CN108420794A - The liposome cascade delivering single medicine of program targeting is used for chemical drug combination therapy - Google Patents
The liposome cascade delivering single medicine of program targeting is used for chemical drug combination therapy Download PDFInfo
- Publication number
- CN108420794A CN108420794A CN201810211490.8A CN201810211490A CN108420794A CN 108420794 A CN108420794 A CN 108420794A CN 201810211490 A CN201810211490 A CN 201810211490A CN 108420794 A CN108420794 A CN 108420794A
- Authority
- CN
- China
- Prior art keywords
- ptx
- program
- liposome
- tpp
- targeting
- 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.)
- Granted
Links
Classifications
-
- 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
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
-
- 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
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dispersion Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to biological medicine technologies and nanosecond science and technology field, and in particular to a kind of preparation method and application of novel program targeting Coliposomes preparation.To be added to the DSPE PEG of lactobionic acid modification in program targeting Coliposomes2000The liposome of LA is shell, Paclitaxel liposome is targeted by the way that Liver targeting Paclitaxel liposome and hepatic mitochondria is prepared separately, two steps mixed again are prepared, the dissolubility and drug bioavailability for containing drug can be improved, realize that drug is delivered to the program of tumour " histocyte organelle ", the antineoplaston effect for improving drug can be used for being injected intravenously diagnosing tumor and Therapy study.
Description
Technical field
The invention belongs to biological medicine technologies and nanosecond science and technology field, and in particular to a kind of novel program target liposomes
Design, structure and application.The characteristics of system combines nano medicament carrying system, and cell-targeting and organelle target, with addition
The DSPE-PEG of lactobionic acid modification2000The liposome of-LA is carrier, plays delivery system and targets the work of tumor cell of liver
With；Free paclitaxel and the taxol (TPP-PTX) of TPP modifications contain thin in liposome bilayers, playing targeting respectively
The effect of intracellular tubulin and mitochondria.The two is in Coliposomes made from certain proportion physical mixed, can improve
The bioavilability and pharmacokinetic profile of drug assign drug good dissolubility, Liver targeting and Mitochondrially targeted
Property can be used for being injected intravenously diagnosing tumor and Therapy study.
Background technology
Liver cancer is one of three big malignant tumour of the world, seriously threatens the health of the mankind.Traditional embolic chemotherapy weak curative effect,
Toxic side effect is big, and therefore, scientists are dedicated to studying the drug delivery system of Liver targeting.Currently, based on people to cell table
The structure function understanding in face deepens continuously, and the delivery system of receptor-mediated active targeting liver causes the extensive of people note that most
Common therapeutic strategy is exactly the Liver targeting and the receptor-mediated Liver targeting of enoxolone that ASGPR is mediated.
ASGPR is present in mammal hepatic parenchymal cells, can single-minded identification end with galactose residue or acetyl half
Oligosaccharides, the glycoprotein of newborn glucosamine residue, and there are more ASGPR on the more normal hepatic tissue cell surface of liver cancer cells.It is common at present
ASGPR aglucons have：Lactobionic acid (lactobionic acid, LA) and glycosyl galactose ligand.For example, the dendroid of LA modifications is big
Molecule after coating contrast agent Jenner's grain of rice, can more be absorbed by ASGPR receptor-mediated effects by HepG2 cells.Gala
The adriablastina albumin nanoparticle of osamine modification can make toxicity bigger of the adriamycin to HepG2 cells.By galactose residue or second
The carrier of acyl galactosamine residue modification has very much, including liposome, polymer micelle, chitosan and dendritic etc..
Wherein, liposome has many good qualities as anti-cancer medicament carrier.Liposome is the closing capsule for having bilayer
Bubble, basis is phosphatide and cholesterol.Phosphatide is made of hydrophilic head base and two hydrophobic aliphatic chains, adjusts the base of phospholipid head
Group can make it with different charges, and PEG modifications can make liposome that there are long cycle characteristics, other aglucon modifications can make its tool
There is targeting.Cholesterol is a kind of neutral lipid, is inserted into film and adjusts the mobility of bilayer to stablize duplicature.In addition,
Liposome can contain the drug of different hydrophilic and hydrophobics using the principle of similar compatibility, improve the water solubility of dewatering medicament, mitigate
Allergy and immune response.
Mitochondria is the energy supply factory of cell activities, and is had with the generation, development and Apoptosis of tumour close
Cut relationship.Under energy deficiency, oxidative stress or other conditions, mitochondria is by changing self structure, as film potential declines, film
The modes such as permeability increase discharge cromoci (Cytochrome C, Cyt C) to cytoplasm from mitochondria, open line grain
The Apoptosis pattern that body mediates.Since mitochondria has important regulating and controlling effect to cell production capacity and apoptosis, become oncotherapy
Important target spot, targeting preparation become research hotspot in recent years.
Delocalization lipophilic cation (delocalized lipophilic cations, DLC) is a kind of hydrophilic by one
Amphiphilic cationic compound made of positively charged group and a hydrophobic grouping are keyed by chemical combination, can be in mitochondrial membrane electricity
Under the driving of position, selectively targeting to mitochondria simultaneously kills cancer cell.Triphenylphosphine is most commonly that in DLC
(triphenylphosphine, TPP) and Dequalinium Chloride (dequalinium, DQA).TPP is a kind of to pass through mitochondrial membrane
DLC, containing there are three phenyl in chemical constitution so that entire molecule has very strong fat-soluble.Meanwhile on TPP phosphorus atoms just
Charge can be formed delocalized positive charge, TPP promoted to pass through immobilized artificial membrane with delocalization to three phenyl ring.This two big feature becomes reality
Existing Mitochondrially targeted basic structural unit.And DQA contains bi-quaternary ammonium salt structure, there are two center of positive charge for tool, and contain
Long aliphatic chain, can penetration cell lipid bilayer, and then be gathered in mitochondria.
Taxol (Paclitaxel, PTX) is that one kind that scientist has found in the middle and later periods in 20th century is pernicious with well resisting
The natural products of tumor promotion forms the tubulin of spindle, interference cell period by acting in fission process
And division, it plays a role in cytoplasm.In addition, have been reported that display taxol enter cell after directly with mitochondrial surface
Anti-apoptotic proteins Bcl-2 is combined, and promotes Apoptosis.Therefore, PTX has the feature of multiple antitumor mechanism.
Program targeting drug delivery system refer to the carrier for having special affinity with cancerous tissue, cancer cell or organelle certain,
Under ligand or antibody effect, targeting drug delivery system selectively positions in cancerous tissue, cancer cell and organelle and discharges anticancer successively
Drug, the anticancer drug released concentration in organelle, the program targeting to realize " tissue-cell-ECM device " are anti-
Cancer drug delivers, relative to conventional medication raising with obvious effects；The enrichment in normal structure and cell is reduced simultaneously, is reduced
The toxic side effect of normal tissue cell.
Invention content
The invention discloses a kind of novel program target liposomes and the preparation sides of each composition part of the lipoid plastid
Method, drug release in vitro characteristic and drug delivery applications.Program targeting Coliposomes prepared by the present invention are by taxol
(PTX) it is contained in liposome respectively with the taxol (TPP-PTX) of TPP modifications；Again by two kinds of liposomes with different volumes ratio
Physical mixed is made；Liposome is by lecithin, cholesterol and DSPE-PEG2000- LA is mixed with certain proportion, is disperseed using film
It is prepared by method.Program prepared by the method targets Coliposomes size in 130~250nm or so；The lipid physical efficiency significantly improves purple
China fir alcohol realizes that drug is delivered to the program of " tissue-cell-ECM device " in the accumulation at tumor tissues position.
The preparation of the novel program targeting Coliposomes of the present invention includes following three step：
(1) Liver targeting ligand DSPE-PEG in the present invention2000The preparation process of-LA is as follows：
Weigh appropriate DSPE-PEG2000-NH2It is dissolved in DMSO, lactobionic acid is added, after 2h is stirred at room temperature, take appropriate
EDCI and NHS is added in mixed solution, adds catalytic amount triethylamine TEA to adjust pH weakly acidic pHs, reaction solution magnetic stirring apparatus is existed
Stirring 20h or so at room temperature.Crude product is transferred in bag filter and is dialysed, to remove the lactobionic acid that is not coupled, TEA, EDCI,
NHS, -20 DEG C freeze realities after be lyophilized be made.
(2) preparation process of Mitochondria targeted drug TPP-PTX of the present invention is as follows：
The synthesis of 2 '-TBS-PTX：Appropriate tert-butyl chloro-silicane (TBSCl) is taken, imidazoles is dissolved in dimethylformamide
(DMF) in, as storing solution；Above-mentioned storing solution is dissolved into appropriate taxol (PTX), room temperature (25 DEG C) is stirred to react 60min, nitrogen
Gas shielded is protected from light.After dichloromethane (DCM) is diluted and washed, n-hexane concentration extracts and is dried to obtain white solid product.
The synthesis of 2 '-TBS-7-TPP-PTX：Take appropriate 2 '-TBS-PTX, (4- carboxylics butyl) triphenylphosphinebromide (TPP) and
4-dimethylaminopyridine (DMAP) is dissolved in appropriate DCM, stirs 10min, and appropriate N '-diisopropylcarbodiimide (DIC) is molten
It in DCM, is added dropwise in above-mentioned reaction system, is reacted for 24 hours under room temperature (25 DEG C), nitrogen protection is protected from light.Dichloromethane
(DCM) after diluting and washing, column chromatography (dichloromethane: methanol=40: 1) isolated white solid product.
The synthesis of 7-TPP-PTX：Appropriate 2 '-TBS-7-TPP-PTX are taken to be dissolved in appropriate tetrahydrofuran (THF), by four fourths
The tetrahydrofuran solution (1mol/L TBAF/THF) of base ammonium fluoride is added dropwise in above-mentioned reaction system, under room temperature (25 DEG C)
6h is reacted, nitrogen protection is protected from light.It is spin-dried for THF, after dichloromethane (DCM) is diluted and is washed, column chromatography (dichloromethane: methanol=
50: 1) isolated white solid product.
(3) preparation process of program target liposomes is as follows：
The preparation of Liver targeting Paclitaxel liposome (Gal-Lips-PTX)：Weigh a certain amount of lecithin, cholesterol and
DSPE-PEG2000- LA is dissolved in chloroform and is denoted as A liquid, and another precision, which weighs PTX and is dissolved in chloroform, is denoted as B liquid, and A, B liquid are closed
And be transferred in round-bottomed flask, it is sufficiently mixed, in 40 DEG C, 100r/min rotary evaporation in vacuo 30min wait for chlorine in round-bottomed flask
It imitates after volatilizing completely, 30min is hydrated with a certain amount of 28 DEG C of pure water 50r/min.It is transferred in beaker, Probe Ultrasonic Searching (ultrasound
Parameter：Every 3 seconds ultrasounds 1 second, 15%, ultrasonic 30min).
The preparation of the Mitochondrially targeted liposome of liver-(Gal-Lips-TPP-PTX)：Weigh a certain amount of lecithin, cholesterol
And DSPE-PEG2000- LA is dissolved in chloroform and is denoted as A liquid, and another precision, which weighs TPP-PTX and is dissolved in chloroform, is denoted as B liquid, will
A, B liquid merges, and is transferred in round-bottomed flask, is sufficiently mixed, and in 40 DEG C, 100r/min rotary evaporation in vacuo 30min, waits for that round bottom is burnt
After chloroform volatilizes completely in bottle, 30min is hydrated with a certain amount of 28 DEG C of pure water 50r/min.It is transferred in beaker, Probe Ultrasonic Searching
(ultrasound parameter：Every 3 seconds ultrasounds 1 second, 15%, ultrasonic 30min).
Program targets the preparation of Coliposomes (Gal-Lips-PTX/TPP-PTX)：Using above-mentioned Paclitaxel liposome
Preparation method prepares Liver targeting PTX liposomes and Liver targeting TPP-PTX liposomes respectively, by the two with different volumes than mixing
(from 100: 0 to 0: 100) is made program and targets Coliposomes.
Description of the drawings
Attached drawing 1 is the program target liposomes preparation route figure of the present invention.
Attached drawing 2 is that (A) of each Liposomal formulation group in example 2 is hydrated grain size and (B) potential diagram.
Attached drawing 3 is cell survival rate of each Liposomal formulation group in (A) HepG2 cells and (B) L02 cells in example 3
Curve.
Attached drawing 4 is (a) physiological saline in example 4, (b)(c) Gal-Lips-PTX, (d) Lips-PTX/TPP-
The pharmacodynamic result of PTX 3: 1 (e) Gal-Lips-PTX/TPP-PTX 3: 1 and (f) Gal-Lips-TPP-PTX：(A) Mice Body
Weight, (B) life cycle, (C) swollen opposite knurl are accumulated, (D) tumor weight and (E) tumour photo.
Specific implementation mode
The invention discloses a kind of novel program target liposomes design, structure, preparation method, vitro Drug characterizes,
Drug zoology property research；The preparation of Liver targeting ligand, cell in vitro absorb characteristic；The preparation of Mitochondrially targeted drug, body
Outer cell common location characteristic.The preparation of Program of the present invention targeting Coliposomes includes：(1) Liver targeting ligand DSPE-
PEG2000The synthesis of-LA；(2) synthesis of Mitochondrially targeted drug TPP-PTX；(3) preparation of program targeting Coliposomes.
Program targeting Coliposomes prepared by the present invention are to contain PTX and TPP-PTX in liposome respectively；Again will
Two kinds of liposomes are made with different volumes than physical mixed；Matrix material is then lecithin, cholesterol and DSPE-PEG2000-LA
It is mixed with certain proportion.Program prepared by the method targets Coliposomes size in 130~250nm or so, can significantly carry
High taxol realizes that drug is delivered to the program of " tissue-cell-ECM device " in the accumulation of tumor tissues.
The preparation of the novel program targeting Coliposomes of embodiment 1
1. Liver targeting ligand DSPE-PEG2000The synthesis of-LA：
Weigh appropriate DSPE-PEG2000-NH2It is dissolved in DMSO, lactobionic acid is added, after 2h is stirred at room temperature, take appropriate
EDCI and NHS is added in mixed solution, adds catalytic amount triethylamine TEA to adjust pH weakly acidic pHs, reaction solution magnetic stirring apparatus is existed
Stirring 20h or so at room temperature.Crude product is transferred in bag filter and is dialysed, to remove the lactobionic acid that is not coupled, TEA, EDCI,
NHS, -20 DEG C freeze realities after be lyophilized be made.
2. the synthesis of Mitochondrially targeted drug TPP-PTX：
The synthesis of 2 '-TBS-PTX：Appropriate tert-butyl chloro-silicane (TBSCl) is taken, imidazoles is dissolved in dimethylformamide
(DMF) in, as storing solution；Above-mentioned storing solution is dissolved into appropriate taxol (PTX), room temperature (25 DEG C) is stirred to react 60min, nitrogen
Gas shielded is protected from light.After dichloromethane (DCM) is diluted and washed, n-hexane concentration extracts and is dried to obtain white solid product.
The synthesis of 2 '-TBS-7-TPP-PTX：Take appropriate 2 '-TBS-PTX, (4- carboxylics butyl) triphenylphosphinebromide (TPP) and
4-dimethylaminopyridine (DMAP) is dissolved in appropriate DCM, stirs 10min, and appropriate N '-diisopropylcarbodiimide (DIC) is molten
It in DCM, is added dropwise in above-mentioned reaction system, is reacted for 24 hours under room temperature (25 DEG C), nitrogen protection is protected from light.Dichloromethane
(DCM) after diluting and washing, column chromatography (dichloromethane: methanol=40: 1) isolated white solid product.7-TPP-PTX's
Synthesis：Appropriate 2 '-TBS-7-TPP-PTX are taken to be dissolved in appropriate tetrahydrofuran (THF), the tetrahydrofuran of tetrabutyl ammonium fluoride is molten
Liquid (1mol/L TBAF/THF) is added dropwise in above-mentioned reaction system, reacts 6h under room temperature (25 DEG C), nitrogen protection is protected from light.
It is spin-dried for THF, after dichloromethane (DCM) is diluted and is washed, column chromatography (dichloromethane: methanol=50: 1) isolated white solid
Product.
3. program targets the preparation of Coliposomes：
The preparation of Liver targeting Paclitaxel liposome (Gal-Lips-PTX)：Weigh a certain amount of lecithin, cholesterol and
DSPE-PEG2000- LA is dissolved in chloroform and is denoted as A liquid, and another precision, which weighs PTX and is dissolved in chloroform, is denoted as B liquid, and A, B liquid are closed
And be transferred in round-bottomed flask, it is sufficiently mixed, in 40 DEG C, 100r/min rotary evaporation in vacuo 30min wait for chlorine in round-bottomed flask
It imitates after volatilizing completely, 30min is hydrated with a certain amount of 28 DEG C of pure water 50r/min.It is transferred in beaker, Probe Ultrasonic Searching (ultrasound
Parameter：Every 3 seconds ultrasounds 1 second, 15%, ultrasonic 30min).
The preparation of the Mitochondrially targeted liposome of liver-(Gal-Lips-TPP-PTX)：Weigh a certain amount of lecithin, cholesterol
And DSPE-PEG2000- LA is dissolved in chloroform and is denoted as A liquid, and another precision, which weighs TPP-PTX and is dissolved in chloroform, is denoted as B liquid, will
A, B liquid merges, and is transferred in round-bottomed flask, is sufficiently mixed, and in 40 DEG C, 100r/min rotary evaporation in vacuo 30min, waits for that round bottom is burnt
After chloroform volatilizes completely in bottle, 30min is hydrated with a certain amount of 28 DEG C of pure water 50r/min.It is transferred in beaker, Probe Ultrasonic Searching
(ultrasound parameter：Every 3 seconds ultrasounds 1 second, 15%, ultrasonic 30min).
Program targets the preparation of Coliposomes (Gal-Lips-PTX/TPP-PTX)：Using above-mentioned Paclitaxel liposome
Preparation method prepares Liver targeting Paclitaxel liposome and the Mitochondrially targeted liposome of liver-respectively, by the two with different volumes than mixed
It closes (from 100: 0 to 0: 100) and program targeting Coliposomes is made.
2 program of embodiment targets the characterization of Coliposomes
Particle diameter distribution and potential measurement：
Take freshly prepared Liver targeting Paclitaxel liposome, the Mitochondrially targeted Paclitaxel liposome of liver-, program targeting mixing
Liposome 3: 1, program target Coliposomes 1: 1, and program targets 1: 3 each 200 μ L of Coliposomes, and distilled water is diluted to 3mL.
Incorporation time is set as 0min, it is carried out to Liposomal formulation on grain size potentiometer in mixed 5min, 15min, 30min
It is hydrated the measurement of grain size and current potential.
3 program of embodiment targets the cytotoxicity of Coliposomes
The method that present procedure targets the cytotoxicity of Coliposomes is as follows：
By HepG2In in 96 orifice plates, inoculum density is 1 × 10 for cell and L02 cell inoculations4A/hole, and in 5%CO2Nothing
It is incubated overnight in bacterium incubator (37 DEG C, saturated humidity).After for 24 hours, original fluid is sucked out, coubling dilution is separately added into and prepares
5% serum-DMEM solution of the Liposomal formulation of various concentration.5%CO2(37 DEG C, saturated humidity) of sterile culture case is incubated for 24 hours
Afterwards, supernatant is discarded, is washed 2 times using 37 DEG C of PBS solutions, be added and contain tetrazolium bromide (3- (4,5-dimethyl-2-
Thiazolyl) -2,5-diphenyl-2-H-tetrazolium bromide, MTT) 0.5mg/mL 200 μ L of PBS solution.After
It is continuous to be incubated 4h, supernatant is discarded, be added 150 μ L DMSO solutions MTT reagents are combined with living cells the first a ceremonial jade-ladle, used in libation of generation crystallize into
Row is sufficiently uniformly dissolved.It is protected from light concussion 10min, the absorbance value in each hole is measured using enzyme-linked immunosorbent assay instrument, at this
Using setting wavelength 570nm, reference wavelength 630nm is as measurement wavelength.
It is that zeroing compares with the hole of cell by above-mentioned processing but without test preparation, by above-mentioned processing but without the thin of test preparation
Born of the same parents are blank control, and every group of 6 multiple holes operation repetitive (n=6) of preparation calculates cell survival rate according to following formula：
4 program of embodiment targets the pharmacodynamic study of Coliposomes
The method that present procedure targets the pharmacodynamics of Coliposomes is as follows：
Oxter is carried out to healthy ICR mouse and plants tumor, every mouse injection Heps tumors solution (1 × 107A/mL) 100 μ L, when
Knurl is accumulated to about 100~200mm3When, transplantable tumor mouse is randomly divided into 6 groups (n=5), the 0th was set as by first day of administration
It, then respectively at the 0th, 2,4,6,8 day injecting normal saline,Gal-Lips-PTX、Lips-PTX/TPP-PTX 3∶
1, Gal-Lips-PTX/TPP-PTX 3: 1 and Gal-Lips-TPP-PTX, dosage are 20mg/kg.Mouse is recorded every other day simultaneously
The size of weight and tumour mouse is put to death after last time is administered, remove tumour, and weigh.The computational methods of knurl product
Using following formula：Volume=(W2× L)/2 wherein W be the shortest radius of tumour, L be tumour greatest radius.
Claims (10)
1. a kind of program target liposomes, it is characterised in that using liposome as carrier, size is in 130-250nm, chemotherapeutics
It contains in liposome bilayers.
2. program target liposomes according to claim 1, it is characterised in that liposome be by lecithin, cholesterol and
DSPE-PEG2000- LA is prepared with film dispersion method, and its ratio be 63: 11: 1.
3. Liver targeting ligand DSPE-PEG according to claim 22000- LA, it is characterised in that DSPE-PEG2000The system of-LA
Standby is to pass through DSPE-PEG2000-NH2Acylation reaction occurs with the ligand lactobionic acid of ASGPR to be made.
4. program target liposomes according to claim 1, it is characterised in that contain chemotherapeutics PTX or TPP-PTX
In in liposome bilayers.
5. TPP-PTX according to claim 4, it is characterised in that the preparation of TPP-PTX uses TBSCl for protective agent, right
2 '-OH of PTX are made after carrying out TPP modifications to 7-OH of PTX by esterification after being protected, and PTX is made to have mitochondria
Targeting ability.
6. program target liposomes according to claim 1, it is characterised in that cascade delivers single chemotherapeutics PTX to thin
Born of the same parents' device, the program targeted therapy effect with " tissue-cell-ECM device ".
7. program target liposomes according to claim 1, pharmacokinetic parameters are sustained-release preparation.
8. program target liposomes according to claim 1, control group pharmaceutical business is compared in Tissue distribution data
Agent type is compared apparent accumulation in tumour.
9. program target liposomes according to claim 1, control group pharmaceutical business agent is compared in Pharmacodynamic Data
Type, gross tumor volume significantly reduce, and quality of life is obviously improved, and administration posterior tuberosity is remarkably decreased again, in H＆E dyeing and Tunel dyeing
In, it can be seen that the death for having tumour cell shows good therapeutic effect.
10. program target liposomes according to claim 1, it is characterised in that use physical admixture by medicine lipid
Body mixes and PTX/TPP-PTX program targeting Coliposomes is made.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810211490.8A CN108420794B (en) | 2018-03-12 | 2018-03-12 | Programming targeted liposomal cascade delivery of single drugs for chemical combination therapy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810211490.8A CN108420794B (en) | 2018-03-12 | 2018-03-12 | Programming targeted liposomal cascade delivery of single drugs for chemical combination therapy |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108420794A true CN108420794A (en) | 2018-08-21 |
| CN108420794B CN108420794B (en) | 2020-07-28 |
Family
ID=63158533
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810211490.8A Active CN108420794B (en) | 2018-03-12 | 2018-03-12 | Programming targeted liposomal cascade delivery of single drugs for chemical combination therapy |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108420794B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112755005A (en) * | 2019-11-04 | 2021-05-07 | 四川大学 | Oral nano drug delivery system mediated by small molecular nutrient substances |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977360A (en) * | 2012-12-06 | 2013-03-20 | 北京大学 | Triphenylphosphine-polyethyleneglycol 1000 vitamin E succinate (TPGS 1000-TPP) conjugated compound, and preparation method and application thereof |
| CN104292289A (en) * | 2014-07-10 | 2015-01-21 | 程怡 | Galactose ligand and its application in liver targeting liposome |
| CN105664176A (en) * | 2016-03-24 | 2016-06-15 | 浙江大学 | Mitochondria-targeted polysaccharide nano preparation and preparing method thereof |
-
2018
- 2018-03-12 CN CN201810211490.8A patent/CN108420794B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977360A (en) * | 2012-12-06 | 2013-03-20 | 北京大学 | Triphenylphosphine-polyethyleneglycol 1000 vitamin E succinate (TPGS 1000-TPP) conjugated compound, and preparation method and application thereof |
| CN104292289A (en) * | 2014-07-10 | 2015-01-21 | 程怡 | Galactose ligand and its application in liver targeting liposome |
| CN105664176A (en) * | 2016-03-24 | 2016-06-15 | 浙江大学 | Mitochondria-targeted polysaccharide nano preparation and preparing method thereof |
Non-Patent Citations (2)
| Title |
|---|
| DIVYA BANSAL,ET AL.: "Lactobionic acid coupled liposomes: an innovative strategy for targeting hepatocellular carcinoma", 《DRUG DELIVERY》 * |
| SWATI BISWAS,ET AL.: "Liposomes loaded with paclitaxel and modified with novel triphenylphosphonium-PEG-PE conjugate possess low toxicity, target mitochondria and demonstrate enhanced antitumor effects in vitro and in vivo", 《JOURNAL OF CONTROLLED RELEASE》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112755005A (en) * | 2019-11-04 | 2021-05-07 | 四川大学 | Oral nano drug delivery system mediated by small molecular nutrient substances |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108420794B (en) | 2020-07-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105833284B (en) | The building of taxol-oleic acid small molecule prodrugs self-assembled nanometer grain | |
| Wang et al. | Supramolecularly engineered phospholipids constructed by nucleobase molecular recognition: upgraded generation of phospholipids for drug delivery | |
| CN111494640B (en) | Redox double-sensitive trithio bond bridged dimer prodrug and self-assembled nanoparticles thereof | |
| Li et al. | Effects of magnetic dihydroartemisinin nano-liposome in inhibiting the proliferation of head and neck squamous cell carcinomas | |
| CN105997880A (en) | Anti-tumor nano medicine based on cross-linking biodegradable polymer vesica and preparation method of anti-tumor nano medicine | |
| CN105753922A (en) | Quadrivalent-platinum glycosyl complex for treating tumors and preparation method thereof | |
| Ni et al. | Lymph cancer chemotherapy: Delivery of doxorubicin–gemcitabine prodrug and vincristine by nanostructured lipid carriers | |
| Ling et al. | Self-assembled liposomes of dual paclitaxel-phospholipid prodrug for anticancer therapy | |
| CN105287383A (en) | Application of novel liposome-entrapped mitoxantrone combined chemotherapeutic drug in antineoplastic treatment | |
| CN105055375B (en) | Adriamycin and resveratrol with the effect of anti-multidrug resistance deliver nanoscale medicine delivery system altogether | |
| CN107998082A (en) | A kind of application for reducing responsive polymer vesica Nano medication in treatment of brain tumor medicine is prepared | |
| CN106139151A (en) | Ascorbic acid palmityl ester and the synergistic pharmaceutical composition of antitumor drug | |
| CN107936058A (en) | Taxotere 01 derivatives and its preparation method and application | |
| May et al. | Synthesis of a gemcitabine prodrug for remote loading into liposomes and improved therapeutic effect | |
| CN108948152A (en) | A kind of amphipathic cell-penetrating peptide key compound, preparation method and the usage | |
| Li et al. | Impact of the amount of PEG on prodrug nanoassemblies for efficient cancer therapy | |
| Yang et al. | A novel self-targeting theranostic nanoplatform for photoacoustic imaging-monitored and enhanced chemo-sonodynamic therapy | |
| Liang et al. | A NAG-guided nano-delivery system for redox-and pH-triggered intracellularly sequential drug release in cancer cells | |
| Wang et al. | Endoplasmic reticulum-targeted glutathione and pH dual responsive vitamin lipid nanovesicles for tocopheryl DM1 delivery and cancer therapy | |
| CN108420794A (en) | The liposome cascade delivering single medicine of program targeting is used for chemical drug combination therapy | |
| CN104368011A (en) | Pharmaceutical betaine conjugate and pharmaceutical composition and application thereof | |
| CN105832668A (en) | Folic acid-targeted acid sensitive core-crosslinked drug-loaded micelles based on polyphosphoester | |
| Chen et al. | Lipid composition has significant effect on targeted drug delivery properties of NGR-modified liposomes | |
| Hu et al. | Construction of redox-sensitive liposomes modified by glycyrrhetinic acid and evaluation of anti-hepatocellular carcinoma activity | |
| CN106554329B (en) | Water-soluble paclitaxel anti-cancer drug compounds and its preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |