CN105641704B - A kind of production bubble polylactic-co-glycolic acid effervesce drug and preparation method and application - Google Patents
A kind of production bubble polylactic-co-glycolic acid effervesce drug and preparation method and application Download PDFInfo
- Publication number
- CN105641704B CN105641704B CN201511022287.9A CN201511022287A CN105641704B CN 105641704 B CN105641704 B CN 105641704B CN 201511022287 A CN201511022287 A CN 201511022287A CN 105641704 B CN105641704 B CN 105641704B
- Authority
- CN
- China
- Prior art keywords
- acid
- effervesce
- glycolic acid
- concentration
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
Abstract
Polylactic-co-glycolic acid effervesce drug is steeped in a kind of production of the present invention, is made of polylactic-co-glycolic acid, effervesce object, chemotherapeutics and organic solvent, the g/mL of a concentration of 0.1g/mL~1.0 of polylactic-co-glycolic acid in organic solvent；Effervesce object is made of organic acid and alkaline matter, the g/mL of a concentration of 0.1g/mL~0.5 in organic solvent of organic acid, the g/mL of a concentration of 0.1g/mL~0.5 of the alkaline matter in organic solvent；A concentration of 1 10mg/mL of the chemotherapeutics in organic solvent.Additionally provide a kind of production bubble polylactic-co-glycolic acid effervesce drug and a kind of preparation method of production bubble polylactic-co-glycolic acid effervesce drug stent material.Under the stimulation of HIFU, effervesce produce anger steeps and enhances ablation effects of the HIFU to tumour in timbering material；The chemotherapeutics of load releases, and assigns the ability of holder chemotherapeutic treatment tumour.
Description
Technical field
The invention belongs to medicinal chemistry arts, are related to a kind of drug for treating tumour, specifically a kind of poly- breast of production bubble
Sour hydroxyacetic acid effervesce drug and preparation method and application.
Background technology
It is well known that cancer has become the huge killer that today's society threatens human life and health.With material science with
The development of nanometer engineering, develop high curative effect, less toxic side effect tumour diagnosis and treatment method, to improving quality of life and the development of the mankind
National economy etc. is of great significance.High intensity focused ultrasound（High-intensity focused ultrasound, HIFU）
Treatment tumour be rising in recent years a kind of tumour it is micro-/non-invasive treatment methods, it using ultrasonic wave have good directionality, wear
The features such as saturating ability is strong, by certain method by focusing ultrasonic wave at tumor targets, and with minimally invasive or Noninvasive side
The mode of method deposits acoustic energy into tissue.High sound intensity energy is almost fully focussed at pathological tissues, and generates moment
High temperature and pressure causes pathological tissues that a large amount of physics, chemical change and necrosis occurs.It is swollen to be used for part from the forties in last century
After tumor treatment, HIFU has become a kind of clinically widely used oncotherapy means.Relative to traditional operative treatment, change
It treats, radiotherapy and other micro- non-invasive therapy means, easy to operate, radiationless, noninvasive, conformal heat possessed by HIFU Treatment tumour
The technical characterstics such as ablation, real-time imaging monitoring have complied with current high curative effect, the demand for development of less toxic side effect treatment tumour, become
The hot spot of medical research circle research.
Currently, clinically mostly using Magnetic resonance imaging（MRI）Or ultrasonic imaging（US）Mediate the lower HIFU for realizing tumour
Ablation.Applicable therapeutic domain also develops to current liver cancer, breast cancer, osteosarcoma and fibroid etc. from initial cancer of pancreas
Kinds of tumors.However, popularizations of the HIFU in clinical cancer therapy application also needs to solve following two major issue.First,
Accurately HIFU Treatment needs to utilize advanced clinical imaging system（Such as US, MRI, Computed tomography（CT）, just
Electron emission computerized tomograph（PET-CT）Deng）Tumor focus is positioned；Secondly, in practical HIFU Treatment, surpass
Energy reduction of the sound wave in communication process makes it be difficult to eliminate Deep Lesions tissue.In view of the above-mentioned problems, high in addition to carrying out
Instrument and equipment upgrading it is outer, researcher starts to develop various HIFU synergist, to realize under smaller ultrasonic power,
Reach satisfied tumour ablation effect.In the treatment, the cavitation effect of HIFU Treatment, which refers to the positive and negative acoustic pressure transformation of HIFU, to produce
It gives birth to powerful cavitation effect and forms a large amount of bubbles.These bubbles can absorb acoustic energy, and vibrate, expand, rupture, and increase burnt
The heat of point tissue, the damage that tumor tissues are caused with bigger.Studies have shown that micro-nano biomaterial can change the sound of tissue
Environment is learned, increases deposition of the ultrasonic energy in pathological tissues, increases the ablation effect of tumour.
Based on the fact that from the angle of nanotechnology, researchers are by bubble or can generate the nanometer of bubble
The permeability that material is actively transported or enhanced using tumor tissues position blood vessel by the effect of surface targeting ligand（That is EPR is imitated
It answers）Passively it is enriched in tumor tissues.Under the stimulation of HIFU, these bubbles occur complex reaction with HIFU and increase HIFU pairs
The ablation effect of tumor tissues.For example, sound Novi（That is injection sulfur hexafluoride microvesicle）It is that a kind of ultrasound being commercialized is made
Shadow agent.Studies have shown that other than as clinical ultrasound contrast agent, when sound Novi can also reduce HIFU Treatment fibroid
Ultrasonic energy improves the effect of HIFU ablation fibroids.For another example, using inorganic material mesoporous silicon oxide as carrier, pass through
Priming by vacuum Thermo-sensitive perflenapent, Shi et al. have devised out the HIFU synergist based on mesoporous silicon oxide, real in vitro
The ablation effect tested and enhance HIFU in zoopery to tumour.Zheng et al. is real by loading fluorocarbons with phosphatide
Ultrasonic imaging and the HIFU synergy of tumour are showed.However, the inorganic material largely injected all is captured by organs such as livers；This
Outside, the grain size of organic microvesicle is larger（Micron level）, it is difficult to by the vascular endothelial gap of tumour, lead to bubble within the tumor
Enriching quantity is seldom.Moreover, temperature sensitive type perfluorochemical thermal stability is poor, bubble is easily broken during the storage of material, into
The HIFU clinical applications of one step receive prodigious restriction.
Gas-producing disintegrant is typically organic acid（Such as citric acid）The mixture formed with sodium carbonate, sodium bicarbonate；Effervesce collapses
After being put into water violent metathesis reaction can occur for solution agent, generate great amount of carbon dioxide.The generation of this bubble is a kind of instantaneous
Change procedure, HIFU Treatment can not be directly applied to.Based on above-mentioned technical problem, it is contemplated that certain technology hand can be passed through
Section, is bound by tumor locus, and control the generation speed of bubble, to be applied to HIFU Treatment by gas-producing disintegrant.Polylactic acid hydroxyl
Acetic acid copolymer（Poly (lactide-co-glycolide), PLGA）Be one kind by U.S. Food and Drug Administration
(FDA) approval uses, the high molecular polymer with good biocompatibility and biological degradability.As a kind of excellent life
Object medical material, PLGA have been widely used in implantable material and tissue engineering rack material field.PLGA has one
A significant physical characteristic, i.e. strong-hydrophobicity.Up to now, still without document report by controlling the disintegration of effervesce, melting, profit
Increase ablation effects of the HIFU to tumour with its bubble.
Invention content
For above-mentioned technical problem in the prior art, the present invention provides a kind of productions to steep polylactic-co-glycolic acid effervesce medicine
Object and preparation method and application, this production bubble polylactic-co-glycolic acid effervesce drug and preparation method and application solve
The ineffective technical problem of high-strength focusing ultrasonic therapy tumour is used in the prior art.
The present invention provides a kind of production steep polylactic-co-glycolic acid effervesce drug, by poly lactic-co-glycolic acid, effervesce object,
Chemotherapeutics and organic solvent composition, the organic solvent are in 1-Methyl-2-Pyrrolidone or n,N-Dimethylformamide
It is any；The g/mL of a concentration of 0.1g/mL~1.0 of the poly lactic-co-glycolic acid in organic solvent；The bubble
It rises object to be made of organic acid and alkaline matter, the g/ of a concentration of 0.1g/mL~0.5 in organic solvent of the organic acid
ML, the g/mL of a concentration of 0.1g/mL~0.5 of the alkaline matter in organic solvent, the organic acid are lemon
Any one of acid, tartaric acid, citric acid, tartaric acid or glutamic acid；The alkaline matter is sodium carbonate or bicarbonate
Any one of sodium；The chemotherapeutics is any one of doxorubicin hydrochloride, taxol, camptothecine or Combretastatin,
A concentration of 1-10mg/mL of the concentration of the chemotherapeutics in organic solvent.
The present invention provides a kind of preparation methods of production bubble polylactic-co-glycolic acid effervesce drug, include the following steps：
1) poly lactic-co-glycolic acid is dissolved in organic solvent, stirring makes poly lactic-co-glycolic acid be completely dissolved, institute
The g/mL of a concentration of 0.1g/mL~1.0 of the poly lactic-co-glycolic acid stated in organic solvent；The organic solvent is 1- first
Base-any one of 2-Pyrrolidone or N,N-dimethylformamide；
2) effervesce object and chemotherapeutics under stiring, are dispersed in step（1）The poly lactic-co-glycolic acid of gained is molten
In liquid, poly lactic-co-glycolic acid/effervesce/chemotherapeutics solution is obtained；The effervesce object is made of organic acid and alkaline matter,
After dispersion, the g/mL of a concentration of 0.1g/mL~0.5 of the organic acid, a concentration of 0.1g/mL of the alkaline matter~
0.5 g/mL, the organic acid are any one of citric acid, tartaric acid, citric acid, tartaric acid or glutamic acid；Described
Alkaline matter is any one of sodium carbonate or sodium bicarbonate；The chemotherapeutics is doxorubicin hydrochloride, taxol, happiness
Set any one of alkali or Combretastatin, after dispersion, a concentration of 1-10mg/mL of the chemotherapeutics.
Further, the molecular weight of the poly lactic-co-glycolic acid is 1000~10000 dalton, wherein monomer breast
The molar ratio of acid and hydroxyacetic acid is 10:90~90:10.
Further, step（1）Described in stirring be magnetic agitation, rate be 50-200 r/min, the time 30
- 12 hours minutes.
The present invention also provides a kind of preparation methods of production bubble polylactic-co-glycolic acid effervesce drug stent material, including such as
Lower step：
1) poly lactic-co-glycolic acid is dissolved in organic solvent, stirring makes PLGA be completely dissolved, the polylactic acid-
The g/mL of a concentration of 0.1g/mL~1.0 of hydroxyacetic acid in organic solvent；The organic solvent is 1- methyl -2- pyrrolidines
Any one of ketone or N,N-dimethylformamide；
2) effervesce object and chemotherapeutics under stiring, are dispersed in step（1）In the PLGA solution of gained, breast must be gathered
Acid-hydroxyacetic acid/effervesce/chemotherapeutics solution；The effervesce object is made of organic acid and alkaline matter, described after dispersion
Organic acid the g/mL of a concentration of 0.1g/mL~0.5, the g/mL of a concentration of 0.1g/mL~0.5 of the sodium bicarbonate, institute
The organic acid stated is any one of citric acid, tartaric acid, citric acid, tartaric acid or glutamic acid；The alkaline matter is carbon
Any one of sour sodium or sodium bicarbonate；The chemotherapeutics is doxorubicin hydrochloride, taxol, camptothecine or Kang Pu
Any one of Rui Ting, after dispersion, a concentration of 1-10mg/mL of the chemotherapeutics；
3) poly lactic-co-glycolic acid/effervesce/chemotherapeutics solution is added to the water, the polylactic acid-glycolic base second
The volume ratio of acid/effervesce/chemotherapeutics solution and water is 1:10 ~ 30, form production bubble polylactic-co-glycolic acid effervesce drug stent
Material.
The present invention also provides a kind of above-mentioned production bubble polylactic-co-glycolic acid effervesce drugs to prepare tumor
In application.
The present invention also provides by method obtain a kind of production steep polylactic-co-glycolic acid effervesce drug stent material
Application in preparing tumor.
Gas-producing disintegrant, PLGA and antitumor drug are dissolved in nmp solvent by the present invention, obtain gas-producing disintegrant, PLGA
With chemotherapeutics dispersing liquid.In injection gained dispersing liquid to tumour, after being contacted with hydrone in tumour, PLGA is because hydrophobic
And roll up, gas-producing disintegrant and chemotherapeutics are tied to and are formed by PLGA holders, form PLGA/ effervesces（PT）/ drug
Holder.When no HIFU is stimulated, hydrophobic PLGA prevents the contact of gas-producing disintegrant and drug with hydrone, thus bubble-free
It generates, drug release is slow；Under HIFU stimulations, PLGA molecular gaps instantaneously increase, hydrone and gas-producing disintegrant and drug
Contact generates bubble；The drug being bound by holder can be also released.The HIFU that the bubble of generation can enhance tumour is controlled
Therapeutic effect, and the drug discharged can kill tumour.Therefore, which has both the HIFU synergistic effects and chemotherapeutic of bubble
The effect of chemotherapeutic treatment tumour of object；And bubble stability is high, bubble and utilization ratio of drug are high, avoids normal tissue and dirty
The damage of device effectively compensates for intravenous injection microvesicle or produces the deficiency of foam material and chemotherapeutics, there is important clinic to turn
Change meaning.
It is experimentally confirmed injection PLGA/Dox and applies the HIFU groups of equality strength and time, injects PLGA/PT and apply
Add the HIFU groups of equality strength and time, the tumour growth of HIFU groups injecting PLGA and apply equality strength and time by
Inhibit, but degree is relatively low, inhibition sequence：PLGA/Dox+HIFU ＞ PLGA/PT+HIFU ＞ PLGA+HIFU ＞ PLGA/Dox ＞ couple
According to group.This is the experimental results showed that PLGA/PT/ drug stents can enhance the effect of HIFU ablations, realization HIUF treatments and change
Treat combination therapy.
The present invention is compared with prior art, and technological progress is significant.Present invention process is simple, gained drug and holder
With good blood compatibility and biocompatibility, the chemotherapeutic treatment to tumour may be implemented, and enhance HIFU to tumour
Ablation effect has broad application prospects in fields such as oncotherapies.And PLGA used and gas-producing disintegrant are at low cost, medicine
Object utilization rate is high, and raw material is easy to get.
Description of the drawings
Fig. 1,（a）PLGA/PT/ chemotherapeutics holder FESEM pictures（Gas-producing disintegrant：Citric acid+sodium bicarbonate；Chemotherapy
Drug：Dox）；（b）PLGA/PT（It is left）And PLGA/PT/Dox（It is right）The digital photograph of dispersion, solvent NMP；（c）Standard
PLGA/PT/Dox in 1 mL syringes；（d）The PLGA/PT/Dox of 1 mL syringe needle points of standard is hung in air；（e）
The photo of gas-producing disintegrant vigorous reaction in distilled water；（f）PLGA/PT/Dox forms holder in distilled water.
Before Fig. 2, HIFU stimulation（a）PLGA、（c）PLGA/PT/Dox and post-stimulatory（b）PLGA、（d）PLGA/PT/
Dox photos；（e）The DOX release profiles of PLGA/PT/Dox holders at different conditions.
Gross tumor volume versus time curve after Fig. 3, distinct methods treatment.
Fig. 4,（a）The changes of weight of lotus knurl rabbit after treatment；（b）-（d）The tumour photo of different groups after treating 1 week：（b）It is right
According to group,（c）PLGA/PT+HIFU and（d）PLGA/PT/Dox+HIFU.
Fig. 5, PLGA/PT/Dox holder（a）Hemolytic experiment and（b）Clotting assay result；（c、d）Routine analysis of blood knot
Fruit；（e）H＆E coloration results in each main organs, 30 μ LPLGA/PT/Dox of experimental rabbit intratumor injection, and assign HIFU Treatment
（180W, stimulation time 400ms are spaced 200ms, stimulation number 6 times）, nude mice, photo amplification factor are put to death within the 28th day in injection
For 100 ×.
Specific implementation mode
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, people in the art
Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Range.
Embodiment 1
Weigh 1 g PLGA（Molecular weight is 10000 dalton, LA:GA=1：1, it is purchased from the limited public affairs of Jinan Mount Tai handle of the Big Dipper biotechnology
Department）, mixed with 2 mLNMP, stir 12 hours at room temperature, obtain clear transparent solutions.0.1g citric acids and 0.1g sodium bicarbonates are taken,
It is uniformly mixed with above-mentioned PLGA solution, at room temperature ultrasonic disperse（Output power is 500W）0.5 hour, make citric acid and bicarbonate
Sodium is homogeneously dispersed in above-mentioned PLGA solution.Weigh 5mgDox（Purchased from Beijing Hua Feng drugmakers）, ultrasonic disperse at room temperature
In above-mentioned PLGA/PT dispersions（Output power is 500W）0.5 hour, obtain PLGA/PT/Dox.Take 50 μ L PLGA/PT/
Dox solution, it is rapid to inject in water, to get PLGA/PT/Dox holders after the complete phase transformation of solution.PLGA, PLGA/PT and PLGA/
The preparation method of Dox holders is same as above.
It will be seen from figure 1 that since PLGA has strong-hydrophobicity, after PLGA/PT/Dox is contacted with water, meeting fast exchange goes out
" solid-liquid " phase transformation occurs for solvent, forms PLGA/PT/Dox porous block timbering materials.Gas-producing disintegrant and Dox can be equal
It is scattered in evenly in PLGA solution（Fig. 1（b））, the PLGA/PT/Dox solution of formation is with good syringeability（Fig. 1（c、
d））.Gas-producing disintegrant meets meeting vigorous reaction after water, and quick release goes out CO2Bubble；And it is wrapped in the chance of the gas-producing disintegrant in PLGA
It will not occur significantly to be disintegrated after water, melt, illustrate that PLGA can control the decomposition of gas-producing disintegrant well, increase for its HIFU
Effect is with laying a good foundation.
Embodiment 2
PLGA and PLGA/PT/Dox in 0.5mL embodiments 1 is taken respectively, is injected in the cryopreservation tube for filling distilled water.Wait for phase
After the completion of change, this cryopreservation tube is placed in 37 DEG C of shaking tables and is incubated.In each predetermined point of time, the distillation that 1 mL contains DOX is drawn
Water, and the corresponding fresh buffers of 1 mL are added.The concentration of the DOX released is determined by standard curve, calculates DOX not
With the accumulative total volume at time point, release conditions of the analysis PLGA/PT/Dox holders to DOX.In order to study HIFU to bubble
The influence of generation speed and drug releasing rate use HIFU respectively after being incubated 5min（180W, stimulation time 400ms,
Every 200ms, stimulation number 6 times）PLGA and PLGA/PT/Dox holders are stimulated, bubble and drug release situation are observed, as a result as schemed
Shown in 2.Before and after HIFU stimulations, the equal bubble-free of PLGA holders generates, and HIFU stimulation PLGA/PT/Dox holders can then generate it is bright
Aobvious bubble.In addition, after HIFU stimulations, the rate of release of Dox is obviously accelerated.This is because when no HIFU is stimulated, it is hydrophobic
PLGA prevents the contact of gas-producing disintegrant and drug with hydrone, thus bubble-free generates, and drug release is slow；And in HIFU
Under stimulation, PLGA molecular gaps instantaneously increase, and hydrone and gas-producing disintegrant and medicament contact generate bubble and discharge drug.
Embodiment 3
Take the new zealand white rabbit of 18 lotus VX2 tumours（Diameter of tumor is about 1.5-2.0cm）, stochastic averagina is divided into 6 groups.
1. 30 μ L physiological saline is injected respectively（Blank control group）；②30μL PLGA/Dox；3. 30 μ L PLGA, and it is aided with HIFU thorns
Swash；4. 30 μ L PLGA/PT, and it is aided with HIFU stimulations；5. 30 μ L PLGA/Dox, and it is aided with HIFU stimulations；⑥30μL PLGA/
PT/Dox, and it is aided with HIFU stimulations（180W, stimulation time 400ms are spaced 200ms, stimulation number 6 times）.After treatment, every
Day entry nude mouse tumor volume.After the treatment the 14th day from the 6. group each lab diagram ear vein take blood, test physiochemical indice；
After treatment the 28th day to the 6. group experimental rabbit apply euthanasia, it is each by H＆E staining analysis to each major organs progress histotomy
The pathological change situation of main organs（Separately take consistent Healthy Rabbits as a contrast）.
The experimental results showed that blank control group tumour growth is unaffected, and tumour growth is by different journeys in other 5 groups
Degree ground inhibits（As shown in Figure 3 and Figure 4）.In the case where not applying HIFU stimulations, Dox can be from PLGA/Dox holders slowly
It releases, inhibits the growth of tumour.After applying HIFU stimulations, it is enough that one side HIFU can play repairing for ablated tumor；It is another
Aspect, HIFU can promote the release of drug, chemotherapeutic efficacies of the enhancing Dox to tumour.Importantly, HIFU can promote to steep
Contact of the disintegrant with hydrone is risen, the bubble of generation can absorb the energy of HIFU, and vibrate, expand, rupture, and increase burnt
The heat of point tissue, the damage that tumor tissues are caused with bigger.Therefore, PLGA/PT/Dox
The HIFU synergy treatment to tumour and chemotherapeutic treatment combination therapy may be implemented in holder, and completely inhibits the life of tumour
It is long.As shown in figure 3, the 7th day after the treatment, tumour is completely removed.Over time, cases of complete remission, healing
Tumour is without recurrence.And blank control group or individually apply HIFU, individually apply chemotherapy, can not completely inhibit the growth of tumour.
By being found with healthy nude mice comparative analysis, every physiochemical indice of White Rabbit shows material in normal range (NR) in experimental group
Material has good blood compatibility；The heart, liver, spleen, lung and each organ of kidney had not only shown apparent irritability toxicity, but also nothing
Long-term tissue toxicity；The weight of experimental rabbit does not change significantly during the entire course for the treatment of, it was demonstrated that PLGA/PT/Dox branch
Hypotoxicity of the frame in live body level.
Embodiment 4
5 mL of normal adults whole blood that taking heparin lithium is stablized centrifuges 3 min（Rotating speed is 3000 r/min）, washed with PBS
It washs precipitation 3 times, obtains erythrocyte.With PBS according to 1：100 proportional arrangement adult's erythrocyte suspension, it is standby in 4 DEG C of refrigerators
With.
Weigh 3 parts of certain mass（150 mg or so）Embodiment 1 in the PLGA/PT/Dox holders that prepare.According to holder
Quality：The ratio between human red cell suspension volume is 100 mg:1 mL will be in holder human red cell suspension（Control group is arranged
0.3 mL human red cell suspensions are dissolved in 1.2 mLPBS and 0.3 mL human red cell suspensions are dissolved in 1.2 mL steamings
In distilled water）, and it is incubated 1h under 37 DEG C of environment.Then, the human red cell suspension for impregnating holder is centrifuged into 1 min
（1000 rpm）, supernatant and the light absorption value with 25 type ultraviolet specrophotometers of Lamada test supernatant at 540 nm are taken,
To evaluate the hemolytic of material.The result shows that PLGA/PT/Dox holders will not make erythrocyte that haemolysis occur（See attached drawing 5a）.
Claims (7)
1. polylactic-co-glycolic acid effervesce drug is steeped in a kind of production, it is characterised in that：By poly lactic-co-glycolic acid, effervesce object, chemotherapy
Drug and organic solvent composition, the organic solvent are times in 1-Methyl-2-Pyrrolidone or n,N-Dimethylformamide
It is a kind of；The g/mL of a concentration of 0.1g/mL~1.0 of the poly lactic-co-glycolic acid in organic solvent；The effervesce object
It is made of organic acid and alkaline matter, a concentration of 0.1g/mL~0.5 g/mL of the organic acid in organic solvent are described
Alkaline matter g/mL of a concentration of 0.1g/mL~0.5 in organic solvent, the organic acid is citric acid, winestone
Any one of acid, citric acid, tartaric acid or glutamic acid；The alkaline matter is times in sodium carbonate or sodium bicarbonate
It is a kind of；The chemotherapeutics is any one of doxorubicin hydrochloride, taxol, camptothecine or Combretastatin, the change
Treat a concentration of 1-10mg/mL of drug in organic solvent.
2. a kind of preparation method of production bubble polylactic-co-glycolic acid effervesce drug, it is characterised in that include the following steps：
1）Poly lactic-co-glycolic acid is dissolved in organic solvent, stirring makes poly lactic-co-glycolic acid be completely dissolved, described
The g/mL of a concentration of 0.1g/mL~1.0 of poly lactic-co-glycolic acid in organic solvent；The organic solvent is 1- methyl-
Any one of 2-Pyrrolidone or N,N-dimethylformamide；
2）Under stiring, effervesce object and chemotherapeutics are dispersed in step（1）The poly lactic-co-glycolic acid solution of gained
In, obtain poly lactic-co-glycolic acid/effervesce/chemotherapeutics solution；The effervesce object is made of organic acid and alkaline matter, point
After dissipating, the g/mL of a concentration of 0.1g/mL~0.5 of the organic acid, a concentration of 0.1g/mL~0.5 of the alkaline matter
G/mL, the organic acid are any one of citric acid, tartaric acid, citric acid, tartaric acid or glutamic acid；The alkalinity
Substance is any one of sodium carbonate or sodium bicarbonate；The chemotherapeutics be doxorubicin hydrochloride, taxol, camptothecine,
Or any one of Combretastatin, after dispersion, a concentration of 1-10mg/mL of the chemotherapeutics.
3. a kind of preparation method of production bubble polylactic-co-glycolic acid effervesce drug according to claim 2, it is characterised in that：
The molecular weight of the poly lactic-co-glycolic acid is 1000~10000 dalton, wherein monomer lactic acid and hydroxyacetic acid rub
You are than being 10:90~90:10.
4. a kind of preparation method of production bubble polylactic-co-glycolic acid effervesce drug according to claim 2, it is characterised in that：
Step（1）Described in stirring be magnetic agitation, rate be 50-200 r/min, the time be -12 hours 30 minutes.
5. a kind of preparation method of production bubble polylactic-co-glycolic acid effervesce drug stent material, it is characterised in that including walking as follows
Suddenly：
1）Poly lactic-co-glycolic acid is dissolved in organic solvent, stirring makes poly lactic-co-glycolic acid be completely dissolved, described
The g/mL of a concentration of 0.1g/mL~1.0 of poly lactic-co-glycolic acid in organic solvent；The organic solvent is 1- methyl-
Any one of 2-Pyrrolidone or N,N-dimethylformamide；
2）Under stiring, effervesce object and chemotherapeutics are dispersed in step（1）The poly lactic-co-glycolic acid solution of gained
In, obtain poly lactic-co-glycolic acid/effervesce/chemotherapeutics solution；The effervesce object is made of organic acid and alkaline matter, point
After dissipating, the g/mL of a concentration of 0.1g/mL~0.5 of the organic acid, a concentration of 0.1g/mL~0.5 of the alkaline matter
G/mL, the organic acid are any one of citric acid, tartaric acid, citric acid, tartaric acid or glutamic acid；The alkalinity
Substance is any one of sodium carbonate or sodium bicarbonate；The chemotherapeutics be doxorubicin hydrochloride, taxol, camptothecine,
Or any one of Combretastatin, after dispersion, a concentration of 1-10mg/mL of the chemotherapeutics；
3）Poly lactic-co-glycolic acid/effervesce/chemotherapeutics the solution is added to the water, the poly lactic-co-glycolic acid/bubble
Rise/volume ratio of chemotherapeutics solution and water is 1:10 ~ 30, form production bubble polylactic-co-glycolic acid effervesce drug stent material.
6. a kind of production bubble polylactic-co-glycolic acid effervesce drug that the method described in claim 2 obtains is preparing treatment tumour medicine
Application in object.
It is being made 7. polylactic-co-glycolic acid effervesce drug stent material is steeped in a kind of production obtained by the method described in claim 5
Application in standby tumor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511022287.9A CN105641704B (en) | 2015-12-30 | 2015-12-30 | A kind of production bubble polylactic-co-glycolic acid effervesce drug and preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511022287.9A CN105641704B (en) | 2015-12-30 | 2015-12-30 | A kind of production bubble polylactic-co-glycolic acid effervesce drug and preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105641704A CN105641704A (en) | 2016-06-08 |
| CN105641704B true CN105641704B (en) | 2018-08-28 |
Family
ID=56490768
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201511022287.9A Expired - Fee Related CN105641704B (en) | 2015-12-30 | 2015-12-30 | A kind of production bubble polylactic-co-glycolic acid effervesce drug and preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105641704B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115227833B (en) * | 2022-07-29 | 2023-03-21 | 西安交通大学医学院第一附属医院 | Fluorinated silica drug-loaded nanoparticle and preparation method and application thereof |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101015701A (en) * | 2007-03-12 | 2007-08-15 | 东南大学 | In vivo reaction type micro air bubble ultrasonic contrast medium and its preparing process |
| CN101574530A (en) * | 2009-06-18 | 2009-11-11 | 福建医科大学附属协和医院 | Novel PLGA-PEG-PLGA multipolymer microbubble ultrasound contrast agent and preparation method thereof |
| CN101829326B (en) * | 2009-12-19 | 2012-02-29 | 刘政 | Use of microbubbles with high-intensity cavitation generated by combining ultrasonic in preparation of anti-tumor neovascularization medicaments |
| CN102357250A (en) * | 2011-11-14 | 2012-02-22 | 中国科学院上海硅酸盐研究所 | Magnetic resonance imaging (MRI)-oriented high intensity focused ultrasound (HIFU) synergist and preparation method thereof |
| CN102441179B (en) * | 2011-12-07 | 2013-07-17 | 中国科学院上海硅酸盐研究所 | Silicon dioxide base ultrasonic contrast medium/high intensity focused ultrasound (HIFU) synergist and preparation method thereof |
| CN102824648A (en) * | 2012-09-19 | 2012-12-19 | 重庆医科大学 | Multipurpose contrast agent applied to ultrasonography/magnetic resonance imaging (US/MRI) guidance synergistic high-intensity focused ultrasound ablation and preparation method for multipurpose contrast agent |
| CN104225633A (en) * | 2014-09-05 | 2014-12-24 | 电子科技大学 | Gene and drug co-transported PLGA ultrasonic nano bubbles as well as preparation method and application thereof |
| CN104328160A (en) * | 2014-10-13 | 2015-02-04 | 陕西师范大学 | Method for synergistically killing CT26 cells through Sonovue combined acoustodynamic therapy |
| CN104548095B (en) * | 2015-01-30 | 2017-09-01 | 中国科学院上海硅酸盐研究所 | A kind of PLGA/MoS2Composite medicament stent material and its preparation method and application |
-
2015
- 2015-12-30 CN CN201511022287.9A patent/CN105641704B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN105641704A (en) | 2016-06-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Liu et al. | Water‐responsive hybrid nanoparticles codelivering ICG and DOX effectively treat breast cancer via hyperthermia‐aided DOX functionality and drug penetration | |
| Wang et al. | Injectable 2D MoS2‐integrated drug delivering implant for highly efficient NIR‐triggered synergistic tumor hyperthermia | |
| Zhang et al. | A multifunctional theranostic nanoagent for dual-mode image-guided HIFU/chemo-synergistic cancer therapy | |
| Song et al. | Biomodal tumor‐targeted and redox‐responsive Bi2Se3 hollow nanocubes for MSOT/CT imaging guided synergistic low‐temperature photothermal radiotherapy | |
| Zhu et al. | Responsive hydrogels based on triggered click reactions for liver cancer | |
| CN104548095B (en) | A kind of PLGA/MoS2Composite medicament stent material and its preparation method and application | |
| JP5207247B2 (en) | Radiation or anticancer chemotherapy sensitizer | |
| CN105012272A (en) | Redox sensitive bone-targeting micelle for treating metastatic carcinoma of bone | |
| Sun et al. | Ultrasound microbubbles mediated sonosensitizer and antibody co-delivery for highly efficient synergistic therapy on HER2-positive gastric cancer | |
| CN104758948B (en) | The preparation method and application of multi-functional antineoplastic target diagnoses and treatment medicine based on gold nano star | |
| CN109260472A (en) | Multi-functional temperature sensitive aquagel of one kind and its preparation method and application | |
| CN107998391A (en) | A kind of microwave enhanced sensitivity composite nanometer particle and its preparation method and application | |
| CN107496382A (en) | Composite Nano capsule injection aquagel dual drug-loading slow-releasing system and preparation method | |
| CN103893761B (en) | Tumor cytotoxicity method, system and application of a kind of ultrasonic wave added based on light thermit powder | |
| TWI703990B (en) | Complex with core-shell structure and applications thereof | |
| Qian et al. | Dual-modal imaging and synergistic spinal tumor therapy enabled by hierarchical-structured nanofibers with cascade release and postoperative anti-adhesion | |
| Kang et al. | Multifunctional theranostic nanoparticles for enhanced tumor targeted imaging and synergistic FUS/chemotherapy on murine 4T1 breast cancer cell | |
| CN105641704B (en) | A kind of production bubble polylactic-co-glycolic acid effervesce drug and preparation method and application | |
| CN103751856B (en) | A kind of polylactic acid embolism microsphere with good dispersion | |
| CN107550879A (en) | A kind of preparation method of gelfoam drug bearing microsphere | |
| CN1876177B (en) | Biodegradable material microsphere blood vessel suppository containing liposome cell factor and its preparation and uses | |
| CN104324032B (en) | Antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agent and its production and use | |
| RU2359701C2 (en) | Strengthening agent for therapy with high-intensive focused ultrasound and its application | |
| CN105169420B (en) | A kind of New-type radio-frequency diagnosis and treatment agent and preparation method thereof | |
| CN102670611B (en) | Vascular targeting embolism sustained release agent of triple compound microsphere for antituberculosis drug, preparation method and applications thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180828 Termination date: 20201230 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |