of copolymer mono methoxy polyethylene glycol-polycaprolactone-prepares the disclosure of antimicrobial nano micella.
Summary of the invention
Goal of the invention: (one) is directed to the drug-fast bacteria infection that gets worse, and existing antibiotic, which has been difficult to meet clinic, to be wanted
It asks, it would be highly desirable to develop new antibacterial agent.(2) the quinones photosensitizer such as second generation photosensitizer Elsinochrome element, antibacterial effect with higher
Fruit, but because of its water solubility problems, it is difficult to it is made into preparation, playing antibacterial effect in practical applications has certain limitation, especially
Internal antibacterial.(3) common photosensitizer antibacterial does not have selectivity and targeting.Based on this, the present invention provides a kind of targetings
The antimicrobial nano micella of photosensitizer is discharged, which has lipase sensibility and pH responsiveness, can be in lipase sensibility
Bacterium around target aggregation, the bacterium sensitive to lipase have selectivity and targeting, drug resistance mentioned in the present invention
Some bacteriums such as methicillin-resistant staphylococcus aureus is a kind of bacterium of yielding lipase in bacterium, and the micella in the present invention
It is sensitive to comprising lipase of bacterial origin, therefore can targets and be gathered in around bacterium, which has good antibacterial to the bacterium
Effect, and do not generate drug resistance.The present invention not only solves the problems, such as bacterial resistance with photodynamic therapy, and develops a kind of increasing
Add the delivery system of photosensitizer water solubility and biocompatibility.
In addition, the present invention provides a kind of preparation method of antimicrobial nano micella for discharging photosensitizer, which is obtained
The freeze-dried excipient obtained, the micellar conformation after freeze-drying is uniform, and water dispersible is good, utilizes convenient for storage.
The present invention also provides a kind of applications of antimicrobial nano micella for discharging photosensitizer Elsinochrome element.
Technical solution: in view of the problems of the existing technology, a kind of antimicrobial nano discharging photosensitizer as described herein
Micella forms antimicrobial nano micella by amphipathic three block copolymer embedding quinones hydrophobic photosensitizer, and described amphipathic three is embedding
Section copolymer is the poly- beta-amino ester (mPEG-PCL-PAE) of mono methoxy polyethylene glycol-polycaprolactone-.
Preferably, the antimicrobial nano micella of the described release photosensitizer, mainly by the raw material preparation of following parts by weight and
At: 1-5 parts of photosensitizer, 5-25 parts of mono methoxy polyethylene glycol-polycaprolactone-poly- beta-amino ester, freeze-dried excipient 0.01-0.05
Part.
Preferably, the quinones photosensitizer includes cystolycin A, Elsinochrome element B, Elsinochrome element C, the red bacterium of bamboo
Element or hypericin.
Wherein, the amphipathic three block copolymer is the poly- beta-amino ester of mono methoxy polyethylene glycol-polycaprolactone-
(mPEG-PCL-PAE) water-wet side is mono methoxy polyethylene glycol (mPEG), and hydrophobic side is polycaprolactone (PCL), point of mPEG
Son amount is 10 000Da, and the molecular weight of PCL is 5 000Da;The poly- beta-amino ester of mono methoxy polyethylene glycol-polycaprolactone-
It is first synthesized by ring-opening polymerisation mono methoxy polyethylene glycol-polycaprolactone (mPEG-PCL), then synthesizes single first with Michael's addition method
Oxygroup polyethylene glycol-polycaprolactone-poly- beta-amino ester three block (mPEG-PCL-PAE).
Preferably, the freeze-dried excipient is sucrose, lactose, trehalose, polyethylene glycol, in sorbierite or PEARLITOL 25C
One kind.
The preparation method of the antimicrobial nano micella of release photosensitizer of the present invention, includes the following steps:
(1) it weighs the poly- beta-amino ester (mPEG-PCL-PAE) of mono methoxy polyethylene glycol-polycaprolactone-and photosensitizer is mixed
It closes, organic solvent is added, ultrasound makes it dissolve;
(2) rotary evaporation, volatile organic solvent form the film of clear homogeneous;
(3) freeze-dried excipient and distilled water are added into film, slowly rotates, hydrated films;
(4) film after aquation is ultrasonic under ice-water bath, obtains medicament-carried nano micelle;
(5) obtained medicament-carried nano micelle is crossed into miillpore filter, removes non-encapsulated material and photosensitizer and obtain carrying medicine and receives
Rice glue beam;
(6) medicament-carried nano micelle is freeze-dried and removes moisture, obtain the antimicrobial nano micella of dry release photosensitizer
Lyophilized preparation.
Wherein, step (1) organic solvent is acetone, methylene chloride, chloroform, any one in ethyl alcohol.
Preferably, step (2) rotating evaporation temperature is 40~55 DEG C, 0.5~2h of rotary evaporation, sufficiently removing has
Solvent forms transparent uniform film;
Preferably, step (3) hydration temperature is 40~65 DEG C, hydration time is 2~6h;Step (4) described ice
Ultrasound condition is 10~30min under water-bath, and frequency is 10~20HZ.
Further, miillpore filter diameter described in step (5) is 0.22 μm;
Freeze-drying condition described in step (6) is -50~-80 DEG C, 24~48h.
The antimicrobial nano micella of release photosensitizer of the present invention improves in light power overriding resistance bacterial drug in preparation
Application;The bacterium that light power inhibits is gram-positive bacteria staphylococcus aureus, including methicillin-resistant staphylococcus grape
Coccus.
The antimicrobial nano micella of release photosensitizer of the present invention has the light power antibiotic and sterilizing of targeting in preparation
Application in drug.
The light power antibiotic and sterilizing drug, including be used for gram-positive bacteria and Gram-negative bacteria, drug-fast bacteria with
Non- drug-fast bacteria.
Photosensitizer of the present invention has antitumor action, the encapsulating material mono methoxy polyethylene glycol-of use simultaneously
The poly- beta-amino ester (mPEG-PCL-PAE) of polycaprolactone-can also be used for delivering photosensitizer, be used for antitumor research.
The antimicrobial nano micella of release photosensitizer prepared by the present invention, between 80-120nm, preparation method includes partial size
But it is not limited only to film aquation ultrasonic method, also includes dialysis and solvent diffusion method.
The poly- beta-amino ester (mPEG-PCL- of mono methoxy polyethylene glycol-polycaprolactone-of use is prepared in the present invention
PAE) belong to macromolecule polymer material, there is good biocompatibility, it is water-soluble to improve its to encapsulate hydrophobic drug
Property.Hydrophilic shell mPEG, which has been widely used in, provides stealth characteristics for nano-carrier, keeps it " hidden to cell and microorganism
Shape ", to resist the absorption of protein and extend circulation time in vivo.By the way that hydrophobic drug is loaded into hydrophobic PCL core,
The structure of external hydrophilicity internal drainage can be such that drug not soluble in water is well dispersed in water.PCL and PAE is hydrophobic block, two
Person, which is collapsed, invaginates, and forms hydrophobic core, and when nano-micelle reaches bacterial acid position, PCL can be by wide in most of bacteriums
General existing lipase is degraded, and drug is sensitively discharged so as to lipase and kills bacterium PAE generation protonation and takes
With bacterium surface negative electrical charge electrostatical binding, the at this time loose expansion of nano-micelle occur for positive charge, and Elsinochrome element discharges and thin
The aggregation of bacterium position.PAE have pH responsiveness, can targeting be gathered in bacterium slightly acidic environment.In addition, the material all has
Good biodegradability, biocompatibility.
In addition, the present invention also uses Gao Honglin, (pH responsive polymer PEG-b-PCL-b-PAE delivers vancomycin target
Research to dermatitis, 2016) it is first self-assembly of PEG-PCL-PAE micella described in, this method passes through solvent pairs emulsification volatilization
Method load vancomycin, but we with this method preparation PEG-PCL-PAE carry photosensitizer Elsinochrome element when, due to scab blister cavities
The quinones photosensitizer such as rhzomorph is different from having certain water-soluble vancomycin, and poorly water-soluble, hydrophobic photosensitizer is difficult to by upper
The method of stating, which is contained into PEG-PCL-PAE, causes carrying drug ratio and encapsulation rate low, also, serious group occurs when nanoparticle freeze-drying redissolution
Poly- phenomenon can not redissolve completely, therefore this method is not suitable for delivering the quinones hydrophobic photosensitizers such as Elsinochrome element.In Gao Hong
On the basis of woods the method, the present invention replaces PEG with the better mono methoxy polyethylene glycol of hydrophily (mPEG) first.Except this it
Outside, the present invention is contained photosensitizer and is self-assembly of micella using film aquation ultrasonic method one-step method.To sum up, the present invention utilizes three
The characteristic of kind nano-functional material, has synthesized mPEG-PCL-PAE three block nanocomposite, has been synthesized by ice-bath ultrasonic method
A kind of directed toward bacteria, the antimicrobial nano micella targeted with pH responsiveness and lipase.
The utility model has the advantages that compared by the prior art, the present invention has the advantage that
1, the nano-micelle good biocompatibility that the present invention is prepared using mPEG-PCL-PAE, and be biodegradable
's.
2, the present invention solves the quinones such as Elsinochrome element by the way that nano-micelle is made in the quinones photosensitizer such as Elsinochrome element
Class hydrophobic photosensitizer is difficult to the shortcomings that being administered because of poorly water-soluble.
3, the antimicrobial nano micella of release photosensitizer prepared by the present invention has the characteristics that targeting by PCL in micella, this is received
Rice glue beam can be assembled around the bacterium of secretion lipase, the photosensitizers such as targeting NO release Elsinochrome element, while have pH
Responsiveness converts charge in weak acid environment as positive charge to have the function that accumulate around drug to negative electrical charge bacterium.
Under illumination condition, anti-medicine bacterium, methicillin-resistant staphylococcus aureus sensitive to lipase etc. are killed by photodynamic therapy
Drug-fast bacteria has good antibacterial action.
4, medication in hydrophobic photosensitizer body may be implemented in the antimicrobial nano micella of release photosensitizer prepared by the present invention, prolongs
The residence time of long drug in vivo reduces photosensitizer dark toxicity.
5, preparation method of the present invention is simple and convenient, and raw material availability is high, can extensive production application.
In short, the present invention is with the amphiphilic poly- β amino ester of block copolymer mono methoxy polyethylene glycol-polycaprolactone-
(mPEG-PCL) micella being self-assembly of improves water solubility as nano-carrier, using hydrophilic mPEG shell, hydrophobic
Kernel polycaprolactone (PCL) wraps up Elsinochrome element, and the pH responsiveness of PAE keeps it thin to the highly expressed cause of disease of lipase active
Bacterium has Targeting delivery and the characteristic in phage surface accumulation, enhances its photodynamic effect, release photosensitizer prepared by the present invention
Antimicrobial nano micella have good smooth power antibacterial action to pathogenetic bacteria, especially drug-fast bacteria, and be not likely to produce drug resistance.
Nano-micelle in the present invention, targeting is good, and has good biocompatibility and biodegradability, is easy to answer to clinic
It is converted with direction.The nano-micelle good water solubility, targeting and drug accumulation are high, light dynamic pasteurization significant effect, have good
Good application prospect.
Detailed description of the invention
Fig. 1 is the poly- β amino ester of mono methoxy polyethylene glycol-polycaprolactone-- cystolycin A (mPEG-PCL-PAE-EA)
Water dispersion figure after micella and freeze-drying;Wherein, mPEG-PCL-PAE-EA micella (A), freeze-dried (B) freeze after in different pH solution
It redissolves (C);
Fig. 2 is mPEG-PCL-PAE-EA micella transmission electron microscope picture.
Specific embodiment
Below in conjunction with drawings and examples, the present invention will be further described.
Embodiment 1
The synthesis of mPEG-PCL-PAE
The synthesis of mPEG-PCL-PAE include two parts, one, mPEG-PCL is obtained by ring-opening polymerization (ROP).
Wherein mPEG-OH is as initiator, stannous iso caprylate (Sn (Oct)2) it is used as catalyst, ε-CL is monomer.The specific steps are claim
It takes mPEG (4.0g, 2.0mmol) and ε-CL (10.0g, 87.8mmol) to be dissolved in 40mL dry toluene, one is added in oscillation
It drips Sn (Oct)2, reaction solution is subjected to liquid nitrogen frozen later, is vacuumized, nitrogen is led to, thaws, in triplicate, drains oxygen.110
It is stirred to react at DEG C overnight, removes solution later, and crude product is dissolved with methylene chloride, then added and decuple dichloromethane
The ice ether precipitating of alkane volume removes impurity, is placed in a vacuum drying oven solid product mPEG-PCL after filtering and washing is clean
Drying, 4 DEG C save backup.Two, it weighs mPEG-PCL (1g), triethylamine (2g) uses 10mL dichloromethane in 250mL round-bottomed flask
Alkane dissolution;After acryloyl chloride (1.5g) is dissolved with 10mL methylene chloride, it is added dropwise in ice-water bath in above-mentioned solution, in ice
2h is reacted in water-bath;After reacting 2h, reacting liquid temperature is warmed to room temperature, under stirring, the reaction was continued for 24 hours;Use saturated carbon
Acid sodium solution, 1mol/L HCL, distilled water extract mixed reaction solution, and solution extracts several times;Organic phase Rotary Evaporators are dense
Contracting, is precipitated in hexane solution, obtains mPEG-PCL-PAE product, and vacuum drying saves.
Embodiment 2
The preparation and representation precision of mPEG-PCL-PAE-EA micella weighs 100mg mPEG-PCL-PAE and 20mg scab blister cavities
15mL amount acetone is added in 25mL round-bottomed flask in rhzomorph A (EA), and ultrasound makes it dissolve.40 DEG C of rotary evaporation about 30min, directly
To the clean acetone that volatilizees, the film of clear homogeneous is formed, PEARLITOL 25C 1mg is added, distilled water is added or is substituted for PBS (pH
5.5,6.5,7.4) 8mL slowly rotates, hydrated films in 55 DEG C of water-baths, after aquation 3h, with probe type ultrasonic instrument in ice water
Bathe lower ultrasound 20min (20HZ), obtain medicament-carried nano micelle (Figure 1A), with the EA of 0.22 μm of filter membrane removing unentrapped, micella in
- 80 DEG C of freeze-drying 48h of vacuum, are made freeze-dried powder (Figure 1B) and save in 4 DEG C of refrigerators.5%D- mannitol is used to protect as freeze-drying
Micella made of agent is protected, solubility is good after freeze drying, and it is not easy to reunite, as shown in Figure 1 C, in distilled water and difference PBS (pH
5.5,6.5,7.4) it in dicyandiamide solution, can redissolve, and stability is good.
It takes appropriate micella drop on copper mesh, observes form under transmission electron microscope after natural air drying, examined with dynamic light scattering
Survey partial size and current potential.As shown in Fig. 2, transmission electron microscope results show that the average grain diameter of the nano-micelle is 90nm, present uniform
It is spherical.Dynamic light scattering is the result shows that the micellar particle size of each solution system preparation is uniform, for 90nm or so.
Embodiment 3
Embodiment 3 is identical as 2 preparation process of embodiment, the difference is that, photosensitizer Elsinochrome element B 5 by weight
Part, 5 parts, 0.01 part of freeze-dried excipient sucrose of the poly- beta-amino ester of mono methoxy polyethylene glycol-polycaprolactone-;Organic solvent replacement
For methylene chloride;Rotating evaporation temperature is 40 DEG C, rotary evaporation 2h;Hydration temperature is 40 DEG C, hydration time 6h;Under ice-water bath
Ultrasound condition is 10min, frequency 20HZ;Freeze-drying condition is -50 DEG C, 48h.
Embodiment 4
Embodiment 4 is identical as 2 preparation process of embodiment, the difference is that, photosensitizer hypocrellin A 1 by weight
Part, 25 parts, 0.05 part of freeze-dried excipient sorbierite of the poly- beta-amino ester of mono methoxy polyethylene glycol-polycaprolactone-;Organic solvent replaces
It is changed to ethyl alcohol;Rotating evaporation temperature is 55 DEG C, rotary evaporation 10min;Hydration temperature is 65 DEG C, hydration time 2h;Ice-water bath
Lower ultrasound condition is 30min, frequency 10HZ;Freeze-drying condition is -80 DEG C, for 24 hours.
Embodiment 5
Embodiment 5 is identical as 2 preparation process of embodiment, the difference is that, cystolycin A is substituted for Elsinochrome
Plain C.
Embodiment 6
Embodiment 6 is identical as 2 preparation process of embodiment, the difference is that, cystolycin A is substituted for Hypericum Chinense
Element.
Embodiment 7
MPEG-b-PCL-PAE-EA micella envelop rate and carrying drug ratio prepared by embodiment 2
Encapsulation rate (EE): precision measures 200 μ L of mPEG-PCL-PAE-EA micella, adds 800 μ L acetonitriles, with 0.22 μm of filter membrane
Filtering, take 10 μ L samples with high performance liquid chromatography (HPLC) in wavelength be 464nm at detected, be denoted as W1.In addition, accurate amount
200 μ L of mPEG-PCL-PAE-EA micella is taken, adds 800 μ L petroleum ethers (30~60 DEG C), vortex oscillation 3min after stratification, is abandoned
Petroleum ether supernatant is removed, repetition is extracted twice.Later, add 800 μ L acetonitriles, with 0.22 μm of membrane filtration, 10 μ L samples is taken to use
HPLC is detected in the case where wavelength is 464nm, is denoted as W2。
EE calculates gained by following formula:
Carrying drug ratio (DL): precision measures 200 μ L of mPEG-PCL-PAE-EA micella, and freeze-drying to constant weight is denoted as W0, add
1000 μ L acetonitriles take 10 μ L samples to be detected with HPLC, Detection wavelength 464nm with 0.22 μm of membrane filtration.According to standard
Curve calculates HA content W1。
DL calculates gained by following formula:
The average encapsulation rate of nano-micelle is 92.3%, carrying drug ratio 15.6%
Embodiment 8
MPEG-b-PCL-PAE-EA micella hemolysis rate prepared by embodiment 2
The Mouse whole blood of anticoagulant mistake is first centrifuged 5min with 2 000rpm, sucks plasma layer, 2-3 times of volume is added in pipe
PBS (pH 7.4), lightly blow and beat repeatedly, mix, then with 2 000rpm be centrifuged 5min, 3 times repeatedly, prolong for the last time
Long centrifugation time makes overstocked red blood cell supernatant clear, colorless, abandons supernatant, red blood cell is diluted with PBS (pH 7.4) to 10min
At 2.5% (V/V) red cell suspension, 4 DEG C of preservations, the limit same day is used.MPEG-PCL-PAE-EA micellar concentration is diluted to
1000,500,250,125,62.5 μ g/mL take 300 μ L red cell suspensions, and the micella and blank glue of 1200 each concentration of μ L is added
Beam.It is placed in the centrifuge tube of 1.5mL, 37 DEG C of mixing 2h, after mixing, 3000rpm is centrifuged 20min, takes 200 μ L supernatants with multi-functional
Microplate reader detects under wavelength 576nm, and with method using distilled water as positive control, PBS is negative control.When micellar concentration reaches
When 1000 μ g/mL, hemolysis rate is still below 5%, illustrates mPEG-PCL-PAE-EA micella good biocompatibility, can be injected intravenously
Administration.
Embodiment 9
The critical micelle concentration (CMC) of mPEG-PCL-PAE-EA micella prepared by embodiment 2
Critical micelle concentration (CMC) is the minimum concentration that mPEG-PCL-PAE-EA forms micella in aqueous solution.This implementation
Make probe with pyrene solution in example, precision weighs pyrene (3mg) and is dissolved in 25mL acetone, measures 10 μ L pyrene solution respectively and is centrifuged in 8
Guan Zhong, volatilize acetone to the greatest extent overnight.MPEG-PCL-PAE-EA micellar concentration is diluted to 5 X 10-3-5ⅹ10-9Then mg/mL will
The micella of each concentration of 4mL moves in the centrifuge tube containing pyrene, vibrates 8h, balances pyrene and micella, at room temperature, stands overnight.It
Sample solution is crossed into 0.45 μm of filter membrane afterwards, takes 200 μ L samples in 96 microwell plates, is detected with multi-function microplate reader, testing conditions
Are as follows: emit and excitation bandwidth is 10nm, excitation wavelength 334nm, scanning speed 240nm/min, record launch wavelength exists
Fluorescence spectrum between 350-500nm.The result shows that the CMC of the micella is 0.883 μ g/mL.Evaluation CMC meaning be, if
In effect experiment, which is higher than CMC (0.883 μ g/mL), illustrates that mPEG-PCL-PAE-EA exists under the concentration
Micelle form is associated in solvent, we can say that be mPEG-PCL-PAE-EA being played a role in the form of micella.If effect
Concentration is lower than CMC, then shows that the surface tension of mPEG-PCL-PAE-EA in the solution becomes larger, micellar structure is destroyed, mPEG-
The action mode of PCL-PAE-EA is not micella.
Embodiment 10
The antibacterial effect of mPEG-PCL-PAE-EA micella prepared by embodiment 2: minimal inhibitory concentration (MIC) and minimum are killed
Bacteria concentration (MBC)
MIC and MBC is measured using 96 microwell plate doubling dilutions.Firstly, picking MRSA single colonie, 37 DEG C of overnight incubations,
Bacterium solution OD is adjusted with ultraviolet specrophotometer later600=0.5.100 μ L concentration are 106The MRSA bacterium solution of cfu/mL, respectively with
100 μ L different given the test agent mPEG-PCL-PAE-EA micella mixing, and be transferred in 96 microwell plates, PBS is as negative right
According to vancomycin (vancomycin hydrochloride, VanH) is used as positive control.In addition, all experimental groups are all divided into
Light group (470nm, 90mW/cm2, 40min) and non-light group.After illumination, sample is placed in 37 DEG C of incubators, is protected from light training
It supports for 24 hours.The Cmin that growth curve does not obviously rise is known as MIC.The Cmin that bacterial growth is not observed is referred to
It is set to MBC.Each experimental group is repeated 10 times experiment.The experimental results showed that the nano-micelle has very strong light under illumination condition
Toxicity, MIC and MBC are respectively 0.0695,0.138 μ g/mL, and antibacterial effect ratio EA raw medicine and positive control medicine hydrochloric acid ten thousand
Ancient mycin is eager to excel.Meanwhile the dark toxicity of the nano-micelle is very low, also demonstrates its safety under non-illumination condition.
Embodiment 11
Anti- MRSA in mPEG-PCL-PAE-EA nano-micelle body prepared by embodiment 2
Mouse is divided into 7 groups, every group 14, injects 500 μ L micellas after modeling 2h, be divided into it is low, in, high 3 dosage groups (contain
There is EA concentration for 100,200,400 μ g/mL), blank micella group, EA raw medicine group (200 μ g/mL) and physiological saline group.At illumination
After reason, every observing mouse state for 24 hours, using mPEG-PCL-PAE-EA micella (400 μ g/mL) non-illumination as control group.Observation refers to
It is designated as mouse survival rate: respectively after mouse infection MRSA for 24 hours, 48h, 72h, 96h, 120h observation, and record dead mouse
Situation draws survivorship curve.The measurement of mouse organs' content of molds: respectively after mouse infection MRSA for 24 hours, 48h, 72h, 96h,
120h, cervical dislocation put to death mouse, take liver and spleen, grinding homogenate, and carry out doubling dilution (1:10) with physiological saline,
It dilutes 4 times altogether, takes 100 μ L dilutions even spread in LB culture medium, 37 DEG C of cultures for 24 hours, carry out bacterium colony counting, calculate liver
With the MRSA colonization amount in spleen.Pathological examination: respectively after mouse infection MRSA for 24 hours, 48h, 72h, 96h and 120h, neck
Mouse is put to death in vertebra dislocation, and coring, liver, spleen, lung, kidney clean 4 times in sterile saline, in 4% paraformaldehyde of immersion for 24 hours it
After be sliced, HE dyeing carry out pathological observation.As a result, it has been found that mPEG-PCL-PAE-EA micella can significantly improve acute abdomen
The survival rate of film inflammation mouse, and dose dependent is presented.When the EA concentration in micella reaches 400 μ g/mL, it is administered in illumination
Afterwards, the survival rate of mouse can be improved to 86%.The experiment of mouse organs' content of molds and HE coloration result demonstrate mPEG-PCL-
The validity and safety of PAE-EA nano-micelle light power antibacterial.
Claims (10)
1. a kind of antimicrobial nano micella for discharging photosensitizer, which is characterized in that dredged by amphipathic three block copolymer embedding quinones
For aqueous photosensitive dosage form at antimicrobial nano micella, the amphipathic three block copolymer is mono methoxy polyethylene glycol-polycaprolactone-
Poly- beta-amino ester.
2. the antimicrobial nano micella of release photosensitizer according to claim 1, which is characterized in that mainly by following parts by weight
Raw material be prepared: 1-5 parts of photosensitizer, 5-25 parts of mono methoxy polyethylene glycol-polycaprolactone-poly- beta-amino ester, freeze-drying assign
0.01-0.05 parts of shape agent.
3. the antimicrobial nano micella of release photosensitizer according to claim 1 or 2, which is characterized in that the quinones is photosensitive
Agent includes cystolycin A, Elsinochrome element B, Elsinochrome element C photosensitizer, hypocrellin or hypericin photosensitizer.
4. the antimicrobial nano micella of release photosensitizer according to claim 1 or 2, which is characterized in that described amphipathic three
Block copolymer is that the water-wet side of the poly- beta-amino ester of mono methoxy polyethylene glycol-polycaprolactone-is mono methoxy polyethylene glycol, is dredged
Water end (W.E.) is polycaprolactone;The poly- beta-amino ester of mono methoxy polyethylene glycol-polycaprolactone-is first synthesized single methoxy by ring-opening polymerisation
Base polyethylene glycol-polycaprolactone, then the poly- beta-amino ester of mono methoxy polyethylene glycol-polycaprolactone-is synthesized with Michael's addition method
Three block.
5. the antimicrobial nano micella of release photosensitizer according to claim 2, which is characterized in that the freeze-dried excipient is
Sucrose, lactose, trehalose, polyethylene glycol, one of sorbierite or PEARLITOL 25C.
6. a kind of preparation method of the antimicrobial nano micella of release photosensitizer described in claim 1, which is characterized in that including such as
Lower step:
(1) it weighs the poly- beta-amino ester of mono methoxy polyethylene glycol-polycaprolactone-to mix with photosensitizer, organic solvent, ultrasound is added
It makes it dissolve;
(2) rotary evaporation, volatile organic solvent form the film of clear homogeneous;
(3) freeze-dried excipient and distilled water are added into film, slowly rotates, hydrated films;
(4) film after aquation is ultrasonic under ice-water bath, obtains medicament-carried nano micelle;
(5) obtained medicament-carried nano micelle is crossed into miillpore filter, removes non-encapsulated material and photosensitizer obtains medicament-carried nano glue
Beam;(6) medicament-carried nano micelle is freeze-dried and removes moisture, obtain the antimicrobial nano micelle freeze-drying system of dry release photosensitizer
Agent.
7. preparation method according to claim 6, which is characterized in that step (1) organic molten preferably acetone, dichloro
Methane, chloroform, any one in ethyl alcohol.
8. preparation method according to claim 6, which is characterized in that step (2) rotating evaporation temperature is 40~55
DEG C, 0.5~2h of rotary evaporation, sufficiently removing organic solvent form transparent uniform film.
9. preparation method according to claim 6, which is characterized in that step (3) hydration temperature is 40~65 DEG C, water
The change time is 2~6h;Ultrasound condition is 10~30min under step (4) described ice-water bath, and frequency is 10~20 HZ.
10. a kind of antimicrobial nano micella of release photosensitizer described in claim 1 improves light power overriding resistance bacterium in preparation
Application in drug.
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020155089A1 (en) * | 2000-05-08 | 2002-10-24 | Chowdhary Rubinah K. | Drug delivery systems for photodynamic therapy |
CN1526695A (en) * | 2003-09-24 | 2004-09-08 | 山东省生物信息工程技术研究中心 | Darr reaction process of quinone derivative composition to produce free radical and its application |
CN102198271A (en) * | 2011-05-18 | 2011-09-28 | 南京师范大学 | Method for preparing medicament-nanometer calcium phosphate composite system taking fat soluble photosensitizer as framework and application of system in preparation of medicaments for photodynamic therapy |
US20130022545A1 (en) * | 2011-07-18 | 2013-01-24 | Research & Business Foundation Sungkyunkwan University | DRUG DELIVERY SYSTEM FOR TREATMENT OF LIVER CANCER BASED ON INTERVENTIONAL INJECTION OF TEMPERATURE AND pH-SENSITIVE HYDROGEL |
CN102988289A (en) * | 2012-10-25 | 2013-03-27 | 南京师范大学 | Preparation method for fat-soluble phtosensitizer nanoparticles and application thereof |
US20160205925A1 (en) * | 2015-01-15 | 2016-07-21 | Ariel-University Research And Development Company Ltd. | Antimicrobial compositions made of a thermoplastic polymer and a photosensitizer |
CN106035351A (en) * | 2016-06-03 | 2016-10-26 | 南开大学 | Preparation method of photosensitizer-supported polymeric micelle and application of micelle in killing of planktobacteria and bacterial biofilms |
CN108498797A (en) * | 2017-02-27 | 2018-09-07 | 蒂尔纳米有限公司 | Methylenum careuleum complex and its application |
-
2019
- 2019-04-02 CN CN201910263711.0A patent/CN109966491B/en active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020155089A1 (en) * | 2000-05-08 | 2002-10-24 | Chowdhary Rubinah K. | Drug delivery systems for photodynamic therapy |
CN1526695A (en) * | 2003-09-24 | 2004-09-08 | 山东省生物信息工程技术研究中心 | Darr reaction process of quinone derivative composition to produce free radical and its application |
CN102198271A (en) * | 2011-05-18 | 2011-09-28 | 南京师范大学 | Method for preparing medicament-nanometer calcium phosphate composite system taking fat soluble photosensitizer as framework and application of system in preparation of medicaments for photodynamic therapy |
US20130022545A1 (en) * | 2011-07-18 | 2013-01-24 | Research & Business Foundation Sungkyunkwan University | DRUG DELIVERY SYSTEM FOR TREATMENT OF LIVER CANCER BASED ON INTERVENTIONAL INJECTION OF TEMPERATURE AND pH-SENSITIVE HYDROGEL |
CN102988289A (en) * | 2012-10-25 | 2013-03-27 | 南京师范大学 | Preparation method for fat-soluble phtosensitizer nanoparticles and application thereof |
US20160205925A1 (en) * | 2015-01-15 | 2016-07-21 | Ariel-University Research And Development Company Ltd. | Antimicrobial compositions made of a thermoplastic polymer and a photosensitizer |
CN106035351A (en) * | 2016-06-03 | 2016-10-26 | 南开大学 | Preparation method of photosensitizer-supported polymeric micelle and application of micelle in killing of planktobacteria and bacterial biofilms |
CN108498797A (en) * | 2017-02-27 | 2018-09-07 | 蒂尔纳米有限公司 | Methylenum careuleum complex and its application |
Non-Patent Citations (6)
Title |
---|
LIPING CHU ET AL: "A charge-adaptive nanosystem for prolonged and enhanced in vivo antibiotic delivery", 《CHEMCOMM》 * |
TINGHUI LI ET AL: "Elsinochrome A photosensitizers: Alternative drugs for photodynamic therapy", 《JOURNAL OF INNOVATIVE OPTICAL HEALTH SCIENCES》 * |
孟胜男 等主编: "《药剂学》", 31 January 2016, 中国医药科技出版社 * |
文宇 等: "纳米光敏剂的研究进展", 《中国现代医学杂志》 * |
李艳 等主编: "《药理学》", 31 December 2018, 华中科技大学出版社 * |
王伟 主编: "《肿瘤药剂学》", 30 November 2017, 江苏凤凰科学技术出版社 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112293416A (en) * | 2020-07-01 | 2021-02-02 | 中国海洋大学 | Environment-friendly non-release CS-b-PEG (polyethylene glycol) antibacterial micelle and preparation method thereof |
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