CN108619096A - Sound power sensitive liposome, medical composition and its use - Google Patents
Sound power sensitive liposome, medical composition and its use Download PDFInfo
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Abstract
The present invention relates to a kind of sound power sensitive liposome, medical composition and its uses.The sound power sensitive liposome includes at least one sound sensitiser and at least one lipid, has sensibility to sound wave, and the content of package-contained can be discharged under sound wave irradiation.The sound power sensitive liposome further includes at least one material with long cycle characteristics and at least one liposoluble active agent and/or water-soluble active agent.The invention further relates to a kind of pharmaceutical compositions including the sound power sensitive liposome.The invention further relates to the purposes that the sound power sensitive liposome and pharmaceutical composition are used to prepare the drug for the treatment of tumour.
Description
Technical field
The present invention relates to liposome fields, and particularly a kind of sound power sensitive liposome, one kind are dynamic comprising the sound
The pharmaceutical composition of power sensitive liposome and the sound power sensitive liposome and pharmaceutical composition are used to prepare antineoplastic
The purposes of object.
Background technology
Cancer is to threaten the major issue of human health, with the in-depth recognized tumour and diagnoses the continuous of medical procedure
It improves, people achieve great progress in terms of cancer diagnosis and treatment.In the treatment of cancer, operation, radiotherapy, drug are controlled
Treatment is most basic method.With going deep into for tumor etiology, Carcinogenesis Mechanism, tumor biochemistry and immunology etc., people
Prodigious hope is expressed to drug therapy (macromolecular drug or small-molecule drug).But drug controls the relative efficiency of tumour
Often to involve the physiological function of normal organ as cost.Therefore, the targeting drug delivery system of anticancer drug in recent years, especially
It is the key points and difficulties for the exploitation always pharmaceutical field research that safe and non-toxic and biodegradable nano target passs release system.
It passs to release using Nano medications such as liposome, drug-polymer conjugate, polymer nanoparticle, polymer micelles and is
System contains drug, thus it is possible to vary the kinetic characteristics of drug in vivo improve drug in the concentration of tumor locus, extend its delay
Time reduces toxic side effect to improve antitumor curative effect.For example, liposome, which is typical Nano medication, passs release system, it is
The micro-capsule that a kind of lipid bilayer (lipid film) by aligned orderly forms, is typically sized to tens to hundreds of nanometers.It can
Drug is wrapped in immobilized artificial membrane, using the physicochemical property and selective distribution feature of liposome, solves macromolecular drug or small
Solubility present in delivery process is low in vivo, stability is poor and absorbs the problems such as limited for molecular drug.
But the key for improving curative effect of medication fruit is how to improve the targeting and validity of drug, reduces the poison of drug
Side effect.And these Nano medications pass release system and still lack selectivity and targeting to tumor tissues at present.It is asked for this
Topic, researcher utilizes tumor locus specific environment (such as pH, enzyme, ion), or utilizes the physical signal applied to tumor locus
(such as illumination, ultrasound, heating) passs release system to design to the Nano medication of tumor locus targeted delivery.Based on tumor locus spy
Determine environmental triggers and pass the mode of release system release drug to place one's entire reliance upon internal factor, and there are individual differences for these factors, lead
The reliability of triggering is caused to need to be further increased.Mode based on physical signal triggering not only relies on less vivo environment factor,
But also intensity and the position of physical signal stimulation can be monitored to a certain extent, thus reliability clinically, practicality
Property higher.
In numerous physical signals, ultrasound is a kind of ideal trigger means.The mechanical wave that ultrasound generates is a kind of standing wave,
It can penetrate human body deep tissue and energy is accurately focused on to tumour target cell, and the Nano medication on the cell site is excited to pass
Release system discharges drug, but small to normal adjacent tissue damage, thus is more suitable for clinically applying.Sound dynamic therapy
(sonodynamic therapy, SDT) is a kind of new oncotherapy theory and method developed in recent years.The original of SDT
Reason is by the ultrasound stimulation sound sensitiser of certain frequency (such as porphyrins, hematoporphyrin derivative, gallium porphyrin class chemical combination
Object etc.) generation sound dynamic response, and then generation singlet oxygen (1O2)。1O2It is strong oxidant, but its service life is very of short duration
(be less than 0.1 μ s), range of scatter is extremely short, and the substance where only very close sound sensitiser could be by1O2Influence.1O2It can be with
The integrality for destroying tumour cell membrane structure, leads to death of neoplastic cells.Sound dynamic therapy technology developing into out clinically
The research that exhibition ultrasonic sensitive Nano medication passs release system is laid a good foundation (bibliography 1).
Based on background above, the present invention proposes to be based on sound principle of dynamics, and group, structure are triggered using sound sensitiser as sound power
Sound power sensitive liposome mentality of designing.The present invention triggers sound power sensitivity fat by applying ultrasound stimulation to tumor locus
Sound power function group in plastid --- sound sensitiser generation sound dynamic response generates1O2, and then lead to the lipid film of liposome
Disintegrate, the drug being wrapped in liposome is come out in tumor locus quick release, improves tumor locus drug concentration, in turn
Enhance the antitumous effect of drug.
Bibliography 1：" photodynamic therapy and sonodynamic treatment ", Li Weina etc.,《Chinese medicine physics magazine》,
2010-03, volume 27, the 2nd phase, the 1781-1792 pages
Invention content
Problems to be solved by the invention
The technical problem to be solved by the present invention is to for the targeting and validity for improving drug, the poison for reducing drug is secondary
This clinical demand is acted on, the sound power sensitive liposome that a kind of preparation method is easy, is easy to industrialized production, and packet are provided
It is prepared by pharmaceutical composition and the sound power sensitive liposome and pharmaceutical composition containing the sound power sensitive liposome
Purposes in antitumor drug.
The solution to the problem
Present invention firstly provides a kind of sound power sensitive liposomes, and it includes at least one sound sensitisers and at least one fat
Matter, and it has sensibility to sound wave, can disintegrate under the action of sound wave.
According to above-described sound power sensitive liposome, the sound sensitiser is selected from porphyrins, blood porphyrin
Close object, gallium porphyrin class compound or their mixture；Preferably, the porphyrins are selected from porphyrins or leaf
Green acid compounds.
According to above-described sound power sensitive liposome, the porphyrins are the compound of following formula：
Wherein, M can be configuration metal ions Zn2+、Sn2+、Fe2+、Cu2+、Mg2+、Ni2+、Co2+, also may not be present logical in the chemistry
In formula；
L is CH=CH2Or CH3-CH-OCH3；
R1For H ,-CH3 or amino acidic group；
R2For CH3Or CH2COOH；
R3For H or amino acidic group；
X is H or amino acidic group；
Y is H or amino acidic group；With
Amino acid in the amino acidic group is selected from glycine, alanine, valine, leucine, isoleucine, phenylpropyl alcohol ammonia
Acid, proline, tryptophan, serine, threonine, cysteine, methionine, aspartic acid, glutamine, aspartic acid, paddy
Propylhomoserin, lysine, arginine or histidine；
Preferably, the porphyrins are chlorin E6.
According to above-described sound power sensitive liposome, the chlorophyllin class compound is the compound of following formula：
Wherein, M can be Zn2+, also may not be present in the chemical general formula；
R1For H or amino acidic group；
R2For H or amino acidic group；
X is H or amino acidic group；
Y is H or amino acidic group；With
Amino acid in the amino acidic group is selected from glycine, alanine, valine, leucine, isoleucine, phenylpropyl alcohol ammonia
Acid, proline, tryptophan, serine, threonine, cysteine, methionine, aspartic acid, glutamine, aspartic acid, paddy
Propylhomoserin, lysine, arginine or histidine；
Preferably, the chlorophyllin class compound is Pyrophaeophorbide-a.
According to above-described sound power sensitive liposome, the lipid is selected from phosphatide, glycolipid, aliphatic acid, dialkyl group two
Methyl ammonium amphiphatic molecule, polyglycerol alkyl ether, polyoxyethylene alkyl ether or combinations thereof；Preferably, the lipid is selected from two palms
Phosphatidyl choline, diacetylenic glycerophosphatidylcholine, egg yolk lecithin, cholesterol or combinations thereof.
According to above-described sound power sensitive liposome, the sound wave can cause sound sensitiser to generate singlet selected from various
Oxygen1O2Sound wave, preferred ultrasonic wave, more preferable frequency is 0.1MHz~10MHz, the sound intensity is 0.01~5W/cm2Ultrasonic wave.
According to above-described sound power sensitive liposome, at least one material with long cycle characteristics is further included
Material, phosphatide, gangliosides, the nonionic surface active agent of the preferred Pegylation of the material with long cycle characteristics
Or polymer, more preferable distearoylphosphatidylethanolamine-polyethylene glycol 2000.
According to above-described sound power sensitive liposome, the lipid, sound sensitiser, material with long cycle characteristics
Weight ratio is 60-90：0.5-10：4-15.
According to above-described sound power sensitive liposome, content is further included, the content is selected from least
A kind of liposoluble active agent and/or water-soluble active agent, preferably fat-soluble anticancer agent and/or water-soluble anticancer agent, more preferable Ah
Mycin or taxol.
According to above-described sound power sensitive liposome, the lipid, sound sensitiser and the material with long cycle characteristics
Total weight and content weight ratio be 20-130：1-10.
According to the above-described sound power sensitive liposome of claim, the sound power sensitivity plastid is graininess,
Grain size is 70~300nm.
In addition, the present invention also provides a kind of pharmaceutical composition, it includes according to above-described sound power sensitive liposome
Body and pharmaceutically acceptable carrier.
Further, the present invention also provides according to above-described sound power sensitive liposome or above-described medicine group
Close the purposes of object in the preparation of antitumor drugs.
The effect of invention
The sound power sensitive liposome of the present invention can improve the targeting and validity of drug, reduce the secondary work of poison of drug
With this clinical demand, provide that a kind of preparation method is easy, is easy to the sound power sensitive liposome of industrialized production.
In compared with the existing technology, only made with the substance (such as singlet oxygen) that sound sensitiser itself releases under the excitation of sound wave
Effect is weaker when to inhibit the phenomenon that or destroy tumour cell, and improvements of the invention are released sound sensitiser as control drug
The controlling agent put, that is, what is utilized is that the substance released after sound sensitiser is excited destroys lipid, to release drug, into
And enhance targeting and validity.
Description of the drawings
Fig. 1：Sound power sensitive liposome principle schematic.By applying ultrasound stimulation to tumor locus, it is dynamic to trigger sound
Sound sensitiser generation sound dynamic response in power sensitive liposome generates1O2, and then the lipid film of liposome is caused to disintegrate, it will wrap up
Content in lipid film comes out in tumor locus quick release.
Fig. 2：The external sound power sensitization test figure of adriamycin sound power sensitive liposome.
Fig. 3：Sound power sensitization test figure in adriamycin sound power sensitive liposome body, wherein abscissa indicate different samples
Product, ordinate indicate adriamycin in intramuscular content.
Specific implementation mode
The main object of the present invention be for improve drug targeting and validity, reduce drug toxic side effect this
Clinical demand, provides that a kind of preparation method is easy, is easy to the sound power sensitive liposome of industrialized production, and includes the sound
The pharmaceutical composition of power sensitive liposome and the sound power sensitive liposome and pharmaceutical composition are preparing antineoplastic
Purposes in object.
The present inventor has found in prolonged research, when a certain amount of sound sensitiser is added in the lipid film in liposome,
Again by the ultrasound stimulation of certain condition after, sound dynamic response can occur for the sound sensitiser in lipid film, generate1O2, lead to lipid film
Disintegrate, and then content quick release therein will be wrapped in and come out.It is accomplished the present invention is based on above-mentioned discovery.
One aspect of the present invention is related to a kind of sound power sensitive liposome, it is characterised in that it includes at least one lipids
With at least one sound sensitiser, and its to sound wave have sensibility, can disintegrate under the action of sound wave.Specifically, the lipid
Quick dose of harmony forms lipid film.The sound sensitiser can generate in generation sound dynamic response under sound wave such as ultrasonic wave triggering1O2,
Or physical action is generated under the cavitation of ultrasonic wave, so that lipid film is disintegrated, and then lead to the sound power sensitive liposome solution
Body.
The sound power sensitive liposome further includes at least one material with long cycle characteristics.
The sound power sensitive liposome further includes content, and the content is selected from least one liposoluble active
Agent and/or water-soluble active agent.Specifically, the content is covered by the cavity of lipid film formation.When lipid film disintegrates
When, the content is released.
Wherein described lipid, sound sensitiser, material with long cycle characteristics weight ratio be 60-90：0.5-10：4-
15。
The total weight of the lipid, sound sensitiser and the material with long cycle characteristics and the weight ratio of content are 20-
130：1-10.
In the present invention, the lipid is not particularly limited, it can be any known lipid, such as phosphatide,
Glycolipid, aliphatic acid, dialkyl dimethyl ammonium amphiphatic molecule, polyglycerol alkyl ether or polyoxyethylene alkyl ether etc..
The example of above-mentioned phosphatide includes natural or synthetic phosphatide, for example, lecithin (soybean lecithin, egg yolk lecithin,
Dilauroyl lecithin, two myristoyl lecithin, Dipalmitoyl Lecithin or distearoylphosphatidylcholine etc.), phosphatidyl ethanol
Amine (two lauroyl phosphatidyl-ethanolamines, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine or distearyl
Phosphatidyl-ethanolamine etc.), phosphatidylserine (two lauroyl phosphatidylserines, two myristoyl phosphatidylserines, two palm fibre
Palmitic acid acyl phosphatidylserine or distearoylphosphatidyl serine etc.), phosphatidic acid, (two lauroyl phosphatidyls are sweet for phosphatidyl glycerol
Oil, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, dipalmitoylphosphatidylglycerol or distearoylphosphatidylglycerol etc.), phosphatidylinositols
(two lauroyl phosphatidylinositols, two myristoyl phosphatidylinositols, two palmityl phosphatidylinositols or distearoylphosphatidyl flesh
Alcohol etc.), lysolecithin, sphingomyelins, hydrogenated phospholipid etc..
The example of above-mentioned glycolipid includes glyceroglycolipid, glycosyl sphingolipid and sterol etc..
The example of above-mentioned glyceroglycolipid includes digalactosyl diglyceride (two lauroyl diglyceride of double galactolipins, double half
Two myristoyl glyceride of lactose, double galactolipin dipalmitoyl-glycerol esters or double galactolipin distearyl glyceride etc.) or gala
Sugared diglyceride (two lauroyl glyceride of galactolipin, two myristoyl glyceride of galactolipin, galactolipin dipalmitoyl-glycerol ester or
Galactolipin distearyl glyceride etc.) etc..
The example of above-mentioned glycosyl sphingolipid includes galactoside cerebroside, lactosyl cerebroside or gangliosides etc..
The example of above-mentioned sterol includes cholesterol, carbamoyl cholesterol, Cholesteryl hemisuccinate, ergosterol or sheep
Hair sterol etc..
In the present invention, the lipid can be used alone or is used in combination by combining two of which or more.
Particularly, the lipid is selected from dipalmitoylphosphatidylcholine, diacetylenic glycerophosphatidylcholine, yolk lecithin
Fat, cholesterol.
In the present invention, the material with long cycle characteristics is to refer to imparting liposome to escape in vivo
Reticuloendothelial system removes the material of characteristic, refers mainly to the larger and material with hydrophily or hydrophilic radical of molecular weight.Such
Material can interlock in surfaces of carrier materials to be covered into fine and close conformation cloud, is formed thicker sterically hindered layer, is hindered netted
The effect of endothelial system, or enhance due to its hydrophily the solvation of carrier, the opsonic action on its surface is effectively prevented,
To reduce the affinity with mononuclear phagocyte system macrophage so that liposome can be stabilized simultaneously in the circulatory system
Make its Increased Plasma Half-life.The material with long cycle characteristics such as can be the phosphatide of Pegylation, gangliosides,
Nonionic surface active agent or polymer etc..
In the present invention, the material with long cycle characteristics includes but not limited to the poly- second that average molecular weight is 2000
Glycol-hydrogenated soya phosphatide acyl ethanol amine (HSPE-PEG2000), polyethylene glycol-hydrogenated soybean phosphorus that average molecular weight is 5000
Acyl ethanol amine (HSPE-PEG5000), polyethylene glycol-distearoylphosphatidylethanolamine that average molecular weight is 2000
(DSPE-PEG2000), polyethylene glycol-dipalmitoylphosphatidylethanolamine (DPPE- that average molecular weight is 2000
The polyethyleneglycol modified cytoskeletal protein phosphatide of different molecular weights such as PEG2000), gangliosides, polyvinyl alcohol, poly- second
Alkene pyrrolidone, tween, poloxamer etc..
Particularly, the material with long cycle characteristics is selected from distearoylphosphatidylethanolamine-polyethylene glycol
2000。
In the present invention, term " sound sensitiser " refers to that can generate singlet oxygen etc. under sound stimulation lipid structure can be caused to send out
The raw substance changed.The sound sensitiser be selected from porphyrins, hematoporphyrin derivative, gallium porphyrin class compound or they
Mixture.
Above-mentioned porphyrins are selected from porphyrins or chlorophyllin class compound.
The porphyrins are the compound of following formula：
Wherein, M can be configuration metal ions Zn2+、Sn2+、Fe2+、Cu2+、Mg2+、Ni2+、Co2+, also may not be present logical in the chemistry
In formula；
L is CH=CH2Or CH3-CH-OCH3；
R1For H ,-CH3Or amino acidic group；
R2For CH3Or CH2COOH；
R3For H or amino acidic group；
X is H or amino acidic group；
Y is H or amino acidic group；With
Amino acid in the amino acidic group is selected from glycine, alanine, valine, leucine, isoleucine, phenylpropyl alcohol ammonia
Acid, proline, tryptophan, serine, threonine, cysteine, methionine, aspartic acid, glutamine, aspartic acid, paddy
Propylhomoserin, lysine, arginine or histidine.
The chlorophyllin class compound is the compound of following formula：
Wherein, M can be Zn2+, also may not be present in the chemical general formula；
R1For H or amino acidic group；
R2For H or amino acidic group；
X is H or amino acidic group；
Y is H or amino acidic group；With
Amino acid in the amino acidic group is selected from glycine, alanine, valine, leucine, isoleucine, phenylpropyl alcohol ammonia
Acid, proline, tryptophan, serine, threonine, cysteine, methionine, aspartic acid, glutamine, aspartic acid, paddy
Propylhomoserin, lysine, arginine or histidine.
Particularly, the porphyrins are selected from chlorin E6, and the chlorophyllin class compound is selected from burnt de-magging leaf
Green acids-α.
Sound wave used herein can be it is various can cause sound sensitiser generate singlet oxygen (1O2) sound wave, it is preferably super
Sound wave.
Above-mentioned ultrasonic wave be it is a kind of can mechanical wave, can be impulse wave or continuous wave, and its frequency be 0.1MHz~
10MHz, the sound intensity are 0.01~5W/cm2, action time is 0.25~180 minute.The occurring source of the ultrasonic wave may include but
It is not limited to function generator, power amplifier and ultrasonic transducer electrical connection composition.Ultrasonic transducer is piezoceramic material,
Two sides is coated with silver conductive film, forms two electrodes, it can be driven by the amplified sinusoidal signal of power amplifier and generate ultrasound
Wave.
In embodiments of the invention, content is further included, the content is selected from least one fat-soluble work
Property agent and/or water-soluble active agent.The liposoluble active agent and/or water-soluble active agent are fat-soluble anticancer agent and/or water
Dissolubility anticancer agent.Other liposoluble active agent and/or water-soluble active agent include but not limited to antibiotic, antifungal agent, are immunized
Inhibitor, antivirotic etc..
In the present invention, the anticancer agent is selected from alkylating agent, antimetabolite, spindle poison plant alkaloid, cell toxicant
Property antitumor antibiotics, topoisomerase enzyme inhibitor, monoclonal antibody or its segment, kinase inhibitor, antitumor enzyme and enzyme
Inhibitor, cell death inducer, antihormones, retinoids, compound containing platinum, albumen, polypeptide and nucleic acid drug.
Particularly, the fat-soluble anticancer agent and/or water-soluble anticancer agent are selected from adriamycin or taxol.
In the present invention, the grain size of the sound power sensitive liposome is 70~300nm.
Another aspect of the present invention relates to a kind of pharmaceutical compositions, and it includes sound power sensitive liposomes according to the present invention
And pharmaceutically acceptable carrier.The carrier is selected from dipalmitoylphosphatidylcholine, diacetylenic glycerophosphatidylcholine, two
The liposome of the preparations such as stearoyl phosphatidyl ethanol amine-polyethylene glycol 2000.
It is anti-in preparation that another aspect of the invention is related to sound power sensitive liposome according to the present invention or pharmaceutical composition
Purposes in tumour medicine.
The sound power sensitive liposome of the present invention can use any approach appropriate to snibject, for example, vein
Interior administration, intramuscular delivery, Intraperitoneal medication, subcutaneous administration, intra-articular administration, intrathecal drug delivery, is given in telocoele intraarterial delivery
Medicine, nasal spray, lung sucking, oral medication and other suitable administration route well known by persons skilled in the art.It can profit
Tissue with the method treatment of the present invention includes but not limited to nose, lung, liver, kidney, soft tissue, muscle, adrenal tissue and breast.
Any tissue or body fluid that ultrasonic wave can reach can use the sound power sensitive liposome treatment of the present invention.
Those skilled in the art are easily determined gives activity using the sound power sensitive liposome of the present invention to subject
The dosage of agent.As known in the art, the dosage of activating agent can be adjusted according to comprising activating agent in the carrier.
During and/or after giving the sound power sensitive liposome of the present invention, the target area of subject can be carried out
Ultrasound.In one embodiment of the invention, the sound power sensitive liposome of the present invention is delivered to subject, upon administration
Ultrasonic target area as quickly as possible.
The beneficial effects of the present invention are the present invention is based on sound principles of dynamics, it is quick to add sound in existing liposome prescription
Agent triggers group as sound power, and liposome is made to have good ultrasonic sensitive degree.It is triggered, can will be wrapped in by ultrasonic wave
Content in lipid film comes out in target area quick release, improves the drug concentration of target area, and then enhance controlling for drug
Therapeutic effect reduces the general toxicity of drug, has a good application prospect.
Embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited
In following embodiments.One of skill in the art, can be with it can be appreciated that under the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.
The present invention carries out general and/or specific description to the material and test method that are arrived used in experiment.Though
So many materials and operating method used in purpose are it is known in the art that still the present invention is still herein to realize the present invention
It is described in detail as far as possible.
Abbreviation used in following embodiment is as follows：
DPPC：Dipalmitoylphosphatidylcholine
DC8,9PC：Diacetylenic glycerophosphatidylcholine
DSPE-PEG2000：Distearoylphosphatidylethanolamine-polyethylene glycol 2000
HPPH：Pyrophaeophorbide-a
HEPES：Hydroxyethyl piperazine second sulphur acid buffer
EPC：Egg yolk lecithin
Chol：Cholesterol
Embodiment 1：The preparation of adriamycin sound power sensitive liposome
(1) material and dosage：(dosage of 100ml liposomes, the following table 1)
[table 1]
(2) preparation method
Various matrix materials, material and sound sensitiser with long cycle characteristics are weighed by the dosage in table 1, is dissolved in 200ml
Chloroform：Methanol (4:1) in solution, evaporating organic solvent is rotated at 50~60 DEG C, dried, be uniformly attached to glass
The film of bottom of bottle.Gained film forms one using the citric acid solution 220ml of pH=4.0 in 50~60 DEG C of aquation 30min
Even liposome solutions.Then, polycarbonate membrane was squeezed, the polycarbonate membrane that aperture is 200nm is first crossed, is after aperture
The polycarbonate membrane of 100nm.Obtained liposome adjusts outer aqueous phase pH value using aqueous sodium carbonate (500mM) to 7.0- in right amount
7.4.Obtained liposome and adriamycin (ten thousand happy medicine company of Shenzhen, lot number 20140815) aqueous solution 200ml (adriamycin 1mg/
Ml 1h) is co-cultured in 37 DEG C, obtains the sound power sensitive liposome for being loaded with adriamycin.Later, it saves backup under the conditions of 4~7 DEG C.
Embodiment 2：The entrapment efficiency determination of adriamycin sound power sensitive liposome
Adriamycin sound power sensitive liposome 1ml prepared by Example 1 is in 1.5ml EP pipes, 10000r/min, from
Heart 10min.Take supernatant 0.2ml in 10ml volumetric flasks, after methanol solution rupture of membranes constant volume, high performance liquid chromatography (HPLC) into
Sample analyzes (C18 columns, Agilent SB-C18,4.6 × 150mm, 1.8 μm, methanol-acetonitrile-phosphate buffer (25mM NH4H2PO4-
30mM H3PO4, pH 5.0) (5: 2: 3) be mobile phase, 1.0mlmin-1, Detection wavelength 233nm, similarly hereinafter), obtain loading lipid
Adriamycin medicament contg (C1) 0.211mg in body；It is another take the adriamycin sound power sensitive liposome sample 0.2ml that does not centrifuge in
In 10ml volumetric flasks, it is settled to graduation mark with the dilution of methanol solution rupture of membranes, sample introduction is analyzed for high performance liquid chromatography (HPLC), obtains Ah mould
Total medicament contg (C2) 0.214mg of adriamycin in plain sound power sensitive liposome suspension.Encapsulation rate (E)=C1/C2 ×
100%.The result shows that the encapsulation rate of adriamycin sound power sensitive liposome is 98.7%.
Embodiment 3：The external sound power sensitization test of adriamycin sound power sensitive liposome
Adriamycin sound power sensitive liposome prepared by the embodiment 1 of 0.5ml is taken to be put into cellulose acetate bag filter respectively
(celluloseacetate dialysis bag, MWCO 8-14kDa) (BioVision, Inc., lot number C413103001)
In, and immerse in the HEPES solution of 30ml in 60r/min magnetic agitations.By sonicator (2776,
Chattanooge, USA) use ultrasonic wave (1MHz, 1W/cm2) irradiate, ultrasound takes out the release liquid of 0.5ml simultaneously after 2 minutes
Cross after 0.22 μm of filter membrane using HPLC carry out in release liquid medicine assay (C18 columns, Agilent SB-C18,4.6 ×
150mm, 1.8 μm, methanol-acetonitrile-phosphate buffer (25mM NH4H2PO4-30mM H3PO4, pH 5.0) (5: 2: 3) be flowing
Phase, 1.0mlmin-1, Detection wavelength 233nm).The sample for not using ultrasound wave irradiation as a contrast, HPLC is used by same procedure
Carry out medicine assay.Burst size %=release drugs total amount/contain drug total amount × 100%.
By Fig. 2 results it is found that adriamycin sound power sensitive liposome is after ultrasound, release amount of medicine (77.4 ±
2.4%) it is apparently higher than not ultrasonic control group (4.7 ± 3.3%).Therefore, adriamycin sound power sensitive liposome of the invention
There is apparent sound power sensitivity drug release feature in vitro.
Embodiment 4：Sound power sensitization test in adriamycin sound power sensitive liposome body
15 kunming mices (Beijing Vital River Experimental Animals Technology Co., Ltd., KM) are randomly divided into three groups (every group 5
Only).
First group of tail vein injection (0.5ml, 1mg) doxorubicin injection (meaning Pharmacia, 10mg/ bottles, lot number
132550013) (injection group).Second group of tail vein injection (0.5ml, 0.5mg) adriamycin conventional liposome (stone medicine Ou Yi medicine
Industry, 10ml:20mg, lot number 691160402) (conventional liposome group).Third group tail vein injection (0.5ml, the 0.5mg) present invention
The adriamycin sound power sensitive liposome (sound power sensitive liposome group) of middle embodiment 1.
After administration immediately to the left front leg position of each mouse by sonicator (2776,
Chattanooge, USA) use ultrasonic wave (1MHz, 1W/cm2) irradiation, not ultrasonic right front leg is as own control, 2 points of ultrasound
Ultrasonic and not ultrasonic mouse leg muscle doxorubicin content is measured after clock respectively.Assay method is as follows.
C18 columns (Agilent SB-C18,4.6 × 150mm, 1.8 μm), mobile phase are methanol-acetonitrile -0.01molL-1 phosphorus
Acid dihydride ammonium-glacial acetic acid (50: 22: 28: 0.6), flow velocity 1.0mlmin-1, excitation wavelength 479nm, launch wavelength 587nm, column
30 DEG C of temperature.Using daunomycins as internal standard compound, musculature 0.5g is taken, adds phosphate buffer solution (p H=7.4) 1ml, is homogenized,
Internal standard solution, the extraction of chlorination imitation-carbinol (4: 1) mixed liquor, residue is added to be dissolved, filtered, sample introduction with methanol.
Medication amount/tissue weight in content=tissue.
By Fig. 3 results it is found that injection group (2.5 ± 0.3 μ g/g), conventional liposome group (2.2 ± 0.3 μ g/g) harmony are dynamic
The content of adriamycin in the not ultrasonic position of power sensitive liposome group (2.1 ± 0.4 μ g/g) does not have notable difference；Injection group
The medicament contg at (2.6 ± 0.4 μ g/g) and conventional liposome group (2.4 ± 0.4 μ g/g) ultrasound position is compared with not ultrasonic position
There is no significant difference, and the medicament contg (4.2 ± 0.5 μ g/g) in adriamycin sound power sensitive liposome group ultrasound position
Nearly 1 times is increased than not ultrasonic position (2.1 ± 0.4 μ g/g), significantly improves the medicament contg at ultrasonic position.Therefore, this hair
Bright adriamycin sound power sensitive liposome has apparent sound power sensitivity drug release feature in vivo.
Embodiment 5：The pharmacodynamic observation of adriamycin sound power sensitive liposome
Logarithmic growth phase MCF-7 breast cancer cells (the Shanghai bio tech ltd Mei Xuan), by every 0.2ml
(liquid medium is diluted to 2 × 10 to MCF-7 breast cancer cells suspension6/ ml) being inoculated in mouse, (60, the experiment of tonneau China is tieed up in Beijing
Zoo technical Co., Ltd, BALB/c nude mices) the right inclined dorsal sc of armpit.
The 10th day after inoculated tumour cell, the mouse 50 for selecting tumor size relatively uniform (accumulates big float by knurl
It is uniformly divided into each group at random after sequence), it is divided into five groups (every group 10)：Control group, normal injection group, conventional liposome group, sound
Power sensitive liposome group (ultrasound) harmony power sensitive liposome group (not ultrasonic).In addition to control group tail vein injection physiology salt
Outside water, other four groups respectively tail vein injection be equivalent to normal injection, conventional liposome and the embodiment of 10mg/kg adriamycins
1 adriamycin sound power sensitive liposome.
After injection, tumour portion of the above-mentioned sonicator to mouse in sound power sensitive liposome group (ultrasound) is used immediately
Position ultrasound 2 minutes (1MHz, 1W/cm2), the mouse of other groups does not deal with.It is administered three times altogether, every three days once.Take each group
The tumour of mouse is weighed, and is calculated tumor control rate according to formula, be the results are shown in Table 2.
Tumor control rate=(1-Ws/Wx) × 100%
[table 2] results of pharmacodynamic test
Wherein, Ws is the tumor quality for the treatment of group；Wx is the tumor quality of physiological saline group.
(x ± s indicates average value ± standard variance；Gross tumor volume=length × wide × wide/2)
Data above shows adriamycin sound power sensitive liposome with after combination of ultrasound, and tumor killing effect is remarkably reinforced.Therefore,
It can be used for preparing antitumor drug.
Embodiment 6：The preparation of taxol sound power sensitive liposome
(1) material and dosage：(dosage of 100ml liposomes, the following table 3)
[table 3]
(2) preparation method
Various matrix materials, sound sensitiser and activating agent are weighed by the dosage of table 3, is dissolved in chloroform：Methanol (4:1) solution
In 300ml, evaporating organic solvent is rotated at 50~60 DEG C, is dried, the uniform film for being attached to bottle bottom.With containing
Lactose 5% phosphate buffer 1 50ml (pH=7.4) aquation, obtains multilamelar liposome solution.Homogeneous multilamelar liposome under high pressure
Solution obtains solution (700MPa, 6 cycles) of the grain size less than 200nm, after the polycarbonate membrane that aperture is 100nm.Using
It is about 150nm, the transparent blue-opalescent of liposome solutions, and good fluidity that dynamic laser light scattering experimental method, which measures grain size,.
Industrial availability
The sound power sensitive liposome of the present invention can be implemented in the industrial production.
Claims (12)
1. a kind of sound power sensitive liposome, which is characterized in that it includes at least one sound sensitisers and at least one lipid, and its
There is sensibility to sound wave, can disintegrate under the action of sound wave,
The lipid is selected from phosphatide, glycolipid, aliphatic acid, dialkyl dimethyl ammonium amphiphatic molecule, polyglycerol alkyl ether, polyoxyethylene
Alkyl ether or combinations thereof；Preferably, the lipid be selected from dipalmitoylphosphatidylcholine, diacetylenic glycerophosphatidylcholine,
Egg yolk lecithin, cholesterol or combinations thereof.
2. sound power sensitive liposome according to claim 1, which is characterized in that the sound sensitiser is selected from porphyrin chemical combination
Object, hematoporphyrin derivative, gallium porphyrin class compound or their mixture；Preferably, the porphyrins are selected from porphin
Pheno class compound or chlorophyllin class compound.
3. sound power sensitive liposome according to claim 2, which is characterized in that the porphyrins are following formula
Compound：
Wherein, M can be configuration metal ions Zn2+、Sn2+、Fe2+、Cu2+、Mg2+、Ni2+、Co2+, also may not be present in the chemical general formula；
L is CH=CH2Or CH3-CH-OCH3；
R1For H ,-CH3Or amino acidic group；
R2For CH3Or CH2COOH；
R3For H or amino acidic group；
X is H or amino acidic group；
Y is H or amino acidic group；With
Amino acid in the amino acidic group be selected from glycine, alanine, valine, leucine, isoleucine, phenylalanine,
Proline, tryptophan, serine, threonine, cysteine, methionine, aspartic acid, glutamine, aspartic acid, paddy ammonia
Acid, lysine, arginine or histidine；
Preferably, the porphyrins are chlorin E6.
4. sound power sensitive liposome according to claim 2, which is characterized in that the chlorophyllin class compound is following formula
Compound：
Wherein, M can be Zn2+, also may not be present in the chemical general formula；
R1For H or amino acidic group；
R2For H or amino acidic group；
X is H or amino acidic group；
Y is H or amino acidic group；With
Amino acid in the amino acidic group be selected from glycine, alanine, valine, leucine, isoleucine, phenylalanine,
Proline, tryptophan, serine, threonine, cysteine, methionine, aspartic acid, glutamine, aspartic acid, paddy ammonia
Acid, lysine, arginine or histidine；
Preferably, the chlorophyllin class compound is Pyrophaeophorbide-a.
5. according to claim 1-4 any one of them sound power sensitive liposomes, which is characterized in that the sound wave is selected from various
Sound sensitiser can be caused to generate singlet oxygen1O2Sound wave, preferred ultrasonic wave, more preferable frequency is 0.1MHz~10MHz, the sound intensity is
0.01~5W/cm2Ultrasonic wave.
6. according to claim 1-4 any one of them sound power sensitive liposomes, which is characterized in that it is further included at least
A kind of material with long cycle characteristics, phosphatide, the neuromere of the preferred Pegylation of the material with long cycle characteristics
Glycosides fat, nonionic surface active agent or polymer, more preferable distearoylphosphatidylethanolamine-polyethylene glycol 2000.
7. sound power sensitive liposome according to claim 6, which is characterized in that the lipid, there is length to follow at sound sensitiser
The weight ratio of the material of ring property is 60-90：0.5-10：4-15.
8. sound power sensitive liposome according to any one of claim 1 to 7, which is characterized in that it is further included
Content, the content are selected from least one liposoluble active agent and/or water-soluble active agent, preferably fat-soluble anticancer agent
And/or water-soluble anticancer agent, more preferable adriamycin or taxol.
9. sound power sensitive liposome according to claim 8, the lipid, sound sensitiser and the material with long cycle characteristics
The total weight of material and the weight ratio of content are 20-130：1-10.
10. according to claim 1-4 any one of them sound power sensitive liposomes, which is characterized in that the sound power is sensitive
Plastid is graininess, and grain size is 70~300nm.
11. a kind of pharmaceutical composition, it includes according to claim 1-10 any one of them sound power sensitive liposome and medicine
Acceptable carrier on.
12. according to claim 1-10 any one of them sound power sensitive liposome or drug according to claim 11
The purposes of composition in the preparation of antitumor drugs.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111358945A (en) * | 2018-12-24 | 2020-07-03 | 深圳先进技术研究院 | Metalloporphyrin-loaded liposome nanoparticle and preparation method and application thereof |
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