CN106963756A - Pharmaceutical polymer micella and its application in pharmacy are carried altogether - Google Patents
Pharmaceutical polymer micella and its application in pharmacy are carried altogether Download PDFInfo
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- 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
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
Abstract
The invention belongs to field of pharmaceutical preparations, common load pharmaceutical polymer micella and its application in pharmacy are disclosed.This carries pharmaceutical polymer micella and carries legalon and chemotherapeutics altogether as the carrier of micella using amphipathic nature polyalcohol altogether.The polymer micelle preparation, for mutual load legalon and chemotherapeutics, tumor locus and then synchronous release medicine is targeted by intravenous injection in aqueous by being self-assembly of nanoparticle.Utilize regulating and controlling effect of the legalon to tumor microenvironment, the curative effect of Chemotherapy medicine, so as to realize the synergistic treatment to tumour.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, it is related to common load pharmaceutical polymer micella and its application in pharmacy, especially
It is to be related to polymer micelle and its application in pharmacy that a kind of legalon and chemotherapeutic are carried altogether.
Background technology
The interior environment that tumor microenvironment (TME), i.e. tumour cell are produced and lived, wherein not only including tumour cell sheet
Body, also has the various cells such as tumour associated fibroblast cell, immune, inflammatory cell and spongiocyte around it, while also wrapping
Include cytoplasm near zone, the biomolecule of capilary and infiltration wherein.Treatment of the people for tumour before
Thinking is always confined to tumour cell in itself.Up to date, most of researchs find tumours and tumor microenvironment be one not
Alienable entirety.Tumor microenvironment is like a small ecological environment, has close contact with tumour cell therein.
Therefore, the regulation and control for tumor microenvironment also certainly will will influence the therapeutic effect of chemotherapeutics.
Silymarin is the flavone compound extracted from feverfew milk thistle, and legalon is its main activity
Composition, is clinically mainly used in treatment acute hepatitis, chronic hepatitis, hepatic sclerosis and hepatic injury.Recently as pharmacological further investigation
Show, legalon also has the kinds cancers such as suppression prostate cancer, colon cancer, carcinoma of urinary bladder, lung cancer concurrently in addition to hepatoprotective effect
Effect, these find cause legalon pharmacological activity widely paid close attention to.The research table of multinomial animal cancer models
Bright, legalon can be believed by suppressing interleukin, TNF (TNF-α), nuclear factor (NF- κ B), phosphorylation
The secretion and expression of number factor such as transductant and transcription activator 3 (STAT 3), modulate tumor microenvironment adjust the cell cycle,
Suppress tumor neovasculature to be formed, so as to suppress the invasion and attack and transfer of tumour cell, play immune and antitumor action.Cause
This, gets down to modulate tumor microenvironment, promotes tumor locus blood vessel normalization, realizes the profound delivering of chemotherapeutics and has turned into
Another important means of oncotherapy.
Conventional chemotherapeutic drugs, including taxanes, cyclosporine class, antifol, purine antagonist, Pyrimidine antagonists,
Flavonoids, camptothecin, dihydropyridines, vinca, berbine, Anthraquinones, podophillotoxines etc..These medicines can be made
The different phase bred for growth of tumour cell, suppresses or kills tumour cell.Chemotherapeutic drug therapy is still current treatment ovum
The Main Means of a variety of metastatic malignant tumours such as nest cancer, breast cancer, incidence cancer, lung cancer in non-cellule type and prostate cancer.
Zhou Liguang etc. has found suppression of the said composition to ovarian cancer cell by the way that free legalon and taxol are combined
Effect is significantly higher than taxol or legalon is used alone, and legalon can strengthen sensitivity of the ovarian cancer cell to taxol
Property (experimental study [D] the Shandong University that Zhou Liguang legalons influence on ovarian cancer cell paclitaxel-sensitive and invasiveness,
2008.).Free legalon and adriamycin are acted on stomach cancer cell by Zhang Yuanxin etc., it is found that legalon can effectively drop
The administration concentration of low adriamycin, and lifted doxorubicin-induced apoptosis effect (Zhang Yuanxin, Ge Yakun, apply dimension legalons and Ah
Influence and its mechanism [J] Products in China magazine of the mycin synergy to stomach cancer cell SGC-7901 apoptosis, 2014,
27(5):642-646.).Above-mentioned document shows to use legalon with chemotherapy drugs in combination, the curative effect of energy enhanced sensitivity chemical drug,
Tumor proliferation is suppressed by the synergy of pharmaceutical composition jointly, and reduces the toxic side effect of chemical drug.
Existing document will all focus on the inhibitory action for investigating free drug composition to cancer cell.However, this
A little free drugs have that poorly water-soluble, toxic side effect be big, the low defect of bioavilability mostly, greatly affected drug regimen
Therapeutic effect of the thing to tumour.
The content of the invention
The purpose of the present invention is to be more easy to be gathered in tumor tissues release medicine there is provided one kind for above-mentioned technical problem, is risen
To the common load pharmaceutical polymer micella of synergism and attenuation.
Application of the pharmaceutical polymer micella in pharmacy is carried altogether it is a further object to provide above-mentioned.
The present invention inventive concept be polymer micelle in aqueous by being self-assembly of nanoparticle, by legalon
With chemical drug mutual load in the hydrophobic inner core formation preparation of micella, for improving tumor microenvironment, using legalon to tumour
The regulating and controlling effect of microenvironment, the molecule or particle of polymer micelle delivery system (particle diameter 10-1000nm) are more easy to be gathered in tumour
Tissue release medicine, reaches the purpose of " attenuation synergistic ".The high-permeability that post-consumer polymer micella passes through solid tumor mass after administration
With retention effect to tumor locus and then synchronous drug release, the synergy of pharmaceutical composition is significantly improved.
The purpose of the present invention is realized by following technical proposal：
A kind of to carry pharmaceutical polymer micella altogether, this carries pharmaceutical polymer micella using amphipathic nature polyalcohol as micella altogether
Carrier carries legalon and chemotherapeutics altogether, is prepared using following method：
A. amphipathic nature polyalcohol is dissolved or dispersed in water, obtains polymer micelle；By chemotherapeutic, legalon medication
On after acceptable organic solvent dissolving, preformed solution is mixed to obtain with above-mentioned polymer micelle；
B. by preformed solution after ultrasound or high pressure homogenization method processing, using dialysis, ultrafiltration or evaporating organic solvent,
Particle diameter is made and carries micellar solution altogether for 10-1000nm legalon, chemotherapeutic；Or
Evaporate preformed solution is rotated in being formed in bottle wall after film, stirred and redissolved or scattered with water, through ultrasound or high
The processing of homogeneous method is pressed, particle diameter is made and carries micellar solution altogether for 10-1000nm legalon, chemotherapeutic.
Described common load pharmaceutical polymer micella, can also carry the legalon, chemotherapeutic altogether micellar solution addition
Pharmaceutically acceptable freeze drying protectant, freeze-dried powder is made using the method for freeze-drying；The freeze drying protectant is lactose, Portugal
One or more in grape sugar, sucrose, mannitol, sodium chloride, amino acid, citrate, acetate, phosphate.
Described common load pharmaceutical polymer micella, wherein amphipathic nature polyalcohol are gathered from polyethyleneimine, polyethylene glycol, shell
Sugar, hyaluronic acid, glucan and its derivative are as hydrophilic segment, from PLA, polycaprolactone, long chain fatty acids, long-chain
Fatty amine is used as hydrophobic patch.Amphipathic nature polyalcohol is 1 from the molar feed ratio of hydrophilic segment and hydrophobic patch:1-1:5.
Described common load pharmaceutical polymer micella, wherein amphipathic nature polyalcohol is dissolved or dispersed in water with 6-10mg/mL,
Dissolved in two kinds of medicines, the aqueous solution for instilling the amphipathic nature polyalcohol, passed through simultaneously with the cosolvent of chemotherapeutic and legalon
The hydrophobic interaction of micelle inner core and medicine, chemotherapeutic and legalon is carried on simultaneously the hydrophobic cores of micella,
The mass ratio of chemotherapeutics and legalon includes 1:1-1:5.
Described common load pharmaceutical polymer micella, wherein chemotherapeutic includes：Taxanes, cyclosporine class, antifol,
Purine antagonist, Pyrimidine antagonists, flavonoids, camptothecin, dihydropyridines, vinca, berbine, Anthraquinones, ghost
Any one in mortar toxin series antineoplastic medicament.
The pharmaceutically acceptable organic solvent is：Methanol, ethanol, acetone, tetrahydrofuran, N.N- dimethyl formyls
The organic solvents such as amine, dimethyl sulfoxide or their mixed solvent.
Application of the described common load pharmaceutical polymer micella in antineoplastic is prepared.
Injection can be made in the above-mentioned pharmaceutical polymer micella that carries altogether, and the injection includes：By micellar solution or solid
Powder, by parenteral solution or injection preparation conventional process, is directly scattered in cillin bottle and is made；Or after solid powder is dissolved,
Conventional process is prepared by injection, parenteral solution or injection preparation is made.
Effective effect of the present invention：
The common carrying medicine that the present invention is provided has following advantages：
By the solubilized legalon of the hydrophobic inner core of polymer micelle and chemotherapeutics, the solubility of medicine is improved, and
Pass through dialysis and revolving removes organic solvent, it is to avoid the toxic side effect that free drug is dissolved and produced using organic solvent.Should
Carrier micelle is easy to be targeted to tumor locus altogether, improves the bioavilability of pharmaceutical composition.
The described application that common carrying medicine is used to improve to tumor microenvironment includes：Week is administered in animal in carrying medicine altogether
After phase terminates, the reduction of tumor locus new vessels and the increase of permeability, collagen component and tumour associated fibroblast cell
Reduce.
Legalon and chemotherapeutics mutual load are targeted to tumor locus in the hydrophobic inner core of polymer micelle, realize
The synchronous release of two kinds of medicines, using regulating and controlling effect of the legalon to tumor microenvironment, realizes chemotherapeutics to tumor tissues
Profound delivering, and the curative effect of Chemotherapy medicine.
Brief description of the drawings
Fig. 1 is the picture that embodiment 13 carries tumor microenvironment collagen after drug micelles administration altogether.
Fig. 2 is the picture that embodiment 16 carries tumor permeability after drug micelles administration altogether.
Embodiment
It is subject to further instruction to the present invention below by embodiment, but following embodiments are not intended to limit the power of this patent
Sharp scope.
Embodiment 1
Take 0.1mmol hyaluronic acid, 0.3mmol (1- (3- dimethylamino-propyls) -3- ethyl carbodiimide hydrochlorides
Salt) and 0.3mmol N- hydroxy thiosuccinimides be dissolved in 10mL formamides, normal temperature activation half an hour.By the ten of 0.2mmol
Eight amine are dissolved in 5mL N.N- dimethylformamides, instill in the hyaluronic acid solution activated, continue to react after 24h, use third
Product is precipitated out by ketone, and sediment 20mL distilled water redissolves, and is placed in dialysis 2 days in bag filter (MWCO=3500), is freezed
After produce hyaluronic acid-octadecylamine polymer micelle.
Embodiment 2
The DMAP of 0.1mmol glucan, 0.2mmol deoxycholic acid and 10mg is taken to be dissolved in 10mL diformazans
React after 24h, be precipitated out product under sulfoxide, room temperature condition using ethanol, sediment 20mL distilled water redissolves, and is placed in
Dialysis 2 days in bag (MWCO=3500) are analysed, glucan-deoxycholic acid polymer micelle is produced after freezing.
Embodiment 3
Take (1- (3- dimethylamino-propyls) -3- second of 0.1mmol chitosan, 0.2mmol succinic anhydride, 0.3mmol
Base carbodiimide hydrochloride) and 0.3mmol N- hydroxy thiosuccinimides be dissolved in 10mL dimethyl sulfoxides, after reaction 24h, make
Product is precipitated out with acetone, sediment 20mL distilled water dissolves, is placed in dialysis 2 days in bag filter (MWCO=3500),
The chitosan intermediate of a free end carboxyl is obtained after lyophilized.The octylame of 0.1mmol chitosans intermediate and 0.4mmol is dissolved in
Water and methanol (v/v=1:1) in, 0.3mmol (1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides) and
0.3mmol N- hydroxy thiosuccinimides are catalyst, react 24h.Rotary evaporation removes methanol, is placed in bag filter
(MWCO=3500) dialysis 2 days in, chitosan-octylame polymer micelle is produced after freezing.
Embodiment 4
Glucan-deoxycholic acid polymer support is taken, is dissolved in the water with 6mg/mL, uses acetone：Ethanol (1:1, v/v) make
For mixed solvent dissolving legalon and taxol, (paclitaxel concentration is 15mg/mL；Legalon concentration is 30mg/mL).Will
The solution is added drop-wise in polymer micelle solution dropwise, is stirred vigorously 10min.45 DEG C of rotary evaporations remove organic solvent, by shape
Into mixture film be dispersed in water again, under 100W power condition of ice bath after Probe Ultrasonic Searching half an hour cross 0.80 μm of filter membrane,
Produce common polypeptide drug-loaded micelle solution.The micella average grain diameter is 189.6nm, and Zeta potential is -12.5mV.Legalon drugloading rate is
12.6%, paclitaxel carried medicine amount is 10.5%.The mannitol that micellar aqueous solution is added into 1.0% is freezed, and produces lyophilized solid powder
End.Redissolved using preceding with 0.9% physiological saline or 5% glucose, the micella can be used for being injected intravenously.
Embodiment 5
Glucan-deoxycholic acid polymer support is taken, is dissolved in the water, is dissolved with dimethyl sulfoxide as solvent with 6mg/mL
(doxorubicin concentration is 15mg/mL for legalon and adriamycin；Legalon concentration is 30mg/mL).The solution is added dropwise dropwise
Into polymer micelle solution, lucifuge is stirred vigorously 10min.Probe Ultrasonic Searching half an hour under 100W power condition of ice bath.Micella is molten
Liquid is placed in bag filter dialysis 12h in (MWCO=3500), crosses 0.80 μm of filter membrane, produces common polypeptide drug-loaded micelle solution.The micella is put down
Equal particle diameter is 176.5nm, and Zeta potential is -12.0mV.Legalon drugloading rate is 13.3%, and adriamycin drugloading rate is
11.2%.The mannitol that micellar aqueous solution is added into 1.0% is freezed, and produces lyophilized solid powder.Using it is preceding with 0.9% physiology
Salt solution or 5% glucose redissolve, and the micella can be used for being injected intravenously.
Embodiment 6
Glucan-deoxycholic acid polymer support is taken, is dissolved in the water with 6mg/mL, with N.N- dimethylformamide conducts
(cis-platin concentrations are 15mg/mL for solvent dissolving legalon and cis-platinum；Legalon concentration is 30mg/mL).By the solution dropwise
It is added drop-wise in polymer micelle solution, lucifuge is stirred vigorously 10min.Probe Ultrasonic Searching half an hour under 100W power condition of ice bath.Glue
Beam solution is placed in bag filter dialysis 12h in (MWCO=3500), crosses 0.80 μm of filter membrane, produces common polypeptide drug-loaded micelle solution.The glue
Beam average grain diameter is 189.2nm, and Zeta potential is -11.6mV.Legalon drugloading rate is 14.2%, and cis-platinum drugloading rate is
10.1%.The mannitol that micellar aqueous solution is added into 1.0% is freezed, and produces lyophilized solid powder.Using it is preceding with 0.9% physiology
Salt solution or 5% glucose redissolve, and the micella can be used for being injected intravenously.
Embodiment 7
Hyaluronic acid-octadecylamine polymer support is taken, is dissolved in the water with 6mg/mL, uses acetone：Ethanol (1:1, v/v) make
For mixed solvent dissolving legalon and taxol, (paclitaxel concentration is 15mg/mL；Legalon concentration is 30mg/mL).Will
The solution is added drop-wise in polymer micelle solution dropwise, is stirred vigorously 10min.45 DEG C of rotary evaporations remove organic solvent, by shape
Into mixture film be dispersed in water again, under 100W power condition of ice bath after Probe Ultrasonic Searching half an hour cross 0.80 μm of filter membrane,
Produce common polypeptide drug-loaded micelle solution.The micella average grain diameter is 186.3nm, and Zeta potential is -12.1mV.Legalon drugloading rate is
13.1%, paclitaxel carried medicine amount is 11.2%.The mannitol that micellar aqueous solution is added into 1.0% is freezed, and produces lyophilized solid powder
End.Redissolved using preceding with 0.9% physiological saline or 5% glucose, the micella can be used for being injected intravenously.
Embodiment 8
Hyaluronic acid-octadecylamine polymer support is taken, is dissolved in the water, is dissolved with dimethyl sulfoxide as solvent with 6mg/mL
(doxorubicin concentration is 15mg/mL for legalon and adriamycin；Legalon concentration is 30mg/mL).The solution is added dropwise dropwise
Into polymer micelle solution, lucifuge is stirred vigorously 10min.Probe Ultrasonic Searching half an hour under 100W power condition of ice bath.Micella is molten
Liquid is placed in bag filter dialysis 12h in (MWCO=3500), crosses 0.80 μm of filter membrane, produces common polypeptide drug-loaded micelle solution.The micella is put down
Equal particle diameter is 200.2nm, and Zeta potential is -10.8mV.Legalon drugloading rate is 13.6%, and adriamycin drugloading rate is
10.5%.The mannitol that micellar aqueous solution is added into 1.0% is freezed, and produces lyophilized solid powder.Using it is preceding with 0.9% physiology
Salt solution or 5% glucose redissolve, and the micella can be used for being injected intravenously.
Embodiment 9
Hyaluronic acid-octadecylamine polymer support is taken, is dissolved in the water with 6mg/mL, with N.N- dimethylformamide conducts
(cis-platin concentrations are 15mg/mL for solvent dissolving legalon and cis-platinum；Legalon concentration is 30mg/mL).By the solution dropwise
It is added drop-wise in polymer micelle solution, lucifuge is stirred vigorously 10min.Probe Ultrasonic Searching half an hour under 100W power condition of ice bath.Glue
Beam solution is placed in bag filter dialysis 12h in (MWCO=3500), crosses 0.80 μm of filter membrane, produces common polypeptide drug-loaded micelle solution.The glue
Beam average grain diameter is 196.3nm, and Zeta potential is -12.3mV.Legalon drugloading rate is 16.8%, and cis-platinum drugloading rate is
11.5%.The mannitol that micellar aqueous solution is added into 1.0% is freezed, and produces lyophilized solid powder.Using it is preceding with 0.9% physiology
Salt solution or 5% glucose redissolve, and the micella can be used for being injected intravenously.
Embodiment 10
Chitosan-octylame polymer support is taken, is dissolved in the water with 6mg/mL, uses acetone：Ethanol (1:1, v/v) as mixed
(paclitaxel concentration is 15mg/mL for bonding solvent dissolving legalon and taxol；Legalon concentration is 30mg/mL).This is molten
Liquid is added drop-wise in polymer micelle solution dropwise, is stirred vigorously 10min.45 DEG C of rotary evaporations remove organic solvent, by formation
Mixture film is dispersed in water again, is crossed 0.80 μm of filter membrane under 100W power condition of ice bath after Probe Ultrasonic Searching half an hour, is produced
Common polypeptide drug-loaded micelle solution.The micella average grain diameter is 156..2nm, and Zeta potential is -15.4mV.Legalon drugloading rate is
20.1%, paclitaxel carried medicine amount is 15.3%.The mannitol that micellar aqueous solution is added into 1.0% is freezed, and produces lyophilized solid powder
End.Redissolved using preceding with 0.9% physiological saline or 5% glucose, the micella can be used for being injected intravenously.
Embodiment 11
Chitosan-octylame polymer support is taken, is dissolved in the water with 6mg/mL, fine grinding is dissolved as solvent with dimethyl sulfoxide
(doxorubicin concentration is 15mg/mL for Ji guest and adriamycin；Legalon concentration is 30mg/mL).The solution is added drop-wise to dropwise poly-
In compound micellar solution, lucifuge is stirred vigorously 10min.Probe Ultrasonic Searching half an hour under 100W power condition of ice bath.Micellar solution is put
Dialysis 12h in (MWCO=3500), crosses 0.80 μm of filter membrane, produces common polypeptide drug-loaded micelle solution in bag filter.The average grain of the micella
Footpath is 145.6nm, and Zeta potential is -10.8mV.Legalon drugloading rate is 19.2%, and adriamycin drugloading rate is 15.1%.Will
The mannitol that micellar aqueous solution adds 1.0% is freezed, and produces lyophilized solid powder.Using preceding with 0.9% physiological saline or 5%
Glucose redissolve, the micella can be used for be injected intravenously.
Embodiment 12
Chitosan-octylame polymer support is taken, is dissolved in the water with 6mg/mL, solvent is used as with N.N- dimethylformamides
(cis-platin concentrations are 15mg/mL for dissolving legalon and cis-platinum；Legalon concentration is 30mg/mL).The solution is added dropwise dropwise
Into polymer micelle solution, lucifuge is stirred vigorously 10min.Probe Ultrasonic Searching half an hour under 100W power condition of ice bath.Micella is molten
Liquid is placed in bag filter dialysis 12h in (MWCO=3500), crosses 0.80 μm of filter membrane, produces common polypeptide drug-loaded micelle solution.The micella is put down
Equal particle diameter is 156.3nm, and Zeta potential is -13.3mV.Legalon drugloading rate is 19.6%, and cis-platinum drugloading rate is 15.5%.
The mannitol that micellar aqueous solution is added into 1.0% is freezed, and produces lyophilized solid powder.Using it is preceding with 0.9% physiological saline or
5% glucose redissolves, and the micella can be used for being injected intravenously.
Embodiment 13
Influence of the drug micelles to collagen in tumor microenvironment is carried altogether
(1) experimental method：Take the logarithm the A549 cells in growth period, after pancreatin digestion plus serum-containing media terminates digestion,
Cell is collected, is resuspended with 0.9% sodium chloride injection, regulation cell concentration to 106Cell/ is only inoculated under aseptic condition
Armpit is subcutaneous on the right side of nude mice, sets up A549 model of nude mice bearing tumor.Treat tumour length to 50-80mm3When be randomly divided into 5 groups, every group 5
Only, administration is denoted as the 0th day for the first time.By taking glucan-deoxycholic acid micella as an example, it is configured by following group:Control group：
5% glucose solution；A groups：Taxol and legalon free drug composition；B groups：Carry glucan-deoxidation of taxol
Cholic acid micella；C groups：Carry glucan-deoxycholic acid micella of legalon；D groups：The Portugal for carrying taxol and legalon altogether gathers
Sugar-deoxycholic acid micella；Respectively at 0, tail vein injection administration in 3,6,9,12,15,18 days, put to death and dissect within the 3rd day after drug withdrawal
Nude mice, takes the tumor tissues of nude mice to carry out FFPE, paraffin section is made.The paraffin section of nude mouse tumor is routinely dewaxed extremely
Water；Dyed using Masson Trichrome kits, mounting is after observation tumor locus under inverted fluorescence microscope
Collagen population.As a result Fig. 1 is seen.
(2) experimental result：The fine and close extracellular matrix of tumor locus and collagen, which are constituted, adds mesenchyma stroma of tumors pressure, hinders and receives
The grain of rice tumor tissues effective delivering, so as to influence drug effect.Collagen is the chief component of tumor stroma, is tumour micro-loop
The protective barrier in border.Collagen is marked as blueness in the experiment, and cytoplasm is dyed to red.As a result show, dosage period terminates
Carrier micelle is total to afterwards compared with remaining each group, significantly reduces the collagen component of tumor tissues.However, free drug composition is controlled
The effect that therapeutic effect does not carry drug micelles altogether is notable.
Embodiment 14
Influence of the drug micelles to carcinoma-associated fibroblasts in tumor microenvironment is carried altogether
(1) experimental method：Described in nude mice modeling and packet medication be the same as Example 13.By the paraffin section of nude mouse tumor
It is conventional to dewax to water；Entered with pH 9.0 EDTA antigen retrieval buffers (30.27g containing Tris, EDTA1.461g, distilled water 500ml)
Row is repaired and closed with normal rabbit serum (Boster)；Rabbit-anti mouse α-SMA are incubated and are placed in 4 DEG C of refrigerator overnights；FITC marks
Goat antirabbit is incubated；Most after stain nucleus and mounting.In the cancer associated fibroblast that tumor locus is observed under inverted fluorescence microscope
The quantity of cell.
(2) experimental result：Collagen is secreted by tumour associated fibroblast cell, and α-SMA are tumour associated fibroblast cells
Mark.It is consistent with the result of embodiment 13, should test result indicates that, the tumour associated fibroblast cell of tumor locus is very rich
It is rich.Effect of the free drug composition to tumour associated fibroblast cell be not obvious.Chemotherapeutic is producing apoptosis to tumour cell
Also the quantity of tumour associated fibroblast cell can be reduced while effect.Carry altogether in drug micelles due to the presence of legalon,
Regulating and controlling effect is produced to tumor microenvironment.Two kinds of medicine mutual loads can significantly reduce tumour associated fibroblast cell number in micella
Amount, promotes nanoparticle in effective delivering of tumor tissues.
Embodiment 15
Influence of the drug micelles to microvessel density in tumor microenvironment is carried altogether
(1) experimental method：Described in nude mice modeling and packet medication be the same as Example 13.By the paraffin section of nude mouse tumor
It is conventional to dewax to water；With pH 9.0 EDTA antigen retrieval buffers (30.27g containing Tris, EDTA 1.461g, distilled water 500ml)
Repaired and use normal rabbit serum (Boster) to close；Rabbit-anti mouse CD31 is incubated and is placed in 4 DEG C of refrigerator overnights；FITC marks
Goat antirabbit is incubated；Most after stain nucleus and mounting.In the microvessel density that tumor locus is observed under inverted fluorescence microscope.
(2) experimental result：The angiogenesis of tumor locus is that tumor invasiveness growth and transfer provide necessary condition, and just
Normal blood vessel is different, and tumor vessel composition is abnormal, constitutes the physiological barriers of tumor locus, hinders therapeutic substance to tumour portion
The delivering of position.Therefore, chemotherapeutics and anti-angiogenic medicaments are used in combination, Tumor Angiongesis can be suppressed and promoted swollen
Knurl position blood vessel normalization, improves the therapeutic effect of drug-carrying nanometer particle.After dosage period terminates, control group rich blood vessel and presentation
Long and narrow state, free drug composition group blood vessel still enriches.And singly carry legalon and altogether carry medicine group show significantly
Tumor vessel quantity reduction.Further, since regulating and controlling effect of the legalon to tumor microenvironment, is containing legalon
The region of tumor blood vessels normalization can be observed in treatment group.The blood vessel normalization of tumor locus can increase CBF,
Nanoparticle is improved to deliver to the profound level of tumor tissues.
Embodiment 16
Influence of the drug micelles to tumor permeability is carried altogether
(1) experimental method：Described in nude mice modeling and packet medication be the same as Example 13.The dosage period knot of oncotherapy
Shu Hou, nude mice tail vein injection carries vital stain Dil glucan-deoxycholic acid micella, is put to death after 24h and dissects nude mice,
Take the tumor tissues of nude mice that frozen section is made.The frozen section is placed after 30min in room temperature, and cold acetone fixes 10min, PBS
Closed after cleaning with normal rabbit serum (Boster), rabbit-anti mouse CD31 incubations are added dropwise in section and are placed in 4 DEG C of refrigerator overnights；
The goat antirabbit of FITC marks is incubated；Most after stain nucleus and mounting.Carried out in randomly choosing region under inverted fluorescence microscope
Take pictures, distribution situation of the observation living imaging dyestuff in tumor locus.As a result Fig. 2 is seen.
(2) experimental result：The experiment medium vessels is marked as green, and nucleus is dyed to blueness, and Dil dyestuffs are red.
Embodiment 13, embodiment 14, embodiment 15 are all it has proven convenient that load drug micelles are thin by reducing collagen and tumour associated fibroblast altogether
Born of the same parents, may finally modulate tumor matrix.And compared with control group, altogether carry drug micelles can suppress tumor angiogenesis,
Promote tumor locus blood vessel normalization.Control group is due to no by treatment, and mesenchyma stroma of tumors pressure is higher, red fluorescence diffusion
Small, fluorescence intensity is low.Free drug group is low due to bioavilability, although by treatment but drug effect is undesirable, fluorescence intensity according to
It is old very weak.For common load drug micelles, because said preparation is acted on the elimination of tumor locus physiological barriers, red fluorescence is swollen
Diffusion is big in knurl matrix, and fluorescence intensity is high.
Claims (8)
1. a kind of carry pharmaceutical polymer micella altogether, it is characterised in that this is carried pharmaceutical polymer micella and made using amphipathic nature polyalcohol altogether
Legalon and chemotherapeutics are carried altogether for the carrier of micella, are prepared using following method：
A. amphipathic nature polyalcohol is dissolved or dispersed in water, obtains polymer micelle；By chemotherapeutic, legalon with pharmaceutically
After acceptable organic solvent dissolving, preformed solution is mixed to obtain with above-mentioned polymer micelle；
B. preformed solution, using dialysis, ultrafiltration or evaporating organic solvent, is made after ultrasound or high pressure homogenization method processing
Particle diameter is 10-1000nm legalon, chemotherapeutic carries micellar solution altogether；Or
Evaporate preformed solution is rotated in being formed in bottle wall after film, stirred and redissolved or scattered with water, it is equal through ultrasound or high pressure
The processing of matter method, is made particle diameter and carries micellar solution altogether for 10-1000nm legalon, chemotherapeutic.
2. according to claim 1 carry pharmaceutical polymer micella altogether, it is characterised in that can also be by the legalon, change
Treat medicine and carry the pharmaceutically acceptable freeze drying protectant of micellar solution addition altogether, freeze-dried powder is made using the method for freeze-drying；Institute
Freeze drying protectant is stated in lactose, glucose, sucrose, mannitol, sodium chloride, amino acid, citrate, acetate, phosphate
One or more.
3. according to claim 1 carry pharmaceutical polymer micella altogether, it is characterised in that described amphipathic nature polyalcohol is selected
Polyethyleneimine, polyethylene glycol, chitosan, hyaluronic acid, glucan and its derivative as hydrophilic segment, from PLA,
Polycaprolactone, long chain fatty acids, long-chain fat amine are used as hydrophobic patch.
4. according to claim 3 carry pharmaceutical polymer micella altogether, it is characterised in that described amphipathic nature polyalcohol is selected
The molar feed ratio of hydrophilic segment and hydrophobic patch is 1:1-1:5.
5. according to claim 1 carry pharmaceutical polymer micella altogether, it is characterised in that amphipathic nature polyalcohol is with 6-10mg/mL
It is dissolved or dispersed in water, chemotherapeutics is carried on the hydrophobic cores of micella, chemotherapeutics and fine grinding with legalon simultaneously
The mass ratio of Ji guest includes 1:1-1:5.
6. according to claim 1 carry pharmaceutical polymer micella altogether, it is characterised in that the chemotherapeutic includes：Taxane
Class, cyclosporine class, antifol, purine antagonist, Pyrimidine antagonists, flavonoids, camptothecin, dihydropyridines, Changchun
Any one in bases, berbine, Anthraquinones, Antitumor Drugs of Podophyllotoxins.
7. according to claim 1 carry pharmaceutical polymer micella altogether, it is characterised in that described pharmaceutically acceptable organic
Solvent is：Methanol, ethanol, acetone, tetrahydrofuran, N.N- dimethylformamides, dimethyl sulfoxide or their mixed solvent.
8. application of the common load pharmaceutical polymer micella in antineoplastic is prepared described in claim 1.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107714646A (en) * | 2017-10-26 | 2018-02-23 | 苏州大学 | Amphipathic nature polyalcohol micella of tumor extracellular matrix and preparation method thereof can be penetrated |
| CN108837157A (en) * | 2018-09-10 | 2018-11-20 | 成都医学院 | A kind of double polymer nanoparticles and preparation method thereof for carrying the pure and mild flavone compound of Taxotere |
| CN109432084A (en) * | 2018-12-26 | 2019-03-08 | 温州医科大学 | A kind of anti-cancer composition and its application in medicine preparation |
| CN112999151A (en) * | 2019-12-19 | 2021-06-22 | 鲁南制药集团股份有限公司 | Oral paclitaxel composite micelle |
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| CN101554371A (en) * | 2009-04-13 | 2009-10-14 | 中国药科大学 | Preparation and application of Silybin/Silymarin polymer micelle |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107714646A (en) * | 2017-10-26 | 2018-02-23 | 苏州大学 | Amphipathic nature polyalcohol micella of tumor extracellular matrix and preparation method thereof can be penetrated |
| CN108837157A (en) * | 2018-09-10 | 2018-11-20 | 成都医学院 | A kind of double polymer nanoparticles and preparation method thereof for carrying the pure and mild flavone compound of Taxotere |
| CN109432084A (en) * | 2018-12-26 | 2019-03-08 | 温州医科大学 | A kind of anti-cancer composition and its application in medicine preparation |
| CN112999151A (en) * | 2019-12-19 | 2021-06-22 | 鲁南制药集团股份有限公司 | Oral paclitaxel composite micelle |
| CN112999151B (en) * | 2019-12-19 | 2024-03-19 | 鲁南制药集团股份有限公司 | Paclitaxel composite micelle for oral administration |
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Inventor after: Huo Meirong Inventor after: Yin Tingjie Inventor after: Zhou Jianping Inventor after: Cai Han Inventor before: Huo Meirong Inventor before: Zhou Jianping Inventor before: Cai Han Inventor before: Yin Tingjie |
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