CN101574527A - Liver-targeting intelligent nano-micelle prodrug system and preparation thereof - Google Patents
Liver-targeting intelligent nano-micelle prodrug system and preparation thereof Download PDFInfo
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Abstract
The invention relates to a liver-targeting intelligent nano-micelle prodrug system based on polyethylene imine, and provides a method for preparing a macromolecular prodrug. The low-toxicity polyethylene imine modified by polyethylene glycol with a liver-targeting group (T) at the remote end is used as a carrier (T-PEG-PEI), adriamycin (ADR) is used as a treatment medicament, and the carrier is connected with the adriamycin through a lysosome degradable covalent bond to form a prodrug (T-PEG-PEI-ADR). The T-PEG-PEI-ADR prodrug is self-assembled into micelles with grain diameter being 10 to 500 nanometers in water solution. The micelle prodrug system can circulate with long effect in blood, strengthen the phagocytosis of liver cancer cells on polymer nano-micelle, selectively deliver the treatment medicament to the liver tumor part, directionally kill the liver tumor cells, reduce the toxic and side effects of the adriamycin on treating the liver caner, and improve the clinical efficacy and bioavailability of the prior liver cancer treatment medicament.
Description
Technical field
The present invention relates to a kind of liver-targeting intelligent nano-micelle prodrug system, and the method for this nanoscale self assembly macromolecular prodrug of preparation is provided, belong to the biological medicine technology field based on polymine.
Background technology
Hepatocarcinoma is one of modal malignant tumor.Early hepatocarcinoma is owing to lack characteristic sign, show as that dull pain in liver, appetite are poor more, abdominal distention, weak etc., similar to most digestive tract disease symptoms, present detection method is difficult to early stage accurately diagnosis, the hepatocarcinoma of clinical discovery belongs to mid and late liver cancer more, liver has been subjected to grievous injury, so make the selection of clinical treatment and curative effect be subjected to very big restriction.At present, excision is the first-selection of treatment hepatocarcinoma, but postoperative recurs easily, and its main cause is that cancer is residual.If the postoperative adjuvant chemotherapy can obviously reduce relapse rate, improve survival rate, still, mostly there is tangible curative effect-dose-dependence in chemotherapeutics, promptly increases amount of drug and can significantly improve curative effect.But the increase of drug dose must increase the weight of systemic toxic side effect.In order to improve the liver cancer treatment effect, outside need set about from " early finding; diagnosis early, early treatment ", the raising of the discovery of new cancer treatment drug or existing cancer treatment drug curative effect, selectivity and bioavailability became the key of improving the hepatocarcinoma clinical therapeutic efficacy.
The fusion of biological medicine and nanotechnology is integrated and the nano biological medicine technology that is born is showing tempting potentiality aspect the clinic diagnosis of human major diseases such as hepatocarcinoma.Wherein, the nano-medicament carrier technology of targeting is owing to high specificity, and effect is remarkable, avoids damaging normal structure, and for the mankind improve clinical efficacy and the bioavailability that has cancer treatment drug now, reducing its toxic and side effects provides ideal solution.As Japanese Matsumure research group with the di-block copolymer micelle carrier band amycin (code name NK911) of Polyethylene Glycol and aspartic acid with taxol (code name NK105) treatment solid tumor enters the clinical II phase respectively and the clinical I phase is studied (Y.Matsumure, Proceedings of the 2004 international Conference on MEMS, NANO andSmart Systems (ICMENS ' 04)), demonstrate good clinical application prospect.The Kataoka research group is that carrier carried amycin obtains particle size distribution and examines uniformly with the di-block copolymer of poly glycol monomethyl ether and aspartic acid---the shell structural nano micelle, discover that the nano-micelle medicine can be enriched in the solid tumor, at the good (Y.Bae of stability in blood, S.Harada, K.kataoka, Angew Chem.Int.Ed.42 (2003) 4640.).Though the copolymer micelle with Polyethylene Glycol and aspartic acid is that anti-cancer medicament carrier has been obtained many successes (Yip YL etal.Application of phage display technology to cancer research.Curr Pharm Biotechnol.2002,3 (1): 29-43.), but also have the deficiency of several respects.At first, between medicine and pharmaceutical carrier with degraded very slowly amido link is connected, drug release is slow, the fixed time, interior medicine was difficult to reach therapeutic dose; Secondly, hydrophilic polymer shell (PEG) has reduced the phagocytosis of cell to nanoparticle.
Summary of the invention
The object of the present invention is to provide that a kind of toxic and side effects is little, clinical efficacy and bioavailability height, hepatoma carcinoma cell had the liver-targeting intelligent nano-micelle prodrug system of targeting.
Another object of the present invention is to provide the preparation method of above-mentioned liver-targeting intelligent nano-micelle prodrug system.
In order to overcome the defective that prior art exists, the present invention utilizes " proton sponge " effect of polymine (PEI), the targeting of the hepatoma-targeting factor, the amycin excellent curative provides a kind of liver-targeting intelligent nano-micelle prodrug system based on polymine.Polymine is owing to contain multistage amine (as 1 grade, 2 grades, 3 grades amine) in the molecule, the function that " proton sponge " arranged, bring counter ion when after it enters lysosome, under the proton pump effect, absorbing proton (H+) into, lysosome intermediate ion concentration is strengthened, osmotic pressure strengthens, moisture content enters, thereby lysosome membrane is broken, and makes medicine escape lysosome.
Liver-targeting intelligent nano-micelle prodrug system provided by the invention is made up of three funtion parts: the Polyethylene Glycol hydrophilic segment that (1) far-end connects the hepatoma-targeting factor is micellar shell; (2) chemotherapeutics (as amycin) is covalently bound forms hydrophobic part as micellar stratum nucleare impelling on the disruptive water soluble polymer segment of lysosome membrane; (3) connecting key of the lysosome degradable between chemotherapeutics and carrier (sour degradable), its general structure is:
[T-PEG]n-PEI-(ADR)m
Wherein T is a liver targeting group; PEG is a Polyethylene Glycol; PEI is a polymine; ADR is that amycin is as medicine.N, m are the integer of 1-350.
Liver targeting group can be the D-galactose in the liver-targeting intelligent nano-micelle prodrug system provided by the invention, and lactose or targeting peptide are to realize its initiatively targeting.The PEG molecular weight can be 35000Da, 25000Da, 10000Da, 3500Da, 1800Da.Be preferably 3500-25000Da, better realize its long-acting circulation in blood.What the present invention adopted is that molecular weight is respectively 60000Da, 10000Da, 1800Da, 1200Da, 600Da, the branching of 423Da or straight chain PEI.
Be connected by covalent bond between carrier and the amycin in the liver-targeting intelligent nano-micelle prodrug system provided by the invention; The covalent bond here preferably connects by the degradable covalent bond of lysosome, makes its release of degrading in lysosome to reduce toxicity.Specifically can be hydrazine key, hydrazone key, acetal bonds or original acid ester key.
Liver-targeting intelligent nano-micelle prodrug system nano particle diameter provided by the invention is 10～500nm.Be preferably 100～150nm, can realize the effect of passive target to tumor tissues.
The preparation method step of liver-targeting intelligent nano-micelle prodrug system provided by the invention is as follows:
The first step: the polyethyleneglycol modified polymine with far-end band liver targeting group (T) obtains (T-PEG-PEI); Its method is: the reaction 12 hours in cryosel is bathed earlier of a certain amount of polymine (PEI) and galactose Polyethylene Glycol NHS ester, at room temperature reacted then 72 hours, dialyse product.
Second the step: T-PEG-PEI and succinum-4-(nitrogen maleimidomethyl) cyclohexane extraction-1-sodium sulfonate SMCC react T-PEG-PEI-SMCC; Its method is: a certain amount of T-PEG-PEI and succinum-4-(nitrogen maleimidomethyl) cyclohexane extraction-1-sodium sulfonate SMCC is dissolved in the tri-distilled water, stirs under the room temperature 72 hours, dialyse product.
The 3rd step: the preparation of amycin mercapto derivatives (ADR-SH); Its method is: earlier with 3-(2-pyridine dimercapto) propanoic acid N-hydroxy-succinamide ester (SPDP) hydrazinolysis, hydrazinolysis product and doxorubicin hydrochloride (ADM-HCl) reacted 72 hours, dialyse then product.
The 4th the step: ADR-SH and T-PEG-PEI-SMCC react T-PEG-PEI-ADR; Its method is: a certain amount of ADR-SH and T-PEG-PEI-SMCC be stirring reaction 72 hours at room temperature, then reactant liquor is handled through glucosan G-50 gel column, product
Liver-targeting intelligent nano-micelle prodrug system provided by the invention carries out purification with sephadex G-50.
The preparation method of liver-targeting intelligent nano-micelle prodrug system provided by the invention can be expressed as follows:
Compared with the prior art the present invention is than remarkable result: one, and amphipathic macromole amycin prodrug is self-assembled into the micellar structure of nanoscale in aqueous medium; Its two, Polyethylene Glycol is the shell of polymer nano micelle, has guaranteed that the nano-micelle microgranule can long-actingly circulate in blood; They are three years old, the hepatoma carcinoma cell targeting factor of Polyethylene Glycol far-end, can strengthen the phagocytosis of hepatoma carcinoma cell by receptor-mediated endocytic pathway on the one hand to polymer nano micelle, medicine optionally can be transported to the liver tumor position on the other hand, orientation is killed and wounded tumor cell of liver, realizes the active targeting to liver's tumor cell level; They are four years old, after nano-micelle overcomes the cell membrane barrier by cytophagy, at first enter endosome, organelles such as lysosome, because endosome, the pH value of organelles such as lysosome shows acid (5.0＜pH＜6.5), connecting key generation acid catalysis degraded between medicine and carrier, discharge medicine and impel the disruptive polymer segment of lysosome membrane (" proton sponge " effect of PEI), along with breaking of lysosome membrane, chemotherapeutics amycin escape lysosome, enter place---the nucleus of performance therapeutical effect, thereby can reduce the toxic and side effects of cytotoxic drug treatment hepatocarcinoma such as amycin to greatest extent, improve the clinical efficacy and the bioavailability of existing cancer treatment drug, reduce its toxic and side effects.The design philosophy that hepatoma carcinoma cell is had the intelligent nano-micelle medicament carrier system of targeting has originality, is a kind of novel antitumor macromolecular drug, is expected to overcome the unfavorable bottleneck of present hepatocarcinoma clinical therapeutic efficacy.
Description of drawings
The structural representation of Fig. 1, PEI.From figure we as can be seen, PEI contains a large amount of 1 °, 2 °, 3 ° of amino groups, the proton sponge effect is obvious.
Fig. 2, PEI connect the Gal-PEG-PEI that obtains behind the targeting group D-galactose polyethylene active ester (Gal-PEG-NHS)
1H NMR spectrogram.
Fig. 3, Gal-PEG-PEI connect the Gal-PEG-PEI-ADR uv atlas that obtains behind the amycin.
The particle diameter of Fig. 4, liver-targeting intelligent nano-micelle prodrug, particle size distribution figure (Size Distribution byIntensity) (longitudinal axis is represented intensity for transverse axis representative diameter, the nm of unit, and the curve representative diameter distributes).
The transmission electron microscope picture of Fig. 5, liver-targeting intelligent nano-micelle.
The specific embodiment
Further specify the present invention with embodiment below, but the present invention is not limited to this.
Wherein, polymine PEI (Polyethyleneimine) purchases the company in Aldrich, galactose polyethylene active ester (Gal-PEG-NHS) is bought in the Jiankai Science and Technology Co., Ltd., Beijing, and sephadex G-50 is bought the fast science equipment company limited that rubs in Shanghai; Water is No. three distilled water; All the other reagent are commercially available AR reagent.
With the Britain Zetasizer3000HS of MARLVEN company type laser particle size scatterometer, particle diameter and particle size distribution to the liver-targeting intelligent nano-micelle prodrug that the present invention is based on polymine characterize, temperature during test is 25 ℃, the wavelength of incident laser is 633nm, and its polarization direction is vertical with scattering detection optical plane.And use transmission electron microscope (TEM) that the pattern of the nanoparticle behind the purification is characterized.Characterize with the structure of BRUKERAVANCE 500 nuclear magnetic resonance analyser (NMR) Gal-PEG-PEI.The ultraviolet-visible spectrophotometer UV1900PC that grinds Electronics Co., Ltd. with the Asia characterizes Gal-PEG-PEI-ADR.
Embodiment 1:
The first step: with 0.1834g (0.0054mmol) galactose polyethylene active ester (Gal-PEG-NHS) (molecular weight is 35000Da), (molecular weight is 1800Da to the PEI aqueous solution of 0.3773g50%, 0.1048mmol) is dissolved among the 10mlDMF respectively.Under cryosel bath condition, the Gal-PEG-NHS drips of solution is added in the PEI solution, and under cryosel bath condition, reacted 12 hours, at room temperature reacted then 72 hours.Products therefrom was dialysed in tri-distilled water 96 hours with the bag filter of 7000Da, and gained dialysis solution lyophilization 72 hours obtains white cotton-shaped product (Gal-PEG-PEI), and this product that takes a morsel is dissolved in the heavy water, and its NMR characterization result is seen accompanying drawing 3.
Second step: get Gal-PEG-PEI 0.2733g, be dissolved in the 100ml round-bottomed flask with the 20ml tri-distilled water, and add 50 times of excessive succinum-4-(nitrogen maleimidomethyl) cyclohexane extraction-1-sodium sulfonate SMCC, stirring reaction is 72 hours under the room temperature, reactant liquor was dialysed in tri-distilled water 72 hours with the bag filter of 7000Da, gained dialysis solution lyophilizing 72 hours gets white solid Gal-PEG-PEI-SMCC.
The 3rd step: amycin mercapto derivatives ADR-SH's is synthetic
Getting 70mg (0.22mmol) 3-(2-pyridine dimercapto) propanoic acid N-hydroxy-succinamide ester (SPDP) is dissolved in the round-bottomed flask with 3ml oxolane (THF), under the condition of ice-water bath, aqueous isopropanol to this solution adding 0.3ml 1M hydrazine reacted 20 minutes down at 0 ℃.With above-mentioned reactant liquor dichloromethane extraction, use the Anhydrous potassium carbonate drying then.The above-mentioned product of 21mg, 48mg doxorubicin hydrochloride (ADM-HCl) (0.083mol) use the 5ml dissolve with methanol in round-bottomed flask, and the lucifuge stirring reaction is 6 days under the room temperature, then reactant liquor are separated with reverse thin layer chromatography post, concentrate.Product after concentrating is dissolved in the water, adds excessive dithiothreitol, DTT (DTT), stirred 2 hours under the room temperature, silicagel column separates, and obtains product A DR-SH.
The 4th step:
Get Gal-PEG-PEI-SMCC0.2554g, be dissolved in the 100ml round-bottomed flask, and add excessive ADR-SH with the 20ml tri-distilled water, at room temperature stirring reaction is 72 hours, products therefrom is carried out with sephadex G-50 post, after 72 hours, get Gal-PEG-PEI-ADR in lyophilization then.
Embodiment 2
With embodiment 1 method, fixedly the molecular weight of PEI is 1800Da, and the employing molecular weight is that the galactose polyethylene active ester (Gal-PEG-NHS) of 25000Da experimentizes
Embodiment 3
With embodiment 1 method, fixedly the molecular weight of PEI is 1800Da, and the employing molecular weight is that the galactose polyethylene active ester (Gal-PEG-NHS) of 10000Da experimentizes
With embodiment 1 method, fixedly the molecular weight of PEI is 1800Da, and adopting molecular weight respectively is 3500Da, galactose polyethylene active ester (Gal-PEG-NHS) experimentize
Embodiment 5
With embodiment 1 method, fixedly the molecular weight of PEI is 1800Da, and adopting molecular weight respectively is that the galactose polyethylene active ester (Gal-PEG-NHS) of 1800Da experimentizes
Embodiment 6
With embodiment 1 method, fixedly (Gal-PEG-NHS) molecular weight of galactose polyethylene active ester is 3500Da, and the employing molecular weight is that the polymine of 60000Da experimentizes
Embodiment 7
With embodiment 1 method, fixedly (Gal-PEG-NHS) molecular weight of galactose polyethylene active ester is 3500Da, and the employing molecular weight is that the polymine of 10000Da experimentizes
With embodiment 1 method, fixedly (Gal-PEG-NHS) molecular weight of galactose polyethylene active ester is 3500Da, and the employing molecular weight is that the polymine of 1800Da experimentizes
Embodiment 9
With embodiment 1 method, fixedly (Gal-PEG-NHS) molecular weight of galactose polyethylene active ester is 3500Da, and the employing molecular weight is that the polymine of 1200Da experimentizes
With embodiment 1 method, fixedly (Gal-PEG-NHS) molecular weight of galactose polyethylene active ester is 3500Da, and the employing molecular weight is that the polymine of 600Da experimentizes
Embodiment 11
With embodiment 1 method, fixedly (Gal-PEG-NHS) molecular weight of galactose polyethylene active ester is 3500Da, and the employing molecular weight is that the polymine of 423Da experimentizes
Embodiment 12
With embodiment 1 method, D-galactose Polyethylene Glycol NHS ester, change into lactose Polyethylene Glycol NHS ester, carry out same experiment
Embodiment 13
With embodiment 1 method, D-galactose Polyethylene Glycol NHS ester, change into polypeptide Polyethylene Glycol NHS ester, carry out same experiment
Embodiment 14
With embodiment 1 method, change the amount ratio of D-galactose Polyethylene Glycol NHS ester, amycin mercapto derivatives (ADR-SH), carry out same experiment
With nuclear magnetic resonance, NMR embodiment 1 product is characterized, the results are shown in accompanying drawing 3, occurred the chemical shift peak of polymine, Polyethylene Glycol in the spectrogram, illustrate that the polyethyleneglycol derivative of galactose has been received on the polymine of branching; Carry out product with above-mentioned ultraviolet-visible spectrophotometer and characterize, the results are shown in accompanying drawing 4, product has absworption peak at the 495nm place, and the characteristic absorption peak of amycin just herein illustrates that amycin receives on the polymine; Particle diameter with laser particle analyzer PCS measurement product the results are shown in Figure 5, and its particle diameter is that particle size distribution is even less than 100nm.Because the sign of other embodiment is similar to the sign of embodiment 1, so no longer enumerate.
By the foregoing description, the intelligent liver-targeted nanometer polymine medicament carrier system particle diameter that discovery adopts the Polyethylene Glycol NHS ester of 3500Da to make is little, and particle size distribution is even, is suitable as the liver target drug-carrying system.
By the foregoing description, the intelligent liver-targeted nanometer polymine medicament carrier system particle diameter that discovery adopts the branched polyethylene imine of molecular weight 1800Da to make is little, and particle size distribution is even, is suitable as the liver target drug-carrying system.
By embodiment 14, find n: m=1: 4 o'clock, liver-targeted nanometer polymine medicament carrier system particle diameter was little, and particle size distribution is even, is suitable as the liver target drug-carrying system.
In the above-described embodiments, having made particle diameter is the liver-targeting intelligent nano-micelle prodrug based on polymine of 10～500nm.Only in order to explanation the present invention but be not limited thereto, should be appreciated that in not breaking away from spiritual scope of the present invention also can have multiple accommodation or alternative to the foregoing description.
Claims (8)
1, a kind of liver-targeting intelligent nano-micelle prodrug system is characterized in that general structure is:
[T-PEG]
n-PEI-(ADR)
m
Wherein T is the D-galactose, lactose or targeting peptide; PEG is that molecular weight is 35000Da, 25000Da, 10000Da, the Polyethylene Glycol of 3500Da or 1800Da; PEI is that molecular weight is 60000Da, 10000Da, 1800Da, 1200Da, the branching of 600Da or 423Da or straight chain PEI polymine; ADR is an amycin; N, m are the integer of 1-350; Nano particle diameter is 10～500nm.
2, liver-targeting intelligent nano-micelle prodrug system as claimed in claim 1 is characterized in that the PEG molecular weight is 3500-25000Da.
3, liver-targeting intelligent nano-micelle prodrug system as claimed in claim 1 is characterized in that PEI is the PEI of branching.
4, liver-targeting intelligent nano-micelle prodrug system as claimed in claim 1 is characterized in that being connected by covalent bond between carrier and the amycin.
5, liver-targeting intelligent nano-micelle prodrug system as claimed in claim 1 is characterized in that being connected by the degradable covalent bond of lysosome between carrier and the amycin.
6, as claim 1,4 or 5 described liver-targeting intelligent nano-micelle prodrug systems, the connecting key between carrier and the amycin can be hydrazine key, hydrazone key, acetal bonds or original acid ester key.
7, liver-targeting intelligent nano-micelle prodrug system as claimed in claim 1 is characterized in that nano particle diameter is 100～150nm.
8, the preparation method of liver-targeting intelligent nano-micelle prodrug system as claimed in claim 1 is characterized in that step is as follows:
The first step: the reaction 12 hours in cryosel is bathed earlier of polymine (PEI) and galactose Polyethylene Glycol NHS ester, at room temperature reacted then 72 hours, dialyse (T-PEG-PEI);
Second the step: T-PEG-PEI and succinum-4-(nitrogen maleimidomethyl) cyclohexane extraction-1-sodium sulfonate SMCC is dissolved in the tri-distilled water, under the room temperature stirring 72 hours, dialyse T-PEG-PEI-SMCC;
The 3rd step: earlier with 3-(2-pyridine dimercapto) propanoic acid N-hydroxy-succinamide ester (SPDP) hydrazinolysis, stirring reaction is 72 hours under hydrazinolysis product and doxorubicin hydrochloride (ADM-HCl) room temperature, dialyse then amycin mercapto derivatives (ADR-SH);
The 4th step: ADR-SH and T-PEG-PEI-SMCC be stirring reaction 72 hours at room temperature, then reactant liquor is handled through glucosan G-50 gel column, must T-PEG-PEI-ADR.
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| CN103990123A (en) * | 2013-02-17 | 2014-08-20 | 华东师范大学 | Liver-cancer-targeted doxorubicin-supporting silica-gold composite material, and preparation method and application thereof |
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| CN105169400B (en) * | 2015-08-10 | 2018-04-20 | 东华大学 | A kind of preparation method of the multi-functional branched polyethylene imine pharmaceutical carrier of hyaluronic acid targeting |
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| CN110423355A (en) * | 2019-08-29 | 2019-11-08 | 武汉轻工大学 | Carboxy methylation lotus root polysaccharide-Trichoderma A conjugates preparation method |
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Open date: 20091111 |