CN108542884B - A kind of sensitive medicament-carried liposome of pH of SPIO tracer and preparation method thereof - Google Patents

A kind of sensitive medicament-carried liposome of pH of SPIO tracer and preparation method thereof Download PDF

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CN108542884B
CN108542884B CN201810417787.XA CN201810417787A CN108542884B CN 108542884 B CN108542884 B CN 108542884B CN 201810417787 A CN201810417787 A CN 201810417787A CN 108542884 B CN108542884 B CN 108542884B
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spio
tracer
liposome
added
sensitive
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CN108542884A (en
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李必波
罗治彬
何美
李必强
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People's Hospital Of Chongqing City
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Abstract

The invention discloses a kind of sensitive medicament-carried liposomes of pH of SPIO tracer, are obtained using following quality proportioning: 1~10 part of bulk pharmaceutical chemicals, 1~50 part of phosphatidyl-ethanolamine, 1~30 part of cholesterol, 1~30 part of linoleic acid, 0~10 part of carboxymethyl chitosan, 0~10 part of SPIO nano particle.The invention also discloses a kind of preparation methods of the sensitive medicament-carried liposome of pH of SPIO tracer: S1: taking phosphatidyl-ethanolamine, cholesterol and linoleic acid in flask, addition chloroform is dissolved, and water soluble drug solution is added and carries out being ultrasonically formed w/o type emulsion；S2: it is performed under reduced pressure and is evaporated to gel state；Buffer is added, continues evaporation and forms aqueous suspension；S3: it is added liposome turbid liquor freeze thawing 3 times after SPIO nano particle；It is centrifuged off the SPIO nano particle and water soluble drug that aqueous suspension is not packed in；S4: carboxymethyl chitosan solution is added, is hydrated.

Description

A kind of sensitive medicament-carried liposome of pH of SPIO tracer and preparation method thereof
Technical field
The present invention relates to pH sensitive liposome technical fields, and in particular to a kind of sensitive medicament-carried liposome of pH of SPIO tracer And preparation method thereof.
Background technique
Liposome (liposome) means a kind of double-deck miniature vesicular body of rouge molecule with similar biofilm structure, diameter 25~1000nm etc. can be used as hydrophily or/and hydrophobic pharmaceutical carrier.With targeting, lymph directionality, sustained release Property, reduce drug toxicity, improve medicine stability the characteristics of.
The quick unordered growth pattern of solid malignant, keeps its angiogenesis insufficient, and blood oxygen supply is insufficient, causes to swell Occurs anoxic cell in tumor.The presence of anoxic cell causes the pH value (6.5 or less) at mesenchyma stroma of tumors compared with normal tissue interstitial The pH value (7.4) at place is low, this provides theoretical foundation for pH sensitive liposome (pH sensitive liposomes).PH is sensitive Liposome is the sensitive liposome of a kind of couple of pH, is made of the membrane material with pH sensibility, the lipid bilayer in structure The stability of layer changes with environment pH and is changed, while can also be called acid-sensitive polymer liposome.When drug-loaded liposome is with blood circulation When reaching tumor locus, since the reduction of pH at interstitial causes membrane material protonation that imitated vesicle structure is caused to destroy, drug is released, The targeting of tumour can be realized.
The research of early stage pH sensitive liposome mainly realizes liposome pH sensibility by selecting different phosphatide.This pH Sensitive liposome is mainly by pH sensitive compound and unsaturated cephalin (phosphatidylethanolamine, PE) group At, wherein common PE is dioleoylphosphatidylethanolamine (dioleoylphosphatidylethanolamine, DOPE). And the hydrophilic segment of pH sensitive liposome compound contains the pH sensitive groups such as carboxyl more, such as oleic acid (oleicacid, OA), gallbladder Sterol hemisuccinic acid ester (cholesteryl hemisuccinate, CHEMS) and palmitoylhomocysteine (Palmitoyl Homocysteine, PHC) etc..Unsaturated cephalin is cone, and the small hydrophobic end of water-wet side is big, and pH sensitive liposome compound Carboxylic acid group in neutral conditions, be inverted conical shape, the big hydrophobic end of water-wet side is small, both has then been complementarily shaped to liposome bilayer Film is simultaneously stable at neutral environment.When pH is reduced to acidity, carboxylic acid group will be protonated, and water-wet side volume opposite will subtract It is small, cannot be complementary with unsaturated cephalin on three-dimensional conformation, cause liposome unstable.The lipid of a variety of different pH sensitivities Body can be obtained by adjusting the composition ratio of lipid or changing membrane material type.Zhang hong etc. uses PE/CHO/OA (6:2:3W/W) is membrane material, is prepared for taxol pH sensitive liposome, and what in vitro test showed in 5.0 solution of pH accumulative releases Degree of putting is at 1.3 times of 7.4 solution of pH.In-vivo test in mice shows: its t1/2And AUC is 1.8 times and 2.6 of taxol respectively Times.Zuo Tiantian etc. substitutes oleic acid using linoleic acid, is combined (16:24:8, W/W) to be prepared for docetaxel pH in proportion with PE, CHO Sensitive liposome, vitro release test show that the accumulative releasing degree in 72h in 7.4 solution of 5.0 solution of pH and pH is respectively 87.81% and 65.21%, show it with apparent pH sensibility.Kim Min-Jung etc. is prepared for using DOPE and CHEMS Using EGF-R ELISA as the pH sensitivity long circulating immunoliposome of target spot, when DOPE/CHEMS (molar ratio) is 6:4, Gained liposome shows stronger acid-sensitive in pH5.5 solution, and gemcitabine is wrapped in the pH sensitivity rouge with antibody In plastid, inhibit A549The effect of cancer cell multiplication is 2 times of free drug.
In addition to pH sensitive compound and unsaturated cephalin can realize the pH sensibility of liposome, containing amino and contain The pH sensibility high score material of carboxylic acid group can also be used to building pH sensitive liposome, often by by pH Sensitive Polymer Materials Modification is formed in outer liposome surface or be embedded in liposome bilayer membrane.With amino high molecular material such as polyhistidyl and Polylysine, pH sensitive liposome could be constructed by needing mutually to merge with negative charged lipid body.Contain the cationic (- NH) base of weak base Group, and contain the amphipathic electrolyte carboxymethyl chitosan of weak acid anion (- COO-) group, lipid is wrapped in by aquation Body surface face, the liposome tablets in vitro after modification show apparent pH sensibility, and possible cause is carboxymethyl chitosan On amino group protonation campaign at a low ph so that modification occurs in the structure of the carboxymethyl chitosan of surface of liposome Variation squeezes liposome bilayer and resets liposome, in rearrangement process, by the drug quick release of encapsulating.Yang Shanxiang etc. It selects carboxymethyl chitosan as dressing agent, prepares pH sensitivity adriamycin nano liposome, in vitro test shows adriamycin in Drug release under property and weak basic condition is relatively slow, drug accumulation release rate only 40% when 8h, close to tumour cell pH Solutions of weak acidity and acid condition under, drug accumulation release rate is up to 60% or more when 8h, and release amount of medicine is with absorption delaying agents PH is reduced and is increased, and illustrates that adriamycin nano liposome has pH sensibility after carboxymethyl chitosan is sugar-modified.
In conclusion passing through pH sensitive compound, the group two-by-two of unsaturated cephalin and pH sensibility high score material It closes or is used alone, manufactured drug-loaded liposome all has certain pH sensibility, but there are still required pH condition values too low, medicine The features such as object release time is too long, accumulative releasing degree is insufficient.
In addition, the height pH sensibility of liposome is to realize the premise of tumor-targeting, tumor-targeting how is confirmed again It is another challenge.The method for confirming tumor-targeting at present includes: Drug content in tissues measurement, fluorescein development, radioactivity Nucleic development etc..Fine jade etc. is prepared for the proliposome of height Lung targeting more than domestic scholars, is studied in rabbit body, by quiet After arteries and veins injecting lipid body, puts to death rabbit and obtain each organs and tissues, extract drug ingedient after tissue homogenate, tissue is carried out by HPLC The detection of drug concentration obtains pharmacokinetics and Tissue distribution data, it was demonstrated that the liposome has the lung tissue of height Targeting.Foreign scholar Hong Myo-Sook is wrapped up using the membrane material of pH sensitivity, is prepared for using fluorescer as developer PH sensitive liposome, and liposome is placed in investigation pH sensibility in vitro human lung cancer tissue, the liposome is in 2h as the result is shown The interior fluorescer by package is discharged up to 100%, and release shows that it has less than 30% in 8h in Isolated Rat normal liver tissue Height pH sensibility.Foreign scholar Vildete Carmo, using 99mTc as radioactive tracer developer, using the film of pH sensitivity Material is prepared for 99mTc-- hexamethylpropyleneamine oxime pH sensitive liposome (99mTc--SpHL), and rat results from vivo experiments is aobvious Show, (after the 60h that is inflamed, the local pH of Inflamed tissue is from originally just in artificial constructed rat inflammation foot by 99mTc--SpHL 7.4 in normal situation are reduced to 18 times that 6.5) cumulative radiation level is simple drug, show that the pH sensitive liposome has Height pH sensibility and targeting.The method that three of the above confirms targeting has distinct disadvantage, such as living tissue drug concentration Detection, can not real-time perfoming, each in vivo dynamic drug concentration change can not be detected；Fluorescer is developer mainly in body Outer cell or in vitro tissue development；99mTc has obvious radioactivity, and half-life short (6.02h).
Summary of the invention
In view of the above shortcomings of the prior art, the technical problems to be solved by the present invention are: how to provide a kind of pH sensitivity Property it is obvious, tracer effect is good, preparation process is simple, the sensitive medicament-carried liposome of pH of stable storing SPIO tracer and its preparation side Method.
In order to solve the above-mentioned technical problem, present invention employs the following technical solutions: including bulk pharmaceutical chemicals, auxiliary material and tracer Agent, the bulk pharmaceutical chemicals are one of water soluble drug or fat-soluble medicine, and the auxiliary material includes that phosphatidyl-ethanolamine, gallbladder are solid Alcohol, linoleic acid and carboxymethyl chitosan, the tracer are SPIO nano particle, and the pH of the SPIO tracer is quick Feel drug-loaded liposome to obtain using following quality proportioning: 1~10 part of bulk pharmaceutical chemicals, 1~50 part of phosphatidyl-ethanolamine, cholesterol 1~ 30 parts, 1~30 part of linoleic acid, 0~10 part of carboxymethyl chitosan, 0~10 part of SPIO nano particle.
Wherein, the auxiliary material further includes dioleoylphosphatidylethanolamine, lecithin, hydrogenated soy phosphatidyl choline, phosphatidyl-4 Alcohol, Distearoyl Phosphatidylethanolamine, Pegylation Distearoyl Phosphatidylethanolamine, Cholesteryl hemisuccinate, palm One of acyl homocysteine, oleic acid, vitamin E, metal chelating agent and butylated hydroxyarisol are any several The combination of kind.
Wherein, the tracer is the SPIO nano particle of glucan package, ferric oxide nanometer particle grain Diameter 5nm, partial size is 30nm-35nm after wrapping up glucan, has superparamagnetism, water solubility, biocompatibility.Superparamagnetic iron oxide Nano particle is no radiography agent, under magnetic resonance in such a way that the T2 for reducing tissue is weighted as signal, makes the background of MRI Signal strength reduces, and pathological tissues is enable clearly to image, to carry out target area development, and can be by dynamically measuring different when Between the signal value put calculate targeting time distribution map.
In this way, the sensitive medicament-carried liposome of pH of SPIO tracer of the present invention has, pH sensibility is obvious, tracer effect is good, preparation The advantages of simple process, stable storing, can be used as water-soluble or fat-soluble medicine carrier, destroy in low ph conditions flowering structure and Drug release realizes the targeting of tumor locus, and then increases cancer cell absorption of drugs, reduces poisonous side effect of medicine, and can be real Existing "dead" tracer and dynamic monitoring.Wherein, liposome can be suspension, be also possible to freeze-dried.
The invention also discloses a kind of preparation methods of the sensitive medicament-carried liposome of pH of SPIO tracer, comprising the following steps:
S1: it takes 1~30 part of 1~50 part of phosphatidyl-ethanolamine, 1~30 part of cholesterol and linoleic acid in flask, chlorine is added It is imitative to be dissolved, 1~10 part of water soluble drug solution is then added and carries out ultrasound, until forming uniform w/o type emulsion；
S2: flask is connect with Rotary Evaporators, is performed under reduced pressure evaporation, forms gel state；Into flask The PBS buffer solution that 1~10 part of pH is 7.4 is added, continues evaporation under reduced pressure and forms aqueous suspension；
S3: it is added -80 DEG C, 50 DEG C of aqueous suspension elder generation postposition after 0~10 part of SPIO nano particle Freeze thawing is carried out, is repeated 3 times；Then the Superparamagnetic Iron Oxide nanometer that aqueous suspension is not packed in is removed using supercentrifugal process Grain and water soluble drug, obtain liposome turbid liquor；
S4: the carboxymethyl chitosan solution that 0~10 part of mass percent is 0.3% being added into liposome turbid liquor, into Capable hydration 30min, ultrasound and mistake miillpore filter obtain the sensitive medicament-carried liposome of pH of SPIO tracer.
Wherein, the water soluble drug is Misonidazole, adriamycin, Epi-ADM, pyrrole adriamycin, vincristine, support Moor any one in glycosides, cis-platinum, Nedaplatin, carboplatin, gemcitabine and Hydroxycamptothecin.
It wherein, further include vitamin E as oxidant in step S1.
In conclusion the sensitive medicament-carried liposome of pH of SPIO tracer provided by the present invention has pH sensibility high, super suitable Magnetic good advantage, to realize that tumor-targeting, reduction drug toxicity, "dead" tracer lay the foundation.Invention additionally discloses The preparation method of the sensitive medicament-carried liposome of pH of SPIO tracer can preferably wrap water-soluble or fat-soluble medicine It wraps up in, preparation method is simple, and particle diameter distribution is uniform, is conducive to industrialize.
Detailed description of the invention
Fig. 1 is the cumulative release of Misonidazole pH sensitive liposome Misonidazole under condition of different pH of SPIO tracer Degree.
Fig. 2 be SPIO tracer Misonidazole pH sensitive liposome under condition of different pH Superparamagnetic Iron Oxide nanometer The accumulative releasing degree of grain.
Fig. 3 is the Misonidazole pH sensitive liposome grain size distribution of SPIO tracer.
Fig. 4 is the Misonidazole pH sensitive liposome potential diagram of SPIO tracer.
Fig. 5 is the Misonidazole pH sensitive liposome scanning electron microscope (SEM) photograph of SPIO tracer.
Fig. 6 is the Misonidazole pH sensitive liposome transmission electron microscope picture of SPIO tracer.
Fig. 7 is the Misonidazole pH sensitive liposome magnetization curve of SPIO tracer.
Specific embodiment
Part formulation embodiment is set forth below.
Embodiment 1: a kind of sensitive medicament-carried liposome of pH of SPIO tracer is obtained: Misonidazole using following quality proportioning 2.5 parts, 30 parts of phosphatidyl-ethanolamine, 10 parts of cholesterol, 10 parts of linoleic acid, 0.5 part of carboxymethyl chitosan, Superparamagnetic Iron Oxide 0.5 part of nano particle, 2 parts of vitamin E.The wherein Misonidazole pH sensitive liposome of SPIO tracer rice under condition of different pH The Accumulation dissolution of rope nitre azoles is as shown in Figure of description Fig. 1, and the Misonidazole pH sensitive liposome of SPIO tracer is in different pH Under the conditions of SPIO nano particle accumulative releasing degree as shown in Figure of description Fig. 2, the misso nitre of SPIO tracer Azoles pH sensitive liposome grain size distribution is as shown in Figure of description Fig. 3, the Misonidazole pH sensitive liposome electricity of SPIO tracer Bitmap is as shown in Figure of description Fig. 4, the Misonidazole pH sensitive liposome scanning electron microscope (SEM) photograph such as Figure of description of SPIO tracer Shown in Fig. 5, the Misonidazole pH sensitive liposome transmission electron microscope picture of SPIO tracer is as shown in Figure of description Fig. 6, SPIO tracer Misonidazole pH sensitive liposome magnetization curve as shown in Figure of description Fig. 7.
A kind of pH sensitive liposome of SPIO tracer and preparation method thereof, comprising the following steps:
S1: take 30 parts of phosphatidyl-ethanolamine, 10 parts of cholesterol and 10 parts of linoleic acid molten in chloroform progress in flask, is added Solution carries out ultrasound 2min after the aqueous solution containing 2.5 parts of Misonidazole is then added, until forming uniform w/o type emulsion；
S2: flask is connect with Rotary Evaporators, is performed under reduced pressure evaporation, forms gel state；Into flask The PBS buffer solution that 8ml pH is 7.4 is added, continues evaporation under reduced pressure and forms aqueous suspension；
S3: it is added -80 DEG C, the 50 DEG C progress freeze thawing of aqueous suspension elder generation postposition after 0.5 part of SPIO, is repeated 3 times；Then, The Misonidazole and SPIO that aqueous suspension is not packed in are removed using supercentrifugal process, obtains liposome turbid liquor；
S4: the carboxymethyl chitosan solution that 0.5 part of mass percent is 0.3% is added into liposome, is hydrated 30min, ultrasound and miillpore filter excessively obtain the pH sensitive liposome of SPIO tracer.
It further, further include the vitamin E of certain mass proportion as antioxidant in step S1.
Embodiment two:
A kind of pH sensitive liposome of SPIO tracer and preparation method thereof, comprising the following steps:
A1: taking 10 parts of 5 parts of taxol, 30 parts of phosphatidyl-ethanolamine, 10 parts of cholesterol and linoleic acid in flask, then plus Enter chloroform to be dissolved, flask connect with Rotary Evaporators, and volatilizes chloroform under 37 DEG C, 100r/min, reduced pressure, Film is formed in beaker inner wall；
A2: the aqueous solution for containing 0.5 part of SPIO being added into beaker, and Rotary Evaporators are protected from light in 50 ± 1 DEG C, 100r/min Under the conditions of aquation 60min obtain liposome solutions；
A3: the taxol and SPIO that liposome is not packed in are removed using supercentrifugal process, obtains liposome turbid liquor；
A4: the carboxymethyl chitosan solution that 0.5 part of mass percent is 0.3% is added into liposome, is hydrated 30min obtains the pH sensitive liposome of SPIO tracer.
It further, further include the vitamin E of certain mass proportion as antioxidant in step A1.
Embodiment three:
A kind of pH sensitive liposome of SPIO tracer and preparation method thereof, comprising the following steps:
B1: it takes 10 parts of 30 parts of phosphatidyl-ethanolamine, 10 parts of cholesterol and linoleic acid in flask, it is mixed that dimethyl sulfoxide is added Cooperation is A phase, regard pure water, glycerol, 5 parts of cis-platinum and 0.5 part of SPIO mixing as B phase, after A phase and B are mixed, pours into It in blender, is stirred 3 minutes at 55 DEG C, then takes out to be put into mulser and emulsify 30 seconds, be put into cream in high-pressure emulsification agent later Change 4 times；
B2: after product of the step B1 after emulsifying in high-pressure emulsification agent is put into the defoaming of supersonic oscillations machine, pH is added For 7.4 PBS buffer solution, liposome turbid liquor is formed；
B3: the cis-platinum and SPIO that liposome is not packed in are removed using supercentrifugal process, obtains liposome turbid liquor；To lipid Body suspension carries out ultrasound, and crosses miillpore filter and obtain liposome；
B4: the carboxymethyl chitosan solution that 0.5 part of mass percent is 0.3% is added into liposome, is hydrated 30min obtains the pH sensitive liposome of SPIO tracer.
It further, further include the vitamin E of certain mass proportion as antioxidant in step B1.
Example IV:
A kind of pH sensitive liposome of SPIO tracer and preparation method thereof, comprising the following steps:
C1: it takes 10 parts of 5 parts of adriamycin, 30 parts of phosphatidyl-ethanolamine, 10 parts of cholesterol and linoleic acid in flask, uncle is added Butanol is dissolved, and 200 parts of aqueous trehalose solutions are then added, and the carboxymethyl chitosan that 0.5 part of mass percent is 0.3% is molten Liquid, 0.5 part of SPIO solution, and be sub-packed in 100ml sterilizing cillin bottle after filtering with microporous membrane, it is placed in cold in freeze drier Be lyophilized it is dry, sealing, obtain the pH sensitivity proliposome of SPIO tracer；
C2: before use, 1 bottle of the pH sensitivity proliposome of SPIO tracer is taken, physiological saline 100ml is added, is shaken in 37 DEG C Bed shakes 30min, obtains the pH sensitive liposome of SPIO tracer.
It further, further include the vitamin E of certain mass proportion as antioxidant in step C1.
When clinical use, injection or freeze-dried can be used.The pH of SPIO tracer provided by the present invention is sensitive medicament-carried Liposome has the advantages that pH sensibility is high, superparamagnetism is good, to realize tumor-targeting, reducing drug toxicity, "dead" Tracer lays the foundation.The invention also discloses the preparation methods of the sensitive medicament-carried liposome of the pH of SPIO tracer, can be preferably right Water-soluble or fat-soluble medicine is wrapped up, and preparation method is simple, and particle diameter distribution is uniform, is conducive to industrialize.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations；Although Present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that；It still may be used To modify to technical solution documented by previous embodiment, or some or all of the technical features are equal Replacement；And these are modified or replaceed, the model for technical solution of the embodiment of the present invention that it does not separate the essence of the corresponding technical solution It encloses, should all cover within the scope of the claims and the description of the invention.

Claims (3)

1. a kind of sensitive medicament-carried liposome of pH of SPIO tracer, which is characterized in that including Misonidazole, auxiliary material and tracer, institute Stating auxiliary material includes phosphatidyl-ethanolamine, cholesterol, linoleic acid and carboxymethyl chitosan, and the tracer is Superparamagnetic Iron Oxide The sensitive medicament-carried liposome of pH of nano particle, the SPIO tracer is obtained using following quality proportioning: 1~10 part of Misonidazole, 1~50 part of phosphatidyl-ethanolamine, 1~30 part of cholesterol, 1~30 part of linoleic acid, 0.5~10 part of carboxymethyl chitosan, superparamagnetic 0.5~10 part of ferric oxide nanometer particle of property.
2. a kind of preparation method of the sensitive medicament-carried liposome of pH of SPIO tracer, which comprises the following steps:
S1: take 1~30 part of 1~50 part of phosphatidyl-ethanolamine, 1~30 part of cholesterol and linoleic acid in flask, be added chloroform into Then row dissolution is added 1~10 part of Misonidazole and carries out ultrasound, until forming uniform w/o type emulsion；
S2: flask is connect with Rotary Evaporators, is performed under reduced pressure evaporation, forms gel state；1 is added into flask The PBS buffer solution that~10 parts of pH are 7.4 continues evaporation under reduced pressure and forms aqueous suspension；
S3: be added after 0.5~10 part of SPIO nano particle by -80 DEG C of aqueous suspension elder generation postposition, 50 DEG C into Row freeze thawing, is repeated 3 times；Then the SPIO nano particle that aqueous suspension is not packed in is removed using supercentrifugal process And water soluble drug, obtain liposome turbid liquor；
S4: the carboxymethyl chitosan solution that 0.5~10 part of mass percent is 0.3% is added into liposome turbid liquor, carries out It is hydrated 30min, ultrasonic and miillpore filter excessively obtains the sensitive medicament-carried liposome of pH of SPIO tracer.
3. a kind of preparation method of the sensitive medicament-carried liposome of pH of SPIO tracer as claimed in claim 2, which is characterized in that step It further include vitamin E as oxidant in rapid S1.
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