CN107334745A - Multifunctional nano pharmaceutical carrier and taxanes lipid nano particle and preparation method thereof - Google Patents
Multifunctional nano pharmaceutical carrier and taxanes lipid nano particle and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 150000002632 lipids Chemical class 0.000 title claims abstract description 30
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 30
- 229940123237 Taxane Drugs 0.000 title claims abstract description 15
- 239000003937 drug carrier Substances 0.000 title abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 58
- 101000999890 Entamoeba histolytica Non-pathogenic pore-forming peptide Proteins 0.000 claims abstract description 29
- 238000001338 self-assembly Methods 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 239000003960 organic solvent Substances 0.000 claims description 15
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 11
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nanotechnology (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a kind of novel multifunctional nano pharmaceutical carrier (APNPs) based on vitamine C palmitate (AP) and the preparation of taxanes lipid nano particle (X APNPs) and the application of anti-tumor aspect.APNPs does not introduce any auxiliary material in preparation process, relies on physical means using the amphiphilic structures of AP, AP is self-assembly of stable lipid nano particle.Novel and multifunctional APNPs prepared by the present invention, the solubility and stability of slightly solubility taxanes medicine can not only be increased, the bioavilability of medicine is improved, be alternatively arranged as antioxidant and chemotherapeutics, prevent oxidation and the prophylactic treatment tumour of medicine.X APNPs lipid nano particles prepared by the present invention, the toxic side effect of taxanes medicine is not only reduced, add the dissolubility and bioavilability of taxanes medicine, the effect of taxanes medicine X and AP also acts synergistic antitumor.
Description
Technical field
The present invention relates to a kind of multifunctional nano pharmaceutical carrier and taxanes lipid nano particle and preparation method thereof, category doctor
Medicine technical agent formulation art.
Background technology
Taxol (paclitaxel, PTX) is a kind of Fourth Ring two for extracting to obtain from natural plants Taxus bark
Terpenoid, belongs to complicated secondary metabolite, and the unique one kind understood at present can promote microtubule polymerization and
The stable medicine for having polymerize micro-pipe.Tagging shows, taxol is bonded only in the micro-pipe of polymerization, not with it is unpolymerized micro-
Tubulin dimerization precursor reactant.PTX has turned into one of clinical the most frequently used cancer therapy drug, and to breast cancer, the treatment of oophoroma is imitated
Fruit is notable, mainly by with tubulin binding, assemble a large amount of tubulins, influence in mitosis spindle and disintegrate, retardance
The mitosis of tumour cell is so as to realizing antitumor action.Due to PTX poorly water-soluble, it is clinical at present mainly using with
Absolute ethyl alcohol and the PTX ejection preparations that Emulsifier EL-60 (1: 1) is solvent.But Emulsifier EL-60 easily causes low blood
The adverse reaction such as pressure and allergic reaction, many difficulties are brought to clinical practice.
To solve to reduce toxic side effects of the PTX in clinical practice, PTX bioavilability and therapeutic effect are improved.State
Inside and outside researcher is directed to the research of taxol drug formulation and administering mode one after another, new administration nano-drug administration system progressively by
Everybody concern.It is to contain purple by pharmaceutical carrier of lecithin that power prepared by Nanjing Lvye Sike Pharma Co., Ltd. of China, which flutters element,
Paclitaxel liposome made of China fir alcohol, it effectively reduces the toxic side effect of Taxol injection preparation while saved original anti-
Tumor promotion, said preparation list for 2004 in China.Abraxane prepared by America Biological Science Co., Ltd is paclitaxel nano blood
Albumin suspension, effectively solve the problems, such as that PTX solubility is low, and 2008 ratify to list in China.In addition, also have
Just under study for action, these nanometer formulations all solve PTX poorly water-solubles to new PTX nanometer formulations to a certain extent, bad
React more, the problems such as bioavilability is low.But PTX nanometer formulation less stables prepared at present, using preceding needing machinery
Vibration makes it be evenly distributed, and this brings all multi-risk Systems to clinical practice.In addition, in the research preparation process of nanometer formulation, no
Evitable can introduce has toxic side effect auxiliary material to human body, or auxiliary material degradation in vivo produces toxicant etc., also the same time limit
PTX clinical practice has been made, therefore, has reduced the nothing of the application of auxiliary material or searching good biocompatibility of trying one's best in PTX nanometer formulations
Malicious auxiliary material replaces the poisonous auxiliary material of poor biocompatibility, prepares metastable nanometer formulation as the research of PTX nanometer formulations
It is crucial.In addition, the occurrence and development of tumour are a processes complicated and changeable, the traditional treatment of " gene, a medicine, a disease "
Pattern has been unable to reach the demand of comprehensive antineoplaston, and the drug combination therapeutic modality of a disease Mutiple Targets drug turns into multiple
The important method of miscellaneous disease treatment.Therefore, drug combination, which turns into, will improve one of PTX effective means of clinical efficacy.
Ascorbic acid aliphatic ester (fatsoluble vitamin C) is vitamin C be esterified to obtain with aliphatic acid it is a kind of fat-soluble good
Good vitamin C derivatives.Wherein, ascorbyl palmitate (ascorbic palmitate, AP) is with palmitic acid and dimension
Raw plain C is raw material, is obtained by esterification, its high degree improves the fat-soluble of water-soluble vitamin c, and adds
Vitamin C is to air, the stability of illumination and temperature.At present, AP is widely used in eating mainly as antioxidant and preservative
Among thing, medicine and cosmetics.In addition, early in 1999, the research such as Kageyama finds that AP can effectively suppress tumour cell
DNA synthesis is so as to suppressing the development of tumour.And in AP ascorbic hydrophilic structure and palmitic acid lipophilic moieties, structure
Into special amphiphilic structure, possess the potential for being self-assembly of lipid nano particle, but at present document report on AP
The preparation of micella or lipid nano particle, formed after appropriate transformation or modification have been carried out on AP architecture basics, lacked
The weary research that micella or lipid nano particle are self-assembly of to AP, and the AP nanoparticles or micella after modifying can introduce it is poisonous, no
Degradable auxiliary material or auxiliary material degraded produce noxious material.Therefore, how to make to form collection pharmaceutical carrier by material self assembles of AP
Then function and anti-tumor function load antineoplastic PTX and realize that AP cooperates with PTX and resist in the multi-functional lipid nanometer of one
Tumor efficiency turns into the difficult point of the present invention.
The content of the invention
The present invention mainly using AP be bulk drug self assembly prepare it is a kind of integrate load medicine function and anti-tumor function it is more
Function lipid nano particle.
Open one kind contains a line taxanes medicine X simultaneously, realizes synergistic antitumor.
An object of the present invention is to form a kind of low auxiliary material in a manner of AP is the self assembly that bulk drug passes through drug molecule
Multifunctional nano pharmaceutical carrier, i.e.,：This pharmaceutical carrier acts not only as the tool for transmitting of various hydrophobic drugs, and medicine
(AP) has antitumor, the multiple functions such as anti-oxidant to carrier in itself.
The invention another object is that using nano medicament carrying system, increase PTX solubility and stability, reduce PTX's
Adverse reaction, improve PTX bioavilability and oncotherapy curative effect.One kind is provided for clinical cancer therapy to prepare simply, and
Stabilization is high, safely and effectively PTX nano injection formulations.
Multifunctional nano pharmaceutical carrier of the present invention based on AP, mainly injects-ultrasonication-rotation by solvent
It is prepared by the method for evaporation.Specific embodiment is as follows：
A weighs the AP of recipe quantity；
AP is dissolved in absolute ethyl alcohol by b, is re-introduced into a certain amount of purified water；
B liquid is immediately placed on water bath sonicator under cell Ultrasonic Cell Disruptor by c；
C liquid is carried out decompression rotary evaporation by d, is removed organic solvent, that is, is obtained APNPs.
As a kind of preparation method of preferable novel multifunctional nano pharmaceutical carrier, it is characterised in that including following step
Suddenly：
A weighs the AP of recipe quantity；
AP is dissolved in 1 volume absolute ethyl alcohol by b, is re-introduced into 0~50 DEG C of purified water of 5~100 volumes；
B liquid is immediately placed on 0~50 DEG C of water bath sonicator 5-30min under cell Ultrasonic Cell Disruptor by c；
C liquid is carried out decompression rotary evaporation by d, removes organic solvent, revolving temperature is 25~50 DEG C, that is, obtains APNPs.
Another mesh of the present invention is to prepare the PTX-APNPs with synergistic antitumor effect, preferably to go out optimal PTX-
APNPs formulation and technologies, the present invention, to the ultrasonic temperature in preparation process, surpass using PTX-APNPs particle diameter and envelop rate as index
Sound time and medicine feeding ratio have carried out single factor test examination.Concrete operations are as follows：
A weighs 5~100mg of AP, 1~100mg of PTX
AP and PTX co-dissolves in 1 volume absolute ethyl alcohol, are re-introduced into 0~50 DEG C of purified water of 5~100 volumes by b
In.
C is by b liquid immediately as 0~50 DEG C of water bath sonicator 5-30min under cell Ultrasonic Cell Disruptor.
C liquid is carried out decompression rotary evaporation by d, removes organic solvent, revolving temperature is 25~50 DEG C, that is, obtains PTX-
APNPs。
As preferable technical scheme, the APNPs in the present invention can also be prepared as the carrier of other taxanes medicines
X-APNPs lipid nano particles.
One of final purpose of the present invention is exactly to prepare APNPs multifunctional nano grains, the transmission system as fat-soluble medicine
System, improve the solubility and bioavilability of fat-soluble medicine.Meanwhile antioxidant or chemotherapeutics can be used as to improve and entirely give
The effect of medicine system.
Another have a definite purpose of the present invention is to prepare stable, high encapsulation rate, while has what synergistic antitumor acted on
X-APNPs, solve it is unstable existing for Taxol injection preparation used in clinic at present, in-convenience in use, adverse reaction is more, biology
The problem of availability is low.
The invention discloses pharmaceutically acceptable nanometer formulation, said preparation made from a kind of ascorbyl palmitate to bear
The medicine of load is to be selected from fat-soluble stronger medicine, and further, the preparation is selected from freeze drying powder injection.
Benefit of the present invention
Novel and multifunctional medicament carrier system APNPs prepared by the present invention, it can both make the transmission platform of insoluble drug,
The solubility, stability and bioavilability of contained insoluble drug are improved, reduces adverse reaction；Also can be used as antioxidant or
Chemotherapeutics, protect contained medicine not oxidized or play synergistic antitumor effect with contained chemotherapeutics.
X-APNPs prepared by the present invention, for particle diameter between 200-300nm, most of particle concentrates on 294nm or so, puts down
Equal zeta current potentials are -26.1mV, relatively stable, can be stabilized under 4 DEG C of environment more than 7 days.Lipid nano particle increase
X hydrophilies and stability, reduce adverse reaction, significantly improve the bioavilability of medicine.
Brief description of the drawings
Fig. 1 a are a kind of preferably APNPs transmission electron microscope (TEM) figure.
Fig. 1 b are a kind of preferably PTX-APNPs transmission electron microscope (TEM) figures.
A kind of preferably PTX-APNPs differential scanning calorimetry (DSC) figures of Fig. 2.
A kind of preferably PTX-APNPs release in vitro pictures of Fig. 3.
A kind of preferably PTX-APNPs preparation stabilities of Fig. 4 are investigated.
A kind of preferably PTX-APNPs vitro cytotoxicity results of Fig. 5.
A kind of preferably PTX-APNPs of Fig. 6 a suppress the direct result of one-tenth knurl ability in tumour cell body.
A kind of preferably PTX-APNPs of Fig. 6 b suppress in tumour cell body into knurl size result.
A kind of preferably PTX-APNPs tail veins administration tumor suppression pharmacodynamic results of Fig. 7.
Embodiment
Following examples only being expanded on further and illustrate to the present invention, without limiting the scope of the present invention.Below
The present invention is further elaborated on reference to embodiment, it should be appreciated to those skilled in the art that the present invention is not limited to these
Embodiment and the preparation method used.Moreover, those skilled in the art can be carried out according to description of the invention to the present invention
Equivalent substitution, combination, improvement or modification, but these are intended to be included in the scope of the present invention.
Embodiment 1
APNPs preparation：Weigh 5mg AP to be placed in 1.5ml centrifuge tubes, add 0.2ml ethanol solution, fully
Dissolving, obtains drug containing organic phase (25mg/ml)；Take 5ml purified waters to be placed in glass cillin bottle, be preheated to 40 DEG C and be used as aqueous phase；
Organic phase is injected into aqueous phase, ultrasonication is carried out using cell Ultrasonic Cell Disruptor immediately, ultrasonic power 50W, super 5s stop
5s, solution in cillin bottle, is then transferred in 100ml round-bottomed flasks, 40 DEG C of water-bath lucifuge vacuum rotary steams remove by ultrasonic 10min altogether
Organic solvent is removed, that is, obtains APNPs solution.The solution appearance is milky, transparent and general opalescence, and laser irradiation has dindar
Phenomenon.Average grain diameter is 280nm, and average zeta current potentials are -48.3mV.
Embodiment 2
APNPs preparation：Weigh 10mg AP to be placed in 5ml centrifuge tubes, add 1ml ethanol solution, it is fully molten
Solution, obtains drug containing organic phase (10mg/ml)；Take 5ml purified waters to be placed in glass cillin bottle, be preheated to 40 DEG C and be used as aqueous phase；Will
Organic phase is injected into aqueous phase, carries out ultrasonication using cell Ultrasonic Cell Disruptor immediately, and ultrasonic power 50W, super 5s stop 5s,
Solution in cillin bottle, is then transferred in 100ml round-bottomed flasks by ultrasonic 10min altogether, and 40 DEG C of water-bath lucifuge vacuum rotary steams remove
Organic solvent, that is, obtain APNPs solution.The solution appearance is milky, transparent and general opalescence, and laser irradiation has dindar to show
As.Average grain diameter is 312nm, and average zeta current potentials are -45mV.
Embodiment 3
APNPs preparation：Weigh 50mg AP to be placed in 5ml centrifuge tubes, add 2ml ethanol solution, it is fully molten
Solution, obtains drug containing organic phase (25mg/ml)；Take 100ml purified waters to be placed in glass cillin bottle, be preheated to 40 DEG C and be used as aqueous phase；
Organic phase is injected into aqueous phase, ultrasonication is carried out using cell Ultrasonic Cell Disruptor immediately, ultrasonic power 50W, super 5s stop
5s, solution in cillin bottle, is then transferred in 250ml round-bottomed flasks, 40 DEG C of water-bath lucifuge vacuum rotary steams remove by ultrasonic 20min altogether
Organic solvent is removed, that is, obtains APNPs solution.The solution appearance is milky, transparent and general opalescence, and laser irradiation has dindar
Phenomenon.Average grain diameter is 303nm, and average zeta current potentials are -46.5mV.
Embodiment 4
APNPs preparation：Weigh 100mg AP to be placed in 5ml centrifuge tubes, add 2ml ethanol solution, it is fully molten
Solution, obtains drug containing organic phase (50mg/ml)；Take 100ml purified waters to be placed in glass cillin bottle, be preheated to 40 DEG C and be used as aqueous phase；
Organic phase is injected into aqueous phase, ultrasonication is carried out using cell Ultrasonic Cell Disruptor immediately, ultrasonic power 50W, super 5s stop
5s, solution in cillin bottle, is then transferred in 250ml round-bottomed flasks, 40 DEG C of water-bath lucifuge vacuum rotary steams remove by ultrasonic 20min altogether
Organic solvent is removed, that is, obtains APNPs solution.The solution appearance is milky, transparent and general opalescence, and laser irradiation has dindar
Phenomenon.Average grain diameter is 310nm, and average zeta current potentials are -47.1mV.
Embodiment 5：
PTX-APNPs preparation：Weigh 5mg AP and 1mg PTX to be placed in 1.5ml centrifuge tubes, add the anhydrous of 0.2ml
Ethanol solution, fully dissolving, obtain drug containing organic phase；Take 8ml purified waters to be placed in glass cillin bottle, be preheated to 40 DEG C and be used as water
Phase；Organic phase is injected into aqueous phase, ultrasonication, ultrasonic power 50W, super 5s are carried out using cell Ultrasonic Cell Disruptor immediately
Stop 5s, solution in cillin bottle, is then transferred in 100ml round-bottomed flasks, 40 DEG C of water-bath lucifuge vacuum rotary steams by ultrasonic 10min altogether
Organic solvent is removed, that is, obtains PTX-ANNPs solution.The solution is milky and limpid transparent, is visible by naked eyes particle or heavy
Form sediment, laser irradiation has Tyndall phenomenon, and its average grain diameter is 295.1nm, and average zeta current potentials are -25.0mV.HPLC detects PTX
Envelop rate be 94.48%.
Embodiment 6：
PTX-APNPs preparation：Weigh 50mg AP and 30mg PTX to be placed in 1.5ml centrifuge tubes, add 0.2ml nothing
Hydrous ethanol solution, fully dissolving, obtain drug containing organic phase；Take 8ml purified waters to be placed in glass cillin bottle, be preheated to 40 DEG C of conducts
Aqueous phase；Organic phase is injected into aqueous phase, ultrasonication is carried out using cell Ultrasonic Cell Disruptor immediately, ultrasonic power 50W, surpassed
5s stops 5s, and solution in cillin bottle, is then transferred in 100ml round-bottomed flasks by ultrasonic 15min altogether, 40 DEG C of water-bath lucifuge decompression rotations
Organic solvent is evaporated off, that is, obtains PTX-APNPs solution.The solution is milky and limpid transparent, be visible by naked eyes particle or
Precipitation, laser irradiation have Tyndall phenomenon, and its average grain diameter is 320.9nm, and average zeta current potentials are -20.0mV.HPLC is detected
PTX envelop rate is 93.12%.
Embodiment 7：
PTX-APNPs preparation：Weigh 100mg AP and 100mg PTX to be placed in 1.5ml centrifuge tubes, add 0.2ml's
Ethanol solution, fully dissolving, obtain drug containing organic phase；Take 8ml purified waters to be placed in glass cillin bottle, be preheated to 40 DEG C of works
For aqueous phase；Organic phase is injected into aqueous phase, immediately using cell Ultrasonic Cell Disruptor carry out ultrasonication, ultrasonic power 50W,
Super 5s stops 5s, and solution in cillin bottle, is then transferred in 100ml round-bottomed flasks by ultrasonic 15min altogether, 40 DEG C of water-bath lucifuge decompressions
Revolving removes organic solvent, that is, obtains PTX-APNPs solution.The solution is milky and limpid transparent, is visible by naked eyes particle
Or precipitation, laser irradiation have Tyndall phenomenon, its average grain diameter is 397nm, and average zeta current potentials are -22.4mV.HPLC is detected
PTX envelop rate is 92.88%.
Embodiment 8：
Load the DTX-APNPs of docetaxel (DTX) preparation：Weigh 5mg AP and 1mg DTX and be placed in 1.5ml centrifuge tubes
In, 0.2ml ethanol solution is added, fully dissolving, obtains drug containing organic phase；8ml purified waters are taken to be placed in glass cillin bottle
In, it is preheated to 40 DEG C and is used as aqueous phase；Organic phase is injected into aqueous phase, it is broken to carry out ultrasound using cell Ultrasonic Cell Disruptor immediately
Broken, ultrasonic power 50W, super 5s stop 5s, and ultrasonic 15min, is then transferred to 100ml round-bottomed flasks by solution in cillin bottle altogether
In, 40 DEG C of water-bath lucifuge vacuum rotary steams remove organic solvent, that is, obtain DTX-APNPs solution.The solution is milky and limpid
It is transparent, particle or precipitation are visible by naked eyes, laser irradiation has Tyndall phenomenon, and its average grain diameter is 282nm, average zeta current potentials
For -23.3mV.HPLC detections DTX envelop rate is 94.3%.
Sign and pharmacodynamic experiment
1st, transmission electron microscope characterizes
Fig. 1 a and Fig. 1 b are APNPs prepared by embodiment 1 and PTX-APNPs prepared by embodiment 5 transmission electron microscope respectively
Figure.It can be seen that APNPs and PTX-APNPs nano-particles are spherical structure, particle diameter is more uniform, wherein APNPs
Particle diameter substantially 100nm or so, load PTX after particle diameter be about 200nm or so.As can be seen here, the APNPs after carrying medicament
Particle diameter distribution broadens.
2nd, differential calorimetric scan characterizes
Fig. 2 is PTX, AP and PTX-APNPs differential scanning calorimetry figure.Wherein negative absorption peak represents endothermic peak.PTX
Occur an endothermic peak at about 221 DEG C, and then occur an exothermic peak at 242 DEG C；AP has an endothermic peak at 118 DEG C；
And in PTX-APNPs heat analysis collection of illustrative plates, only nearby occur an endothermic peak at 110 DEG C, PTX and AP peak almost disappear completely
Lose, after illustrating that AP is self-assembled into APNPs, form new thing phase, and PTX is then highly dispersed in APNPs with molecular forms.
3rd, release in vitro is tested
The detection of preparations of the PTX-APNPs in 25% ethanol solution.25% ethanol solution 150ml is prepared to be divided into
Three equal parts, as dialysis medium.Take respectively PTX-APNPs solution that 2ml prepared by embodiment 4 (PTX containing 0.25mg and
1.25mg AP), PTX alcoholic solutions (0.125mg/ml) and AP alcoholic solutions (0.625mg/ml) be injected into bag filter and seal, so
After be immersed in dialysis medium in discharged.Discharging environment is：In 37C gas bath constant temperature oscillator, kept away with 50 revs/min of speed
Light shakes.In set time point, 1ml dialysis media are respectively taken to carry out HPLC detections, then every group of supplement 1ml Fresh dialysate medium.
Accumulation calculates the release amount of medicine at each time point.Fig. 3 is the releasing curve diagram of each medicine, it can be seen that free PTX and trip
90.61% and 75.40% are released respectively in 24h from AP, and during the 48h of PTX-APNPs upon discharge, only release
75.46% PTX and 66.32% AP.Illustrate that PTX-APNPs can significantly control PTX and AP release, extend medicine in vivo
Action time, the bioavilability of medicine can be increased.
4th, PTX-APNPs preparation stability is investigated.
The PTX-APNPs prepared by embodiment 4 is placed in 4 DEG C of refrigerators, observes the change of size after one week (7 days).By
PTX-APNPs grain size distribution (Fig. 4) is understood, under 4 DEG C of environment, is stabilized in the lipid nanometer in 7 days, and particle diameter is without aobvious
Change is write, illustrates that PTX-APNPs preparation stability is good.
5th, PTX-APNPs extracorporeal anti-tumor ability is investigated.
Using B16F10 cells as model, PTX-APNPs and free medicine PTX and AP is detected to B16F10 cells using mtt assay
Propagation toxicity.Take the logarithm growth period B16F10 cells with 1 × 105The even density in individual/hole is inoculated in 96 orifice plates, titanium dioxide
Carbon incubator overnight incubation.The culture medium in hole is sopped up, is then respectively adding PTX, AP, PTX+ of 100 μ l series concentration gradients
AP (PTX: AP=1: 5, w/w) and the PTX-APNPs as prepared by embodiment 4, every group of medicine set 3 concentration gradients PTX (2.4,
3 and 5 μ g/ml) or AP (12,15 and 25 μ g/ml), each concentration sets 3 multiple holes, and sets 5 holes for giving fresh culture and make
For negative control group.Continue after cultivating 24h, suction out the decoction in 96 orifice plates, with PBS 3 times, 100 μ l are then added per hole
Serum free medium and the pre-configured MTT solution (5mg/ml) of 10 μ l, continue to be put in carbon dioxide incubator culture.After 4h,
96 orifice plates are taken out, careful inhale abandons nutrient solution, and 150 μ l DMSO are then added per hole, low speed on shaking table is placed in and shakes 10min, use enzyme
The absorbance (OD values) in each hole at instrument measure 570nm is marked, and inhibitory rate of cell growth (Inhibition is calculated by following equation
Rate, OR).
IR=(1-OD experimental groups/OD control groups) × 100%
As shown in Figure 5, effects of the PTX-APNPs in low concentration to tumour cell is poor without conspicuousness compared with free drug
Not, the anti-tumor capacity of the PTX-APNPs but under highly concentrated is significantly higher than the free PTX of same concentrations, and dissociate AP and PTX+AP
Physical mixture, illustrate that PTX-APNPs can significantly improve PTX antitumor curative effect, and the AP in lipid nano particle can be speculated
Certain synergistic antitumor effect be present with PTX.
6th, PTX-APNPs lipid nano particles to B16F10 cells in animal body Tumor formation can influence.
The present invention uses C57BL/6 female mices as animal model, and B16F10 cell subcutaneous injections will be treated through different pharmaceutical
To the different parts of mouse, then see look into each treatment group into knurl situation.Concrete operations are as follows：Logarithmic phase will be grown into
B16F10 cells are with pressing 2X10 after 0.25% Trypsin Induced5The even density in individual/hole is inoculated in six orifice plates, is placed in titanium dioxide
Carbon incubator overnight incubation is to fusion rate up to more than 80%.Then each hole is separately added into 1ml free PTX (3 μ g/ml), dissociated
AP (15 μ g/ml), the PTX+AP (PTX of physical mixed：3 μ g/ml, AP：15 μ g/ml) and PTX-APNPs (PTX：3 μ g/ml, AP：
15 μ g/ml) solution co-cultured, and control group adds the culture medium of isometric serum-free.After 5h, digestion collects cell and uses PBS
(PH=7.2) clean 2 times, it is 100/μ l to be then resuspended in serum-free respectively without cell density in dual anti-culture medium, is controlled.
Each administration group cell is subcutaneously injected into same mouse four limbs oxter respectively again, and carries out mark, cellular control unit is expelled to separately
One mouse oxter (n=5).Real Time Observation mouse into knurl situation, the 22nd day group mouse is into knurl after inoculated tumour cell
Situation has obvious trend, and then cervical dislocation puts to death each group mouse, vernier caliper measurement gross tumor volume, finally chooses one group
Control group and one group of experimental mice are dissected, and are observed and are photographed to record.As a result, all mouse are equal in control group and PTX groups
Grow tumour, have 4 in 5 mouse of AP groups and PTX+AP groups respectively and 2 mouse grow tumour, in PTX-APNPs groups 5 it is old
Mouse does not grow tumour, compared with control group, each medicine group can substantially suppress B16F10 cells in Mice Body into knurl energy
Power (Fig. 6 a).From Fig. 6 b, blank control group, PTX groups, AP groups, the mean tumour volume of PTX+AP groups and PTX-APNPs groups
Respectively 667.39,43.42,12.17,1.57 and 0mm3.The tumor size of control group exists notable with other each administration groups
Sex differernce (P ＜ 0.05).Compared with PTX, PTX-APNPs lipid nano particles can significantly inhibit B16F10 cells in Mice Body
One-tenth knurl ability.
7th, it have chosen 50 15~20g female C57BL/6 for antitumor drug effect in research PTX-APNPs bodies, this experiment
As animal model.0.25% Trypsin Induced of logarithmic phase B16F10 cells, the RPMI- being then resuspended in will be grown into
In 1640 cell culture mediums, the control μ l of cell concentration 5 × 106/100, every μ L cell of mouse armpit subcutaneous vaccination 100, with
Observe the growing state of tumour daily afterwards.When gross tumor volume reaches approximately 40mm3When, all mouse are randomized to either control group
In each experimental group, every group of 5 mouse.Control group is not dealt with, other each groups difference intratumor injection PTX (0.5mg/
kg)、AP(2.5mg/kg)、PTX+AP(PTX：0.5mg/kg, AP：2.5mg/kg) and PTX-APNPs (PTX：0.5mg/kg, AP：
2.5mg/kg), inject once within every two days.After one week, cervical dislocation, mouse is put to death, peel off tumour, and photograph to record.Such as Fig. 7
Shown, there is inhibitory action in free PTX, AP and PTX+AP physical mixture, but effect shows to mouse interior tumor growth
Work is weaker than antitumor curative effect inside PTX-APNPs lipid nanometers.
Although embodiments of the present invention are illustrated in specification, these embodiments are intended only as prompting,
It should not limit protection scope of the present invention.It is equal that various omission, substitution, and alteration are carried out without departing from the spirit and scope of the present invention
It should include within the scope of the present invention.
Claims (10)
1. a kind of multi-functional lipid nano particle, it is characterised in that the load of lipid nano particle is used as using ascorbyl palmitate AP
Body.
2. multi-functional lipid nano particle according to claim 1, it is characterised in that include at least one taxanes medicine
X。
3. multi-functional lipid nano particle according to claim 2, it is characterised in that the taxanes medicine X is selected from purple
One or more in China fir alcohol, docetaxel, Cabazitaxel.
A kind of 4. preparation method of multi-functional lipid nano particle according to claim 1, it is characterised in that preparation process
For：
A weighs the AP of recipe quantity；
AP is dissolved in absolute ethyl alcohol by b, is re-introduced into a certain amount of purified water；
B liquid is immediately placed on water bath sonicator under cell Ultrasonic Cell Disruptor by c；
C liquid is carried out decompression rotary evaporation by d, is removed organic solvent, that is, is obtained APNPs.
5. the preparation method of the nano-medicament carrier of multi-functional lipid nano particle according to claim 4, it is characterised in that prepare
Process is：
A weighs the AP of recipe quantity；
AP is dissolved in 1 volume absolute ethyl alcohol by b, is re-introduced into 0~50 DEG C of purified water of 5~100 volumes；
B liquid is immediately placed on 0~50 DEG C of water bath sonicator 5-30min under cell Ultrasonic Cell Disruptor by c；
C liquid is carried out decompression rotary evaporation by d, removes organic solvent, and revolving temperature is 25~50 DEG C, that is, it is empty to obtain not carrying medicament
Bai Zaiti APNPs.
6. the preparation method of the described multi-functional lipid nano particle of a kind of Claims 2 or 3, it is characterised in that using AP as load
Body raw material, adds taxanes medicine, inject by solvent-method of ultrasonication-rotary evaporation makes AP be self-assembly of surely
Fixed lipid nano particle.
7. the preparation method of the multi-functional lipid nano particle described in a kind of claim 6, it is characterised in that prepare step including following
Suddenly：
A weighs the AP and the taxanes medicine X of recipe quantity；
AP and the taxanes medicine X co-dissolves in absolute ethyl alcohol, are re-introduced into purified water by b；
B liquid is immediately placed on water bath sonicator under cell Ultrasonic Cell Disruptor by c；
C liquid is carried out decompression rotary evaporation by d, removes organic solvent, revolving temperature is 25~50 DEG C, that is, obtains paclitaxel loaded class
The X-APNPs of medicine.
8. the preparation method of multi-functional lipid nano particle according to claim 7, its feature includes following preparation process：
A weighs AP5~100mg, taxol PTX1~100mg；
AP and PTX co-dissolves in 1 volume absolute ethyl alcohol, are re-introduced into 0~50 DEG C of purified water of 5~100 volumes by b；
C is by b liquid immediately as 0~50 DEG C of water bath sonicator 5-30min under cell Ultrasonic Cell Disruptor；
C liquid is carried out decompression rotary evaporation by d, removes organic solvent, revolving temperature is 25~50 DEG C, that is, obtains PTX-APNPs.
9. a kind of nano-medicament carrier of the multi-functional lipid nano particle of claim 7 or 8 is preparing the fat containing antineoplastic
Application in matter nano particle preparations.
A kind of 10. purposes of any one of the claim 1-3 lipid nano particle in preparing for antineoplastic.
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| CN114903871A (en) * | 2022-05-09 | 2022-08-16 | 郑州大学第一附属医院 | Anti-inflammatory nano composition loaded with triptolide, preparation method and application |
| CN115414465A (en) * | 2022-10-17 | 2022-12-02 | 苏州明人医药生物科技有限公司 | Application of JWA polypeptide in preparation of antitumor drug synergist |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109042703A (en) * | 2018-09-12 | 2018-12-21 | 中国农业科学院农业环境与可持续发展研究所 | A kind of preparation method of blade face targeting adhesion type hydrogel pesticide drug-loading system |
| CN109042703B (en) * | 2018-09-12 | 2021-01-15 | 中国农业科学院农业环境与可持续发展研究所 | Preparation method of leaf surface targeting adhesion type hydrogel pesticide drug-loading system |
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