CN105561332A - Polylysine nano prodrug micelle with charge turning and targeting functions and preparation and application thereof - Google Patents
Polylysine nano prodrug micelle with charge turning and targeting functions and preparation and application thereof Download PDFInfo
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- CN105561332A CN105561332A CN201610068619.5A CN201610068619A CN105561332A CN 105561332 A CN105561332 A CN 105561332A CN 201610068619 A CN201610068619 A CN 201610068619A CN 105561332 A CN105561332 A CN 105561332A
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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
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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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Abstract
The invention discloses a polylysine nano prodrug micelle with charge turning and targeting functions and preparation and application thereof. The polylysine nano prodrug micelle takes a hydrophobic drug as an inner core, the structure of the hydrophobic drug contains amino, a polylysine chain serves as a shell layer and is composed of 10-25 lysines, the amino of the hydrophobic drug is connected with carboxyl located at the tail end of the polylysine chain through an amido bond, amino located at the tail end of the polylysine chain modifies an upper targeting ligand through an amido bond as well, and beta-carboxyl amidation is performed on amino located at a side chain of the polylysine chain. According to the polylysine nano prodrug micelle with the charge turning and targeting functions and preparation and application thereof, the structure and preparation process of the prodrug micelle are simplified, the prodrug micelle has both the active and passive targeting properties and the pH responding property, the treatment efficiency can be improved, and the toxic and side effects are reduced.
Description
Technical field
The present invention relates to and a kind ofly there is polylysine nano-prodrug micelle and preparation method thereof of electric charge upset and target function and preparing the application in tumor-targeting drug.
Background technology
In the last few years, due to each side such as environment, cancer becomes in daily life more and more for common, and presents the trend become younger, and has just like become the biggest threat of human health.But, because the selectivity of current commonly used cancer therapy drug is low, in order to realize clinical efficacy, generally all can give patient higher drug dose, but this also may cause major injury to healthy cell simultaneously.Therefore, current for cancer comparatively effective method be exactly exploitation efficient drug delivery systems to reduce the damage of medicine to healthy cell.
Common cancer therapy drug is mainly DNA poison control centre, as the term suggests these medicines must enter nucleus can play its due effect at present.But resistant tumors cell has number of mechanisms, can medicine be stoped more efficiently to enter nucleus.Therefore, the carrier for cancer therapy drug transport must have nuclear location ability, the biomacromolecule of more common is some positively chargeds.But, this kind of positively charged polymer to be easy to identify by reticuloendothelial system and clear out of blood circulation, also can bring certain risk with the albumen generation adsorption in blood.For this problem, now comparatively conventional method is modified polymer Polyethylene Glycol, amphion or β-Carboxylamide.
The pharmaceutical carrier that wherein β-Carboxylamide obtains after modifying has the ability of electric charge upset.It can stable existence under the physiological condition of human normal, presents negative electricity, and when arriving in tumor tissues or cancerous cell, because pH environment becomes faintly acid, thus causes β-Carboxylamide hydrolysis, makes original negative electricity system become positive electricity.Therefore, a kind of like this pharmaceutical carrier with electric charge upset ability, can avoid the absorption of albumen in blood circulation on the one hand, also have good nuclear location ability simultaneously.
Polylysine is comparatively popular and research the most a kind of polyamino acid in recent years, the good biocompatibility had except general polyamino acid, to have no side effect, outside non-immunogenicity, the advantage such as biodegradable, synthesis is comparatively simply easy to control comparatively speaking, chemical modification more for convenience, when being used as pharmaceutical carrier, drug loading is comparatively large and have affinity to some cancerous cell, and the pharmaceutical carrier that the amino on its side chain also has electric charge upset ability for preparation is provided convenience.
In addition, above-mentioned have become positive electricity system by electric charge upset in the environment of slant acidity near electric charge upset ability pharmaceutical carrier cancerous cell after can also increase endocytosis.Therefore develop so a kind of polylysine nano-prodrug micelle with electric charge upset and target function and there is important Research Significance and using value.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind ofly to be had polylysine nano-prodrug micelle and preparation method thereof of electric charge upset and target function and is preparing the application in tumor-targeting drug, simplify structure and the preparation process of prodrug micelle, and this prodrug micelle has active and passive targeting and pH response performance concurrently simultaneously, can therapeutic efficiency be improved, reduce toxic and side effects.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
The invention provides a kind of polylysine nano-prodrug micelle with electric charge upset and target function, described nano-micelle take hydrophobic drug as kernel, containing amino in described hydrophobic drug structure, polylysine chain is shell, described polylysine chain is made up of 10 ~ 25 lysines, the amino of hydrophobic drug is connected by amido link with the terminal carboxyl group of polylysine chain, and modify targeting part at polylysine chain end amino by amido link, polylysine chain side-chain amino group is carried out β-carboxy amidation.
Further, described hydrophobic drug can be amycin (DOX), amycin salt, pirarubicin etc., and wherein amycin salt can be amycin inorganic acid salt: as doxorubicin hydrochloride, amycin sulfate, amycin nitrate etc.; Also can be amycin acylate, as amycin oxalates, amycin acetate etc.Preferred hydrophobic drug is amycin.
Further, described polylysine chain is preferably made up of 19 lysines.
Further, described targeting part can be folic acid or lactobionic acid, preferred folic acid.
Further, the reagent carrying out β-carboxy amidation with polylysine chain side-chain amino group can be 2,3-dimethyl maleic anhydride, 2-methyl maleic anhydride, 3,4,5,6-THPA, 2,2,3,3-tetramethyl-succinic acid acid anhydride, succinic anhydride or maleic anhydride, preferably 2,3-dimethyl maleic anhydrides.
Present invention also offers a kind of described in there is the preparation method of polylysine nano-prodrug micelle of electric charge upset and target function, comprise the steps:
(1) hydrophobic drug is dissolved in organic solvent A, add lysine compounds under nitrogen protection, the side-chain amino group of described lysine compounds is protected by blocking group, 2-5 days is stirred in 20-70 DEG C of lucifuge, reaction solution organic solvent D is precipitated, sucking filtration, room temperature in vacuo drying obtains product A;
(2) product A is dissolved in organic solvent B, add I-hydroxybenzotriazole (HOBT), O-BTA-tetramethylurea hexafluorophosphoric acid ester (HBTU), N, N-diisopropylethylamine (DIEA) and targeting part, stirring reaction 2 ~ 24h, by reactant liquor first to organic solvent B dialysis 1 ~ 2 day, again to ultra-pure water dialysis 2 ~ 4 days, wherein the MWCO of bag filter is 500 ~ 1500Da, gets trapped fluid lyophilization and obtains product B;
(3) remove the protecting group in product B on side-chain amino group, obtain product C;
(4) by product C ultrasonic disperse in organic solvent C, add triethylamine (TEA) and carry out the reagent of β-carboxy amidation, stirring reaction 2 ~ 24h, reactant liquor organic solvent D precipitates, and centrifugal final vacuum drying obtains product D;
(5) product D is dissolved in water, ultrasonic leave standstill after namely to obtain aqueous solution lyophilization having the polylysine nano-prodrug micelle of electric charge upset and target function;
Wherein, organic solvent A, organic solvent B, organic solvent C are independently selected from one of following separately: acetonitrile, DMF (DMF), hexamethyl phosphoramide, dimethyl sulfoxide, are preferably DMF; And omnidistance lucifuge in step (1) ~ (4) operating process.Organic solvent D can be ether, propyl ether, petroleum ether, normal hexane, cyclohexane extraction, toluene, preferred ether.
Further, in step (1), described lysine compounds is N ε-benzyloxycarbonyl group-1B, N ε-tertbutyloxycarbonyl-1B or N ε-fluorenylmethyloxycarbonyl-1B, preferred N ε-benzyloxycarbonyl group-1B.
Further, in step (1), described hydrophobic drug is 1:10 ~ 30 with the ratio of the amount of substance of lysine compounds, and preferably the ratio of both amount of substances is 1:25 ~ 30, most preferably is 1:28.4; The consumption of described organic solvent A counts 90 ~ 180L/mol with the amount of substance of hydrophobic drug, preferably 100 ~ 120L/mol, most preferably 116L/mol.
Further, in step (2), the ratio of the amount of substance of described product A, I-hydroxybenzotriazole (HOBT), O-BTA-tetramethylurea hexafluorophosphoric acid ester (HBTU), DIPEA (DIEA), targeting part is 1:1 ~ 3:1 ~ 3:2 ~ 6:3 ~ 6.
Further; in step (3); those skilled in the art can remove protecting group in product B on amino according to literature procedure; such as, when lysine compounds is N ε-benzyloxycarbonyl group-1B; by following method deprotection base: product B is dissolved in a certain amount of trifluoroacetic acid (TFA); ice bath slowly drips a certain amount of 33wt.%HBr/AcOH solution after stirring a period of time; stir 1-2h; blocking group on product B side-chain amino group can be removed, product B is 1:60 ~ 400 with the ratio of the amount of 33wt.%HBr/AcOH solution mass.
Further, in step (4), the ratio of product C, triethylamine (TEA) and the reagent amount of substance that carries out β-carboxy amidation is 1:0.05 ~ 0.1:20 ~ 75.
In the present invention, the amount of substance of product A, product B, product C counts divided by the Mw in GPC result according to its quality respectively.
The polylysine nano-prodrug micelle described in additionally providing herein with electric charge upset and target function is preparing the application in tumor-targeting drug.
Compared with prior art, beneficial effect of the present invention is mainly reflected in:
A () the present invention directly utilizes hydrophobic drug to cause the ring-opening polymerisation of lysine anhydride, this method is comparatively easy;
Prepared nano-prodrug in (b) the present invention be a kind ofly to be made up of pure medicine, the Nano medication of zero content inert carrier, avoid the existence of a large amount of inert pharmaceutical carrier in other similar nanometer medicines, the existence avoided due to these carrier materials is born the metabolism of linked groups's organ in human body, avoids the toxic and side effects that carrier material may exist; Nano-micelle prepared in the present invention has active targeting and passive target concurrently, has good targeting potentiality; Designed by the present invention, the electromotive force of nano-micelle has response to pH, effectively can avoid the absorption of albumen in blood circulation on the one hand, adds the ability entering cell on the one hand in addition.
Accompanying drawing explanation
Fig. 1 is that DOX-PLL (the DMA)-FA of the embodiment of the present invention 1 synthesizes schematic diagram
Fig. 2 is the FTIR spectrum figure of DOX-PLL (the DMA)-FA of the embodiment of the present invention 1;
Fig. 3 is DOX-PLL-FA micelle hydration grain size distribution prepared by the embodiment 1 that recorded by DLS;
Fig. 4 hydration grain size distribution that DOX-PLL (DMA)-FA micellar conformation and DLS record prepared by the embodiment 1 observed in transmission electron microscope;
DOX-PLL (the DMA)-FA micelle of Fig. 5 prepared by embodiment 1 at 37 DEG C, charge reversal figure under different pH environment;
DOX-PLL (the DMA)-FA micelle of Fig. 6 prepared by embodiment 1 at 37 DEG C, the DOX release profiles under different Papain Enzymatic Activity.
Detailed description of the invention
Below detailed introduction is provided to embodiments of the present invention, but protection scope of the present invention is not limited thereto.
Embodiment 1:
(1) phosgenation prepares N ε-benzyloxycarbonyl group-1B anhydride: by the N of 2.62g (0.02mol) ε-benzyloxycarbonyl group-1B ultrasonic disperse in the anhydrous THF of 90mL, omnidistance N
2protection, carries out vigorous stirring at 50 DEG C.Triphosgene after 5.94g recrystallization is dissolved in the anhydrous THF of 15mL, dropwise be added drop-wise in reaction system, until solution becomes clarification, continue stirring reaction 90min afterwards, the solvent of general about 2/3 is fallen in last distilling under reduced pressure, then joins in a large amount of normal hexane, sucking filtration obtains solid, carry out twice recrystallization again, by product at room temperature dried in vacuo overnight, namely prepare Z-Lys-NCA.
(2) DOX-PLL (Z) is prepared in DOX initiation NCA ring-opening polymerisation: be dissolved in by 20mgDOX in the dry DMF of 3mL, above-mentioned for the 320mg Z-Lys-NCA prepared is dissolved in the dry DMF of 1mL, it is slowly added drop-wise in DOX/DMF solution, at N
2under protection, 50 DEG C of oil bath stirring reactions 4 days, are added drop-wise to reacted solution in excessive ether and precipitate, sucking filtration obtain product and at 30 DEG C dried in vacuo overnight.In experimentation, whole process carries out shading treatment.The GPC result of table 1 DOX-PLL (Z) prepared by embodiment;
Table 1
According to GPC result, in DOX-PLL (Z), the chain hop count of lysine is 19.
(3) preparation of DOX-PLL (Z)-FA: take the above-mentioned DOX-PLL (Z) prepared of 100mg and be dissolved in the dry DMF of 5mL, add the HOBT of HBTU and 24mg of 70mg, and add the DIEA of 25 μ L, in addition the folic acid of 33.5mg is dissolved in after in the dry DMF of 15mL and it is slowly added drop-wise in DOX-PLL (Z) solution, stirring reaction 24h, reacted solution is transferred in the bag filter of MWCO=1000, first 1 day is dialysed to remove excessive folic acid and all the other unreacted raw materials to DMF, again 4 days are dialysed to remove DMF to ultra-pure water, postlyophilization, obtain product.Omnidistance shading treatment.
(4) deprotection of DOX-PLL (Z)-FA: above-mentioned for 50mg DOX-PLL (the Z)-FA prepared is dissolved in the trifluoroacetic acid of 3.1mL; ice bath slowly drips the 33wt.%HBr/AcOH solution of 1.125mL after stirring 15min; stirring reaction 1h; reacted solution is added drop-wise in excess diethyl ether and precipitates; solid is obtained after centrifugal; at room temperature dried in vacuo overnight, obtains DOX-PLL-FA.Omnidistance shading treatment.
Getting a certain amount of DOX-PLL-FA is dissolved in water, after ultrasonic standing a period of time, measure its particle size distribution by laser particle size analyzer (ZetasizerNano-ZS90), this system can stable dispersion in aqueous, as shown in Figure 3, its particle diameter is probably 110nm.
(5) preparation of DOX-PLL (DMA)-FA micelle: by 28mgDOX-PLL-FA ultrasonic disperse in the dry DMF of 3mL, add the DMA of TEA and 44mg of 48 μ L, stirring reaction spends the night.Afterwards reacted solution is added drop-wise in excess diethyl ether and precipitates, the at room temperature dried in vacuo overnight of the product after centrifugal, omnidistance shading treatment.Taking appropriate product is dissolved in a certain amount of water, leaves standstill and can obtain micelle after ultrasonic a period of time.
Table 2 is the Zeta potential data summary table of DOX-PLL-FA and DOX-PLL (DMA)-FA.
Table 2
As shown in Figure 4, due to the introducing of too much carboxyl, its dispersibility in water is slightly deteriorated, and transmission electron microscope picture shows its form for circular, and overlapping phenomenon is comparatively obvious, and it is probably 130nm that DLS result shows its hydration particle diameter.As shown in Figure 5, this system has good response performance to pH, and about when pH=6.8, charge reversal is obvious.
(6) the tablets in vitro research of DOX-PLL (DMA)-FA micelle: the activation of papain: the pH that the papain getting 53mg is dissolved in 2mL is in the PBS buffer solution of 6.8, add the ethylenediaminetetraacetic acid of 0.02mM (1mg) and the sodium ascorbate (3mg) of 10mM, constant temperature oscillation 30min at 37 DEG C.
Tablets in vitro is tested: be dissolved in the ultra-pure water of 8mL by the material of 5mg, respectively get 1.25mL and put into three bag filters (MWCO:1000) respectively, label 0,1,2 respectively, afterwards respectively to the PBS buffer solution of pH=6.8 of the papain solution added in three bag filters after 0mL, 0.125mL, 0.625mL activation and 1.25mL, 1.125mL, 0.625mL, three bag filters are put into the corresponding centrifuge tube containing the above-mentioned buffer solution of 5mL, be put in agitator, temperature is set to 37 DEG C, and does shading treatment.From dialysis solution, take out 2mL solution according to the interval of setting, and add the corresponding buffer solution of 2mL in dialysis solution to ensure that the cumulative volume of dialysis solution remains unchanged.The amount of the DOX discharged from micelle under different condition, by its fluorescence intensity at 560nm of fluorescent spectrophotometer assay (excitation wavelength is 480nm), utilizes standard curve to calculate.Often group experiment is divided equally three Duplicate Samples and is carried out meansigma methods for result of calculation and error simultaneously.Accumulation drug release patterns is calculated by formula: cumulative release amount (%)=(M
t/ M
∞) × 100, wherein M
tthe burst size of medicine in the t time, M
∞it is the medicine total amount that prodrug micelle comprises.
As Fig. 6, this system has good medicament slow release performance, and its release efficiency also increases accordingly to some extent when Papain Enzymatic Activity increases.
Embodiment 2:
(1) phosgenation prepares N ε-benzyloxycarbonyl group-1B anhydride: by the N of 2.62g (0.02mol) ε-benzyloxycarbonyl group-1B ultrasonic disperse in the anhydrous THF of 90mL, omnidistance N
2protection, carries out vigorous stirring at 50 DEG C.Triphosgene after 5.94g recrystallization is dissolved in the anhydrous THF of 15mL, dropwise be added drop-wise in reaction system, until solution becomes clarification, continue stirring reaction 90min afterwards, the solvent of general about 2/3 is fallen in last distilling under reduced pressure, then joins in a large amount of normal hexane, sucking filtration obtains solid, carry out twice recrystallization again, by product at room temperature dried in vacuo overnight, namely prepare Z-Lys-NCA.
(2) DOX-PLL (Z) is prepared in DOX initiation NCA ring-opening polymerisation: be dissolved in by 20mgDOX in the dry DMF of 2.5mL, above-mentioned for the 210mg Z-Lys-NCA prepared is dissolved in the dry DMF of 0.7mL, it is slowly added drop-wise in DOX/DMF solution, at N
2under protection, 60 DEG C of oil bath stirring reactions 3 days, are added drop-wise to reacted solution in excessive ether and precipitate, sucking filtration obtain product and at 30 DEG C dried in vacuo overnight.In experimentation, whole process carries out shading treatment.The GPC result of table 3 DOX-PLL (Z) prepared by embodiment;
Table 3
(3) preparation of DOX-PLL (Z)-FA: take the above-mentioned DOX-PLL (Z) prepared of 60mg and be dissolved in the dry DMF of 4mL, add the HOBT of HBTU and 14.4mg of 42mg, and add the DIEA of 15 μ L, in addition the folic acid of 20.1mg is dissolved in after in the dry DMF of 9mL and it is slowly added drop-wise in DOX-PLL (Z) solution, stirring reaction 24h, reacted solution is transferred in the bag filter of MWCO=1000, first 1 day is dialysed to remove excessive folic acid and all the other unreacted raw materials to DMF, again 3 days are dialysed to remove DMF to ultra-pure water, postlyophilization, obtain product.Omnidistance shading treatment.
(4) deprotection of DOX-PLL (Z)-FA: above-mentioned for 40mg DOX-PLL (the Z)-FA prepared is dissolved in the trifluoroacetic acid of 2.5mL; ice bath slowly drips the 33wt.%HBr/AcOH solution of 0.9mL after stirring 15min; stirring reaction 1.5h; reacted solution is added drop-wise in excess diethyl ether and precipitates; solid is obtained after centrifugal; at room temperature dried in vacuo overnight, obtains DOX-PLL-FA.Omnidistance shading treatment.
(5) preparation of DOX-PLL (DMA)-FA micelle: by 38mgDOX-PLL-FA ultrasonic disperse in the dry DMF of 3mL, add the DMA of TEA and 60mg of 65 μ L, stirs 6h.Afterwards reacted solution is added drop-wise in excess diethyl ether and precipitates, the at room temperature dried in vacuo overnight of the product after centrifugal, omnidistance shading treatment.Taking appropriate product is dissolved in a certain amount of water, leaves standstill and can obtain micelle after ultrasonic a period of time.
Claims (10)
1. one kind has the polylysine nano-prodrug micelle of electric charge upset and target function, it is characterized in that: described polylysine nano-prodrug micelle take hydrophobic drug as kernel, containing amino in described hydrophobic drug structure, polylysine chain is shell, described polylysine chain is made up of 10 ~ 25 lysines, the amino of hydrophobic drug is connected by amido link with the terminal carboxyl group of polylysine chain, modify targeting part by amido link equally at polylysine chain end amino, and the side-chain amino group of polylysine chain is carried out β-carboxy amidation.
2. there is the polylysine nano-prodrug micelle of electric charge upset and target function as claimed in claim 1, it is characterized in that: described hydrophobic drug is amycin, amycin salt or pirarubicin.
3. there is the polylysine nano-prodrug micelle of electric charge upset and target function as claimed in claim 1 or 2, it is characterized in that: described targeting part is folic acid or lactobionic acid.
4. the polylysine nano-prodrug micelle with electric charge upset and target function as described in one of claims 1 to 3, it is characterized in that: the reagent carrying out β-carboxy amidation with the side-chain amino group of polylysine chain is 2,3-dimethyl maleic anhydride, 2-methyl maleic anhydride, 3,4,5,6-THPA, 2,2,3,3-tetramethyl-succinic acid acid anhydride, succinic anhydride or maleic anhydride.
5. there is a preparation method for the polylysine nano-prodrug micelle of electric charge upset and target function as claimed in claim 1, comprise the steps:
(1) hydrophobic drug is dissolved in organic solvent A, add lysine compounds under nitrogen protection, the side-chain amino group of described lysine compounds is protected by blocking group, 2-5 days is stirred in 20-70 DEG C of lucifuge, reaction solution organic solvent D is precipitated, sucking filtration, room temperature in vacuo drying obtains product A;
(2) product A is dissolved in organic solvent B, add I-hydroxybenzotriazole, O-BTA-tetramethylurea hexafluorophosphoric acid ester, N, N-diisopropylethylamine and targeting part, stirring reaction 2 ~ 24h, by reactant liquor first to organic solvent B dialysis 1 ~ 2 day, again to ultra-pure water dialysis 2 ~ 4 days, wherein the MWCO of bag filter is 500 ~ 1500Da, gets trapped fluid lyophilization and obtains product B;
(3) remove the protecting group in product B on side-chain amino group, obtain product C;
(4) by product C ultrasonic disperse in organic solvent C, add triethylamine and carry out the reagent of β-carboxy amidation, stirring reaction 2 ~ 24h, reactant liquor organic solvent D precipitates, and centrifugal final vacuum drying obtains product D;
(5) product D is dissolved in water, ultrasonic leave standstill after namely aqueous solution lyophilization is obtained polylysine nano-prodrug micelle;
Wherein, organic solvent A, organic solvent B, organic solvent C are independently selected from one of following separately: acetonitrile, DMF, hexamethyl phosphoramide, dimethyl sulfoxide; Organic solvent D is ether, propyl ether, petroleum ether, normal hexane, cyclohexane extraction or toluene; And omnidistance lucifuge in step (1) ~ (4) operating process.
6. preparation method as claimed in claim 5, it is characterized in that: in step (1), described lysine compounds is N ε-benzyloxycarbonyl group-1B, N ε-tertbutyloxycarbonyl-1B or N ε-fluorenylmethyloxycarbonyl-1B.
7. the preparation method as described in claim 5 or 6, is characterized in that: in step (1), and described hydrophobic drug is 1:10 ~ 30 with the ratio of the amount of substance of lysine compounds.
8. the preparation method as described in claim 5 or 6, it is characterized in that: in step (2), the ratio of the amount of substance of described product A, I-hydroxybenzotriazole, O-BTA-tetramethylurea hexafluorophosphoric acid ester, DIPEA, targeting part is 1:1 ~ 3:1 ~ 3:2 ~ 6:3 ~ 6.
9. the preparation method as described in claim 5 or 6, is characterized in that: in step (4), and the ratio of product C, triethylamine and the reagent amount of substance that carries out β-carboxy amidation is 1:0.05 ~ 0.1:20 ~ 75.
10. the polylysine nano-prodrug micelle as claimed in claim 1 with electric charge upset and target function is preparing the application in tumor-targeting drug.
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| CN109265680A (en) * | 2018-09-21 | 2019-01-25 | 中国科学院理化技术研究所 | A kind of epsilon-polylysine and its preparation method and application of pH response |
| CN109394691A (en) * | 2018-12-12 | 2019-03-01 | 青岛大学 | A kind of multistage pH sensitivity nano medicament carrying system |
| CN111939268A (en) * | 2019-05-14 | 2020-11-17 | 南京中医药大学 | Nano particle compound for responsive deformation of tumor microenvironment |
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| CN111939268A (en) * | 2019-05-14 | 2020-11-17 | 南京中医药大学 | Nano particle compound for responsive deformation of tumor microenvironment |
| CN111939268B (en) * | 2019-05-14 | 2023-03-31 | 南京中医药大学 | Nano particle compound for responsive deformation of tumor microenvironment |
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