CN105168230B - A kind of cancer target prodrug and its nanometer formulation and preparation method with endosome escape function - Google Patents
A kind of cancer target prodrug and its nanometer formulation and preparation method with endosome escape function Download PDFInfo
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Abstract
The present invention provides a kind of cancer target prodrugs with endosome escape function, are P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA)；Wherein, POEGMA is to have effects that the water soluble polymer of long circulating, BUF is chemotherapeutics Bufalin with anti-tumor activity, and cRGD is the polypeptide for capableing of effective active targeting tumor tissues, and P (DEA-co-BMA) is the macromolecule with endosome escape function；Additionally provide the method for preparing the cancer target prodrug, the nanometer formulation and preparation method thereof of the cancer target prodrug with endosome escape function, the nanometer formulation, cancer cell can be effectively killed under the conditions of relatively low-dose, free Bufalin drug is substantially better than to the fragmentation effect of a variety of cancer cells.
Description
Technical field
The present invention relates to cancer target deliverings and Atrigel technical field, more particularly to one kind to escape with endosome
The nanometer formulation of the cancer target prodrug for function of escaping, the preparation method of the prodrug and the prodrug and the preparation side of the nanometer formulation
Method.
Background technique
Cancer morbidity has become one of the disease for threatening human health most serious in trend is risen year by year at present
(Siegel R.L.et al,2015,CA Cancer J Clin,2015,65:5-29).Chemotherapy as operation and
The important treatment means of one kind are used widely in worldwide except radiotherapy.But most of chemotherapeutics (such as Ah
Mycin, taxol, camptothecine etc.) there are poorly water-soluble, uncontrollable release, bioavilability are low and toxic side effect is big etc. serious lacks
Point.And a kind of development of new anticancer drug often with it is risky it is big, investment is big and opens the unfavorable factors such as the period is long.Therefore, how
For the deficiency of existing anticancer drug, design, exploitation novel form are increasingly becoming biomedical neck to improve the deficiency of existing dosage form
One of the important front edge of domain research and hot spot.Nano medication preparation method multiplicity based on polymer micelle, chemical modification are simple,
The technical advantage become stronger day by day is shown in the novel form exploitation of anticarcinogen, application aspect.
Existing Nano medication generallys use physically trapping, absorption or covalent modified mode and is prepared into anti-tumor drug and receives
Rice drug, and in the further chemical modification tumor targeted molecular in its surface to promote it to be enriched with and then reach near tumor tissues
Improve the purpose of curative effect.It is a series of based on micellar nanoparticles, liposome, inorganic nano-particle (gold nanoparticle, quantum dot,
Graphene, carbon nanotube etc.) and the Nano medication of hybrid nanoparticle be developed (such as Langer et
al.,Nat Nanotechnol.,2007,2(12):751-60；Chen et al.,Adv.Mater.2014,65(1):104-
120).It is worth noting that most Nano medications enter cell and in endosome/lysosome in a manner of cell endocytic
Discharge drug.Regrettably, drug needs the competence exertion antitumor action that escapes from endosome/lysosome；And it is existing
Nano medication system does not have good endosome escape capability usually, this frequently results in the drug into cell in lysosome
In be degraded, its drug effect cannot be given full play to.
In order to which more effectively medicament transport plays a role into cytoplasm, researcher is using virus, protein, more
Peptide, small molecule compound, photosensitizer and synthesis macromolecule etc. various ways break endosome/lysosome envelope barrier.Its
In, synthesis macromolecule due to its accurate designability, can prepare with scale and good endosome escape capability by wide
General concern.In the recent period, Stayton etc. is by poly- (N, N- dimethylaminoethyl methacrylate)-b- (N, the N- diethyl of block copolymer
Base aminoethyl methacrylate-co- n-BMA), i.e. PDMAEMA-b-P (DEA-co-BMA) is passed for gene
Defeated (Biomaterials, 2012,33,2301-2309).The experimental results showed that P (DEA-co-BMA) block is in BMA content
Strong endosome escape capability is shown when 30-40%.The possible reason is P (DEA-co-BMA) block is in endosome/lyase
DEA is changed into protonation by deprotonation in the acidic environment (pH~5) of body, leads to the dissociation of this pH sensitivity micella, in turn
The phosphide bilayer interaction of the butyl and film of BMA primitive is promoted to destroy the film of endosome.Finally make nanoparticle
It escapes from endosome/lysosome.Liu et al. has synthesized the block copolymer with endosome escape function in turn, poly- (N,
N- dimethacrylamide)-b- (N, N- diethyl aminoethyl acrylate-co- n-BMA), i.e.,
PDMA-b-P (DEA-co-BMA), and mark respectively on two block the fluorescent dye of upper pH sensitivity and pH it is insensitive in
Mark molecule.Gained new polymers base pH fluorescence probe have the function of the escape of good endosome and can delicately real-time monitoring it is thin
PH change procedure (Liu et al., Biomacromolecules, 2014,15 (11): 4293-301) in cytoplasm.
Valine-arginine-glycine-aspartic acid-glutamic acid cyclic peptide, abbreviation cRGD are a kind of effective targeting peptides,
Numerous experiments are it has been confirmed that it has good Targeting Effect (James et al., Adv Drug Deliver to tumor vessel
Rev,2008,60:1615-1626).If can combine cRGD with response medicine nanoparticle, building has tumor tissues
The Nano medication of good specificity target function, inventor believe that it will have certain facilitation to curative effect of medication is improved.
Summary of the invention
For various deficiencies existing in the prior art, applicant is intended to provide a kind of swollen with endosome escape function
Tumor targeted drug.
In the present invention, inventor is obtained by controllable polymerization means containing P (DEA-co-BMA) and poly- oligomeric ethylene glycol
Methacrylate (POEGMA) polymer chain, the scopiform copolymer with endosome escape function, and use esterase responsiveness
Anti-tumor drug Bufalin (BUF) is covalently attached on the polymer by the thio ester bond of β-, will be to swollen using stable amido bond
There is tumor new vessels the cRGD of selectively targeted function to be connected on the polymer, be finally prepared to function of escaping with endosome
The cancer target prodrug and its nanometer formulation of energy.Wherein, since that nano-carrier can be made effectively to escape is netted for the long-chain of POEGMA
The phagocytosis of endothelial system, to reach macrocyclic purpose.Since the thio key of β-can hydrolyze rapidly release under esterase effect
BUF raw medicine makes it play drug effect, it is possible to prevente effectively from pharmaceutical activity sharp fall caused by general chemistry key modification of pharmaceutical
Problem.Targeting peptides cRGD is covalently attached on macromolecular chain promotes it to be enriched at tumor tissues position to improve the biology benefit of drug
Expenditure.Meanwhile the introducing of P (DEA-co-BMA), can make into intracellular endosome/lysosome Nano medication in time from
In escape into cytoplasm play drug effect, can effectively avoid the enzyme pair of strong acid and strong degradation capability in endosome/lysosome
The degradation of drug molecule improves utilization ratio of drug.
Therefore, in a first aspect, being P the present invention provides a kind of cancer target prodrug with endosome escape function
(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA).Wherein, POEGMA is the water-soluble high score with long circulating
Son, BUF are chemotherapeutics Bufalin with anti-tumor activity, and cRGD is the polypeptide for capableing of effective active targeting tumor tissues, P
It (DEA-co-BMA) is the macromolecule with endosome escape function.
It is to be solved by this invention another in order to prepare above-mentioned P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA)
How one technical problem is effectively by P (DEA-co-BMA), the targeting peptides cRGD of endosome escape function and antitumor
Drug BUF is integrated on same polymer, is allowed to that BUF poorly water-soluble can be overcome, the low problem of bioavilability again can be effective
The method CPT for avoiding conventional physical from the embedding premature disconnection problem in transportational process in vivo.Meanwhile and it can effectively promote to enter cell
Interior Nano medication escapes from endosome/lysosome to be avoided being degraded, and is really played a role, thus to the maximum extent
Play curative effect of medication.
Second aspect, the present invention provides a kind of preparation sides of above-mentioned cancer target prodrug with endosome escape function
Method, comprising the following steps:
(1) intermediate product P (OEGMA-co-BSMA-co-BEMA) is prepared:
A certain amount of Reversible Addition Fragmentation Chain Transfer initiator B PTPA, oligomeric ethylene glycol methacrylate OE GMA are contained
β-thiocarboxyl group monomer BSMA, the monomer BEMA containing atom transferred free radical initiator, solvent and radical initiator add
Enter in glass tube, tube sealing after vacuum freeze thawing three times；Later, it is reacted 0.5-40 hours under the conditions of 20-80 DEG C, obtains crude product P
(OEGMA-co-BSMA-co-BEMA), the crude product P (OEGMA-co-BSMA-co-BEMA) purification process is finally obtained into the P
(OEGMA-co-BSMA-co-B EMA)。
(2) intermediate product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) is prepared:
A certain amount of P (OEGMA-co-BSMA-co-BEMA), DEA, BMA, solvent and mantoquita ligand are added in glass tube,
Mantoquita is added in vacuum freeze thawing afterwards three times, then vacuum freeze thawing is twice, then tube sealing；Later, 0.5-20 is reacted under the conditions of 20-80 DEG C
Hour, obtain crude product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA)；Finally by crude product P (OEGMA-co-BSMA)-
G-P (DEA-co-BMA) crosses silicagel column and removes mantoquita, concentration, then purified handles to obtain the P (OEGMA-co-BSMA)-g-P
(DEA-co-BMA)。
(3) target product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is prepared:
A certain amount of P (OEGMA-co-BSMA)-g-P (DEA-co-BMA), NHS-OH, BUF, condensing agent and catalyst is molten
It is stirred at room temperature in organic solvent 3-72 hours；Then, a certain amount of cRGD is added, and the reaction was continued 1-48 hours, obtains crude product P
(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA)；Finally by the crude product P (OEGMA-co-BUF-co-RGD)-g-
P (DEA-co-BMA) purification process obtains the P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA).
Preferably, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function, the purification process
Are as follows: it dialyses in water, is then freeze-dried.
Preferably, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function, in the step (1)
The OEGMA molecular weight be 100-50000.
Preferably, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function, in the step (1)
The solvent be selected from one of DMF, DMSO, NMP, isopropanol, methanol, ethyl alcohol, dioxane and tetrahydrofuran or a variety of.
Preferably, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function, in the step (1)
The radical initiator be selected from cyclohexanone peroxide, dibenzoyl peroxide, tert-butyl hydroperoxide, two isobutyl of azo
One of nitrile, azobisisoheptonitrile are a variety of.
Preferably, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function, in the step (1)
The initiator B PTPA:OEGMA:BSMA:BEMA: the molar ratio of radical initiator be 1:10-200:0.5-200:0.5-
200:0.01-1.
Preferably, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function, in the step (2)
The solvent be selected from one of DMF, DMSO, NMP, isopropanol, methanol, ethyl alcohol and tetrahydrofuran or a variety of.
Preferably, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function, in the step (2)
The mantoquita ligand be selected from bipyridyl, PMDETA and Me6One of TREN or a variety of.
Preferably, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function, in the step (2)
The mantoquita be selected from one of cuprous bromide, stannous chloride, copper bromide and copper chloride or a variety of.
Preferably, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function, in the step (2)
The P (OEGMA-co-BSMA-co-BEMA) in BEMA:DEA:BMA: mantoquita: the molar ratio of mantoquita ligand be 1:10-
500:10-500:0.1-10:0.1-10.
Preferably, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function, in the step (3)
The condensing agent be selected from one of DCC, EDC, DIC or a variety of.
Preferably, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function, in the step (3)
The catalyst be selected from one of pyridine, dimethylamino naphthyridine, triethylamine and hydroxy benzo triazole or a variety of.
Preferably, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function, in the step (3)
The P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) in BSMA:NHS-OH:BUF: condensing agent: catalyst: cRGD
Molar ratio be 1:0.01-0.1:0.1-0.99:1-10:0.01-0.5:0.01-0.1.
The third aspect, the present invention provides a kind of nanometer systems of above-mentioned cancer target prodrug with endosome escape function
Agent, which is characterized in that the partial size of nanoparticle therein is 10~2000nm, and the targeted prodrug for including is P (OEGMA-
co-BUF-co-RGD)-g-P(DEA-co-BMA).Wherein, with P (OEGMA-co-RGD) for hydrophilic shell, with BUF and P (DEA-
It co-BMA) is hydrophobic core.
Nanometer formulation of the present invention can be made under mechanical stirring, ultrasound, high pressure homogenizer effect, and partial size is 10
~2000nm, surface is smooth, good evenness, regular particles without adhesion, redispersibility is good, carrying drug ratio and encapsulation rate are high；It is available
In the slow release nano-particle for preparing vein or intramuscular injection or oral administration, it is administered as cancer target.The nanometer formulation of preparation can
To be dispersed in solid, semisolid or solution.It is preferably formed the pharmaceutical preparation form of drug administration by injection, is infused in particular for vein
Penetrate use.
Preferably, the nanometer formulation is nanoparticle solution, wherein P (OEGMA-co-BUF-co-R the GD)-g-P
(DEA-co-BMA) concentration is 0.001-30g/L, P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) warp
After crossing human body metabolism, the molar concentration of the active medicine BUF of release is 0.001-10000 μm of ol/L.
Fourth aspect, the present invention provides a kind of preparation methods of above-mentioned nanoparticle solution, which is characterized in that selected from following
One of method: multi-emulsion method, membrane emulsification method emulsify evaporation, interphase precipitate method, self-assembly method.Wherein, used to have
Solvent, which includes that ethyl acetate, methylene chloride, chloroform, acetone, ethyl alcohol and dimethyl sulfoxide etc. are various, to be suitable for preparing nanometer
The organic solvent of grain solution.
Preferably, the preparation method is that multi-emulsion method, comprising steps of taking 4mg P (OEGMA-co-BUF-co-RGD)-g-P
(DEA-co-BMA) it is dissolved in the in the mixed solvent of 200 μ L methylene chloride or methylene chloride and acetone, ultrasonic emulsification (10s x 4),
It adds in the pluronic F68 water dispersion medium that 2.2mL concentration is 1%, again ultrasonic emulsification (10s x 4).Then room temperature
Lower stirring 0.5-5h removes organic phase to get nanoparticle solution.
Preferably, the preparation method is that membrane emulsification method, comprising steps of taking 4mg P (OEGMA-co-BUF-co-
RGD)-g-P (DEA-co-BMA) is dissolved in 400 μ L acetone solvents, and the aqueous solution of 4mL, room temperature is then added in rotary evaporation film forming
Lower stirring 0.5-6h is to get nanoparticle solution.
Preferably, the preparation method is that evaporation is emulsified, comprising steps of taking 4mg P (OEGMA-co-BUF-co-
RGD)-g-P (DEA-co-BMA) is dissolved in 400 μ L acetone/methylene chloride in the mixed solvent, and being added to 2.2mL concentration is 2%
In water dispersion medium containing polyvinyl alcohol (PVA), 2-4h is stirred at room temperature in ultrasound or the even emulsification of high pressure cream, lotion, and waving has to the greatest extent
Solvent is to get nanoparticle solution.
Preferably, the preparation method is that interphase precipitate method, comprising steps of taking 4mg P (OEGMA-co-BUF-co-
RGD)-g-P (DEA-co-BMA) is dissolved in 400 μ L acetone solvents, and under continuous stirring condition, above-mentioned solution is injected
In the PVA water dispersion medium that the concentration of 2.2mL is 2%, pressurization volatilization removal acetone is to get nanoparticle solution.
Preferably, the preparation method is that self-assembly method, comprising steps of taking 4mg P (OEGMA-co-BUF-co-RGD)-
G-P (DEA-co-BMA) is dissolved in 200 μ L DMSO, in the water that solution instillation 2mL is stirred, is packed into solution dialyses later
It dialyses 3-72 hours in bag, removes organic solvent to get nanoparticle solution.
It is further preferred that the preparation method of the nanoparticle solution, which is characterized in that the water dispersion medium is selected from
One of dextrose former times 40-70, pluronic F68 or PVAC polyvinylalcohol are a variety of, and the matter of the water dispersion medium
Amount concentration expressed in percentage by volume is 0.01-10%.
It is further preferred that the preparation method of the nanoparticle solution, which is characterized in that the intensity of the ultrasound is
10-1000W。
It is further preferred that the preparation method of the nanoparticle solution, which is characterized in that the retention of the bag filter point
The range of son amount is 1000-10000Da.
Preferably, the nanometer formulation is that nanometer is freeze-dried, wherein freeze-drying caffolding agent is selected from trehalose, glucose, cream
One of sugar, pan-fried sugar, dextran, sorbierite, mannitol and polyethylene glycol are a variety of, and the quality of the freeze-drying caffolding agent
Percentage concentration is 0.01-20%.
Various preparation methods of the present invention are easy, are suitable for large-scale production, particularly useful for making with long circulating,
Biodegradable, sustained release, active targeting, transports active material, anti-tumor drug at passive target, especially prepares anti-intestinal cancer
Drug.Using the antitumor prodrug and its nanometer formulation that method of the invention obtains be suitable for intravenous injection, intramuscular injection,
The modes such as subcutaneous injection, intracutaneous injection, oral or percutaneous dosing.
Cancer target prodrug nanometer formulation of the present invention with endosome escape function, can be in relatively low-dose condition
Under effectively kill cancer cell, free Bufalin drug is substantially better than to the fragmentation effect of a variety of cancer cells.
Preparation method of the present invention is easy, is suitable for large-scale production, and being particularly adapted to preparation has long circulating, can give birth to
Object degradation, transports active material, anti-tumor drug at sustained release, passive target, active targeting, especially prepares the medicine of anti-intestinal cancer
Object.Intravenous injection, intramuscular injection, subcutaneous injection, intradermal note are suitable for using the anti-tumor drug that method of the invention obtains
It penetrates, take orally or the modes such as percutaneous dosing.
Detailed description of the invention
Fig. 1 is cancer target prodrug P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BM A) of the present invention
A preferred embodiment synthetic route chart；
Fig. 2 is P (OEGMA-co-BSMA)-g-P (DEA-co-BM A) in a preferred embodiment of the present invention
In CDCl3In1H NMR spectra；
Fig. 3 is P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co- in a preferred embodiment of the present invention
BMA) in CDCl3In1H NMR spectra；
Fig. 4 is P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co- in a preferred embodiment of the present invention
BMA the grain size distribution of nanoparticle)；
Fig. 5 is P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co- in a preferred embodiment of the present invention
BMA nanoparticle) is to the cell survival rate figure after the effect of LoVo cell strain 48 hours.
Specific embodiment
The present invention is further elaborated With reference to embodiment, but the present invention is not limited to following embodiment party
Formula.
In a first aspect, being P the present invention provides a kind of cancer target prodrug with endosome escape function
(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA).Wherein, POEGMA is the water-soluble high score with long circulating
Son, BUF are chemotherapeutics Bufalin with anti-tumor activity, and cRGD is the polypeptide for capableing of effective active targeting tumor tissues, P
It (DEA-co-BMA) is the macromolecule with endosome escape function.
Second aspect, the present invention provides a kind of preparation sides of above-mentioned cancer target prodrug with endosome escape function
Method, synthetic route are shown in attached drawing 1, specifically includes the following steps:
(1) intermediate product P (OEGMA-co-BSMA-co-BEMA) is prepared:
A certain amount of Reversible Addition Fragmentation Chain Transfer initiator B PTPA, oligomeric ethylene glycol methacrylate OE GMA are contained
β-thiocarboxyl group monomer BSMA, the monomer BEMA containing atom transferred free radical initiator, solvent and radical initiator add
Enter in glass tube, tube sealing after vacuum freeze thawing three times；Later, it is reacted 0.5-40 hours under the conditions of 20-80 DEG C, obtains crude product P
(OEGMA-co-BSMA-co-BEMA), the crude product P (OEGMA-co-BSMA-co-BEMA) purification process is finally obtained into the P
(OEGMA-co-BSMA-co-B EMA)。
(2) intermediate product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) is prepared:
A certain amount of P (OEGMA-co-BSMA-co-BEMA), DEA, BMA, solvent and mantoquita ligand are added in glass tube,
Mantoquita is added in vacuum freeze thawing afterwards three times, then vacuum freeze thawing is twice, then tube sealing；Later, 0.5-20 is reacted under the conditions of 20-80 DEG C
Hour, obtain crude product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA)；Finally by crude product P (OEGMA-co-BSMA)-
G-P (DEA-co-BMA) crosses silicagel column and removes mantoquita, concentration, then purified handles to obtain the P (OEGMA-co-BSMA)-g-P
(DEA-co-BMA).(3) target product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is prepared:
A certain amount of P (OEGMA-co-BSMA)-g-P (DEA-co-BMA), NHS-OH, BUF, condensing agent and catalyst is molten
It is stirred at room temperature in organic solvent 3-72 hours；Then, a certain amount of cRGD is added, and the reaction was continued 1-48 hours, obtains crude product P
(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA)；Finally by the crude product P (OEGMA-co-BUF-co-RGD)-g-
P (DEA-co-BMA) purification process obtains the P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA).
In a preferred embodiment, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function,
The purification process are as follows: dialyse in water, be then freeze-dried.
In a preferred embodiment, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function,
The molecular weight of the OEGMA in the step (1) is 100-50000.
In a preferred embodiment, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function,
The solvent in the step (1) is in DMF, DMSO, NMP, isopropanol, methanol, ethyl alcohol, dioxane and tetrahydrofuran
It is one or more.
In a preferred embodiment, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function,
The radical initiator in the step (1) is selected from cyclohexanone peroxide, dibenzoyl peroxide, tert-butyl hydroperoxide
One of hydrogen, azodiisobutyronitrile, azobisisoheptonitrile are a variety of.
In a preferred embodiment, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function,
The initiator B PTPA:OEGMA:BSMA:BEMA: the molar ratio of radical initiator in the step (1) is 1:10-
200:0.5-200:0.5-200:0.01-1.
In a preferred embodiment, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function,
The solvent in the step (2) be selected from one of DMF, DMSO, NMP, isopropanol, methanol, ethyl alcohol and tetrahydrofuran or
It is a variety of.
In a preferred embodiment, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function,
The mantoquita ligand in the step (2) is selected from bipyridyl, PMDETA and Me6One of TREN or a variety of.
In a preferred embodiment, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function,
The mantoquita in the step (2) is selected from one of cuprous bromide, stannous chloride, copper bromide and copper chloride or a variety of.
In a preferred embodiment, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function,
The BEMA:DEA:BMA: mantoquita in the P (OEGMA-co-BSMA-co-BEMA) in the step (2): mantoquita ligand rubs
You are than being 1:10-500:10-500:0.1-10:0.1-10.
In a preferred embodiment, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function,
The condensing agent in the step (3) is selected from one of DCC, EDC, DIC or a variety of.
In a preferred embodiment, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function,
The catalyst in the step (3) is selected from one of pyridine, dimethylamino naphthyridine, triethylamine and hydroxy benzo triazole
Or it is a variety of.
In a preferred embodiment, in the preparation method of the above-mentioned cancer target prodrug with endosome escape function,
The BSMA:NHS-OH:BUF in the P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) in the step (3): condensation
Agent: catalyst: the molar ratio of cRGD is 1:0.01-0.1:0.1-0.99:1-10:0.01-0.5:0.01-0.1.
The third aspect, the present invention provides a kind of nanometer systems of above-mentioned cancer target prodrug with endosome escape function
Agent, which is characterized in that the partial size of nanoparticle therein is 10~2000nm, and the targeted prodrug for including is P (OEGMA-
co-BUF-co-RGD)-g-P(DEA-co-BMA).Wherein, with P (OEGMA-co-RGD) for hydrophilic shell, with BUF and P (DEA-
It co-BMA) is hydrophobic core.
In a preferred embodiment, the nanometer formulation is nanoparticle solution, wherein the P (OEGMA-co-BUF-
Co-RGD) concentration of-g-P (DEA-co-BMA) is 0.001-30g/L, P (the OEGMA-co-BUF-co-RGD)-g-P
(DEA-co-BMA) after human body metabolism, the molar concentration of the active medicine BUF of release is 0.001-10000 μm of ol/L.
In a preferred embodiment, the present invention provides a kind of preparation method of above-mentioned nanoparticle solution, feature exists
In selected from one of following methods: multi-emulsion method, membrane emulsification method emulsify evaporation, interphase precipitate method, self-assembly method.Its
In, used organic solvent includes that ethyl acetate, methylene chloride, chloroform, acetone, ethyl alcohol and dimethyl sulfoxide etc. are various suitable
Together in the organic solvent for preparing nanoparticle solution.
In a preferred embodiment, the preparation method is that multi-emulsion method, comprising steps of taking 4mg P (OE GMA-co-
BUF-co-RGD)-g-P (DEA-co-BMA) is dissolved in the in the mixed solvent of 200 μ L methylene chloride or methylene chloride and acetone, ultrasound
It emulsifies (10s x 4), adds in the pluron ic F68 water dispersion medium that 2.2mL concentration is 1%, again ultrasonic emulsification
(10s x 4).Then stirring 0.5-5h removes organic phase to get nanoparticle solution at room temperature.
In a preferred embodiment, the preparation method is that membrane emulsification method, comprising steps of taking 4mg P (OEGMA-
Co-BUF-co-RGD)-g-P (DEA-co-BMA) is dissolved in 400 μ L acetone solvents, and rotary evaporation film forming is then added 4mL's
Aqueous solution stirs 0.5-6h at room temperature to get nanoparticle solution.
In a preferred embodiment, the preparation method is that evaporation is emulsified, comprising steps of taking 4mg P (OEGMA-
Co-BUF-co-RGD)-g-P (DEA-co-BMA) is dissolved in 400 μ L acetone/methylene chloride in the mixed solvent, is added to 2.2mL
In the water dispersion medium containing polyvinyl alcohol (PVA) that concentration is 2%, ultrasound or the even emulsification of high pressure cream, lotion are stirred at room temperature
2-4h waves most organic solvent to get nanoparticle solution.
In a preferred embodiment, the preparation method is that interphase precipitate method, comprising steps of taking 4mg P (OEGMA-
Co-BUF-co-RGD)-g-P (DEA-co-BMA) is dissolved in 400 μ L acetone solvents, will be above-mentioned molten under continuous stirring condition
Liquid injects in the PVA water dispersion medium that the concentration of 2.2mL is 2%, and pressurization volatilization removal acetone is to get nanoparticle solution.
In a preferred embodiment, the preparation method is that self-assembly method, comprising steps of taking 4mg P (OEGMA-co-
BUF-co-RGD)-g-P (DEA-co-BMA) is dissolved in 200 μ L DMSO, in the water that solution instillation 2mL is stirred, later will
Solution is fitted into bag filter and dialyses 3-72 hours, removes organic solvent to get nanoparticle solution.
In a further preferred embodiment, the preparation method of the nanoparticle solution, which is characterized in that described
Water dispersion medium is selected from one of dextrose former times 40-70, pluronic F68 or polyvinyl alcohol (PVA) or a variety of, and institute
The mass percent for stating water dispersion medium is 0.01-10%.
In a further preferred embodiment, the preparation method of the nanoparticle solution, which is characterized in that described
The intensity of ultrasound is 10-1000W.
In a further preferred embodiment, the preparation method of the nanoparticle solution, which is characterized in that described
The range of the molecular cut off of bag filter is 1000-10000Da.
In a preferred embodiment, the nanometer formulation is that nanometer is freeze-dried, wherein freeze-drying caffolding agent is selected from seaweed
One of sugar, glucose, lactose, pan-fried sugar, dextran, sorbierite, mannitol and polyethylene glycol are a variety of, and the freeze-drying
The mass percentage concentration of caffolding agent is 0.01-20%.
Embodiment 1
Poly- (the methacrylic acid oligomeric ethylene glycol ester-co- Bufalin-co- with endosome escape function of cRGD modification
RGD)-g- poly- (N, N- diethyllaminoethyl methacrylate-co- n-BMA) cancer target prodrug, i.e. P
(OEGMA-co-BUF-co-RGD) preparation of-g-P (DEA-co-BMA):
(1) preparation of P (OEGMA-co-BSMA-co-BEMA): by BPTPA (33mg 0.1mmol), OEGMA (3.0g,
6mmol), BSMA (686mg, 2.5mmol), BEMA (140mg, 0.5mmol) and AIBN (1.6mg) are added in glass tube, and add
Enter 10mL dioxane, tube sealing after vacuum freeze thawing three times.Later, it reacts 5 hours for 70 DEG C.Reaction gained crude product is dialysed in water
24 hours removing impurity, after freeze-drying, obtains the P (OEGMA-co-BSMA-co-BEMA).Gained P is measured through GPC
(OEGMA-co-BSMA-co-BEMA) molecular weight Mn=30,300, molecular weight distribution Mw/Mn=1.07.
(2) preparation of P (OEGMA-co-BSMA)-g-P (DEA-co-BMA): by P (OEGMA-co-BS MA-co-BEMA)
(606mg, 74 μm of ol Br), DEA (822mg, 4.44mmol), BMA (420mg, 2.96mmol) and PMDETA (13mg, 74 μ
Mol it) is added in glass tube, and 10m L DMF is added, CuBr (11mg, 74 μm of ol) are added afterwards three times in vacuum freeze thawing, then vacuum is frozen
Melt twice, then tube sealing.Later, it reacts 3 hours for 60 DEG C.Reaction gained crude product crosses silicagel column and removes mantoquita, then concentration exists
It dialyses in water 48 hours removing impurity, after freeze-drying, obtains the P (OEGMA-co-BSMA)-g-P (DEA-co-BMA).Through
The molecular weight M of GPC measurement gained P (OEGMA-co-BSMA)-g-P (DEA-co-BMA)n=70,900, molecular weight distribution Mw/Mn
=1.22, nucleus magnetic hydrogen spectrum is as shown in Figure 2.
(3) preparation of P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA):
By P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) (709mg, 259 μm of ol COOH), NHS-OH (1.7mg,
15 μm of ol), BUF (70mg, 181 μm of ol), DCC (53mg, 259 μm of ol) and DMAP (3mg) be dissolved in methylene chloride and being stirred at room temperature
48 hours.Then cRGD (3.7mg, 6 μm of ol) are added, and the reaction was continued 24 hours.Reaction gained crude product purifying: 24 are dialysed in water
Hour removes impurity, and after freeze-drying, target product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is made.Through
The molecular weight M of GPC measurement gained P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA)n=77,500, molecular weight point
Cloth Mw/Mn=1.21, nucleus magnetic hydrogen spectrum is as shown in Figure 3.
Embodiment 2
The preparation of P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) nanoparticle solution:
It takes 10mg P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) to be dissolved in 1mL DMSO, solution is dripped
Enter in the water that 9mL stirreds, solution is packed into dialysis 24 hours in bag filter (molecular cut off 7,000Da) later, is removed
Organic solvent is to get nanoparticle solution.Its partial size about 148.4nm (± 0.65) (see Fig. 4), potential -7.6mV (± 0.37).Carefully
Cellular toxicity experiment shows that it is substantially better than free Bufalin drug to the fragmentation effect of a variety of cancer cells.As shown in figure 5, targeting
Fragmentation effect of the Nano medication to colorectal cancer cell lines LoVo, IC50 of the IC50 far below free Bufalin.
Specific embodiments of the present invention are described in detail above, but it is merely an example, the present invention is simultaneously unlimited
It is formed on particular embodiments described above.To those skilled in the art, any couple of present invention carries out equivalent modifications and
Substitution is also all among scope of the invention.Therefore, without departing from the spirit and scope of the invention made by equal transformation and
Modification, all should be contained within the scope of the invention.
Claims (19)
1. a kind of preparation method of the cancer target prodrug with endosome escape function, comprising the following steps:
(1) intermediate product P (OEGMA-co-BSMA-co-BEMA) is prepared:
By a certain amount of Reversible Addition Fragmentation Chain Transfer initiator B PTPA, oligomeric ethylene glycol methacrylate OEGMA, contain β-sulphur
For the monomer BSMA of carboxyl, glass is added in the monomer BEMA containing atom transferred free radical initiator, solvent and radical initiator
In glass pipe, tube sealing after vacuum freeze thawing three times；Later, it is reacted 0.5-40 hours under the conditions of 20-80 DEG C, obtains crude product P (OEGMA-
Co-BSMA-co-BEMA), the crude product P (OEGMA-co-BSMA-co-BEMA) purification process is finally obtained into the P (OEGMA-
co-BSMA-co-BEMA)；
(2) intermediate product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) is prepared:
A certain amount of P (OEGMA-co-BSMA-co-BEMA), DEA, BMA, solvent and mantoquita ligand are added in glass tube, vacuum
Mantoquita is added in freeze thawing afterwards three times, then vacuum freeze thawing is twice, then tube sealing；Later, it is small that 0.5-20 is reacted under the conditions of 20-80 DEG C
When, obtain crude product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA)；Finally by the crude product P (OEGMA-co-BSMA)-g-
P (DEA-co-BMA) crosses silicagel column and removes mantoquita, concentration, then purified handles to obtain the P (OEGMA-co-BSMA)-g-P
(DEA-co-BMA)；
(3) target product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is prepared:
A certain amount of P (OEGMA-co-BSMA)-g-P (DEA-co-BMA), NHS-OH, BUF, condensing agent and catalyst, which are dissolved in, to be had
It is stirred at room temperature in solvent 3-72 hours；Then, a certain amount of cRGD is added, and the reaction was continued 1-48 hours, obtains crude product P (OEGMA-
co-BUF-co-RGD)-g-P(DEA-co-BMA)；Finally by crude product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-
Co-BMA) purification process obtains the P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA)；
Also,
The initiator B PTPA:OEGMA:BSMA:BEMA: the molar ratio of radical initiator in the step (1) is 1:
10-200:0.5-200:0.5-200:0.01-1；
The BEMA:DEA:BMA: mantoquita: mantoquita ligand in the P (OEGMA-co-BSMA-co-BEMA) in the step (2)
Molar ratio be 1:10-500:10-500:0.1-10:0.1-10；
The BSMA:NHS-OH:BUF in the P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) in the step (3): contracting
Mixture: catalyst: the molar ratio of cRGD is 1:0.01-0.1:0.1-0.99:1-10:0.01-0.5:0.01-0.1.
2. the preparation method of the cancer target prodrug according to claim 1 with endosome escape function, feature exist
In the purification process are as follows: dialyse in water, be then freeze-dried.
3. the preparation method of the cancer target prodrug according to claim 1 with endosome escape function, feature exist
In the molecular weight of the OEGMA in the step (1) is 100-50000.
4. the preparation method of the cancer target prodrug according to claim 1 with endosome escape function, feature exist
In the solvent in the step (1) is selected from DMF, DMSO, NMP, isopropanol, methanol, ethyl alcohol, dioxane and tetrahydro furan
It one of mutters or a variety of.
5. the preparation method of the cancer target prodrug according to claim 1 with endosome escape function, feature exist
In the radical initiator in the step (1) is selected from cyclohexanone peroxide, dibenzoyl peroxide, t-butyl peroxy
Change one of hydrogen, azodiisobutyronitrile, azobisisoheptonitrile or a variety of.
6. the preparation method of the cancer target prodrug according to claim 1 with endosome escape function, feature exist
In the solvent in the step (2) is selected from one of DMF, DMSO, NMP, isopropanol, methanol, ethyl alcohol and tetrahydrofuran
Or it is a variety of.
7. the preparation method of the cancer target prodrug according to claim 1 with endosome escape function, feature exist
In the mantoquita ligand in the step (2) is selected from bipyridyl, PMDETA and Me6One of TREN or a variety of.
8. the preparation method of the cancer target prodrug according to claim 1 with endosome escape function, feature exist
In the mantoquita in the step (2) is selected from one of cuprous bromide, stannous chloride, copper bromide and copper chloride or a variety of.
9. the preparation method of the cancer target prodrug according to claim 1 with endosome escape function, feature exist
In the condensing agent in the step (3) is selected from one of DCC, EDC, DIC or a variety of.
10. the preparation method of the cancer target prodrug according to claim 1 with endosome escape function, feature exist
In the catalyst in the step (3) is in pyridine, dimethylamino naphthyridine, triethylamine and hydroxy benzo triazole
It is one or more.
11. a kind of preparation method of nanometer formulation, which is characterized in that selected from one of following methods: multi-emulsion method, membrane emulsification
Method emulsifies evaporation, interphase precipitate method, self-assembly method；Also, the nanometer formulation is the tumour with endosome escape function
The nanoparticle solution of targeted prodrug；Wherein, it is described with endosome escape function cancer target prodrug according to claim 1~
Preparation method described in any one of 10 is made.
12. the preparation method of nanometer formulation according to claim 11, which is characterized in that the preparation method is that emulsion
Method, comprising steps of the P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is dissolved in methylene chloride or dichloromethane
The in the mixed solvent of alkane and acetone, ultrasonic emulsification are then added in water dispersion medium, again ultrasonic emulsification, are then stirred at room temperature
It mixes 0.5-5 hours, removes organic phase to get nanoparticle solution.
13. the preparation method of nanometer formulation according to claim 11, which is characterized in that the preparation method is that film is newborn
Change method, comprising steps of the P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is dissolved in acetone, rotary evaporation
Film forming, is then added aqueous solution, stirs 0.5-6 hours at room temperature to get nanoparticle solution.
14. the preparation method of nanometer formulation according to claim 11, which is characterized in that the preparation method is that emulsification is steamed
Hair method, comprising steps of the P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is dissolved in acetone/methylene chloride
In the mixed solvent is added in water dispersion medium, carries out ultrasound or 2-4 is stirred at room temperature in the even emulsification of high pressure cream, gained lotion
Hour, most organic solvent is waved to get nanoparticle solution.
15. the preparation method of nanometer formulation according to claim 11, which is characterized in that the preparation method is that interface is heavy
Shallow lake method is constantly being stirred comprising steps of the P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is dissolved in acetone
Under the conditions of mixing, gained acetone soln is injected into water dispersion medium, pressurization volatilization removal acetone is to get nanoparticle solution.
16. the preparation method of nanometer formulation according to claim 11, which is characterized in that the preparation method is that self assembly
Method, comprising steps of the P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is dissolved in DMSO, by acquired solution
It instills in a certain amount of water that stirred, solution is fitted into bag filter dialyses 3-72 hours later, remove organic solvent to get receiving
Grain of rice solution.
17. the preparation method of nanometer formulation described in any one of 2,14,15 according to claim 1, which is characterized in that the water
Decentralized medium is selected from one of dextran 40-70, pluronic F68 or polyvinyl alcohol (PVA) or a variety of and described
The quality concentration expressed in percentage by volume of water dispersion medium is 0.01-10%.
18. the preparation method of nanometer formulation described in 2 or 14 according to claim 1, which is characterized in that the intensity of the ultrasound is
10-1000W。
19. the preparation method of nanometer formulation according to claim 16, which is characterized in that the retention molecule of the bag filter
The range of amount is 1000-10000Da.
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| Diblock copolymers with tunable pH transitions for gene delivery;Mattew J. Manganiello等;《Biomaterials》;20121231;第33卷;2301-2309 |
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