CN103622915B - A kind of targeted nano delivery system for cerebral glioma - Google Patents
A kind of targeted nano delivery system for cerebral glioma Download PDFInfo
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- CN103622915B CN103622915B CN201210306978.1A CN201210306978A CN103622915B CN 103622915 B CN103622915 B CN 103622915B CN 201210306978 A CN201210306978 A CN 201210306978A CN 103622915 B CN103622915 B CN 103622915B
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Abstract
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of targeted nano delivery system for cerebral glioma and its preparation method and application.This delivery system comprises target function molecule, medicine and nano-carrier, described target function molecule is the small peptide deriving from interleukin-11 3, medicine is the anti-cerebral glioma medicine of micromolecule, nano-carrier is surperficial polyethyleneglycol modified liposome, nanoparticle, polymer waterfloocling, polymer micelle, solid lipid nanoparticle, and described medicine is loaded in described small peptide in nano-carrier with parcel or covalently bound mode bag and is connected by the Polyethylene Glycol of covalently bound mode with nanoparticle surface.This delivery system, by the mediation of brain glioblastoma cell surface Interleukin-13 receptor α 2, promotes the picked-up of brain glioblastoma cell, improves the anti-cerebral glioma effect of chemotherapeutics.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to cancer target and pass medicine research, be specifically related to a kind of targeted nano delivery system for cerebral glioma and its preparation method and application.
Background technology
Malignant glioma has become one of brain major disease affecting human health, reports according to statistics, and it has very high mortality rate, and 5 years survival rates of adult's malignant glioma lower than 5%, but there is no the way of effectively curing at present.For malignant glioma, traditional Therapeutic Method is adopt antitumor drug to carry out chemotherapy again after ocal resection.But excision is very risky, and the traditional antitumor drug of major part does not have selectivity, while killing tumor cell, can cause lethal effect to normal cell yet, causes serious side effect and makes it apply to be restricted.
At present, nano target delivery system is one of focus of antitumor drug research and development.The antitumor research of nanoscale medicine delivery system is devoted in large quantifier elimination and invention, to improve the antitumous effect of medicine, reduces the toxic and side effects of medicine.As patent " nano-micelle preparations of the anthracene nucleus antineoplastic antibiotic that polyglycol derivatization phospholipid bag carries " (number of patent application 200510059621.8), " nano-micelle preparations of the catharanthus roseus alkaloids anti-tumor medicaments that polyglycol derivatization phospholipid bag carries " (number of patent application 200510098381.2), " preparation method of the composite nano-polymers of Tumor suppression multidrug resistance " (number of patent application 200610096365.4), " a kind of tumour-specific targeting drug delivery system and the application in preparation tumor thereof " (number of patent application 02105456.8).And, the preparation listing of existing part nano target delivery system, as Evacet, paclitaxel albumin nano granular.Nano target delivery system treatment tumor main advantage is embodied in following 2 points: first, nanoscale medicine delivery system by the enhancing of tumor locus through with the distribution of being detained (EPR) effect and improve tumor locus, reduce the distribution of non-target site, improve the action effect of medicine, reduce the toxic and side effects of medicine; Second, some normal cell of the normal specificity overexpression of tumor cell surface is not expressed or the receptor of low expression or albumen, a target function molecule is connected on nanoscale medicine delivery system surface, by the combination of the specific receptor of target function molecule and tumor cell surface, the picked-up of tumor cell for medicine can be significantly improved, improve the antitumous effect of nanoscale medicine delivery system.
Prior art discloses Interleukin-13 receptor I α 2(L13R α 2) be interleukin-11 3(IL13) one of receptor, have specific expressed on kinds of tumor cells surface, with interleukin-11 3, there is very high affinity.Research finds, the expression of IL23R α 2 has significant samples of human glioma specificity: only express the glioma in astrocyte source, and normal brain tissue cell is not expressed or trace is expressed; And IL13R α 2 is relevant to the grade of malignancy of astrocytoma, and have closely related with the generation development of astrocytoma.Therefore, IL13R α 2 is considered to new glioma mark of correlation thing, can be used for targeting diagnosis and the treatment of glioma.There is research to confirm, by IL13 and toxic protein molecule construction fusion rotein, to be combined with the IL13R α 2 of tumor surface by IL13, lps molecule targeting is imported in tumor cell, plays the effect of killing tumor cell.As people IL13 and Pseudomonas exotoxin (PE) are formed fusion rotein IL13PE38QQR, IL13PE38QQR just can kill glioma cell in extremely low concentration, and its toxic action can block by excessive IL13, the cytotoxic effect that prompting IL13R α 2 mediates is special.Because normal brain tissue cell expresses IL13R α 2 hardly, so IL13PE38QQR does not show obvious toxicity to these cells or does not have toxicity.Pharmacodynamics test also confirms, IL13PE38QQR has good therapeutic effect to lotus glioblastoma Mus, does not find obvious toxic and side effects.Due to the acquired good preclinical laboratory result of IL13PE38QQR, be used to I/II clinical and experimental study of the glioblastoma patient of recurring.
Although the targeted therapy that construction of fusion protein realizes glioma is the method comparatively approved in the industry, remain in following shortcoming: (1) fusion rotein may reduce the affinity of IL13 and IL13R α 2, also likely reduces the activity of toxin protein simultaneously; (2) stably express of fusion rotein and purification difficulty large, production cost is high; (3) receptor of IL13 is more, and the non-target site cell of fusion rotein possibility targeting, causes the toxic and side effects of normal tissue cell; (4) fusion rotein quiet note Half-life in vivo is short, and medicine is less in the distribution of tumor locus.IL13 peptide (sequence is VDKLLLHLKKLFREGQFNRNFESIIICRDR) is the short peptide sequence deriving from IL13, has very high affinity, and be not combined with other receptor of IL13 with IL13R α 2.Have no the report of IL13 peptide decorated nanometer delivery system treatment cerebral glioma at present both at home and abroad.
For obtaining better glioma targeting, significantly improving the picked-up of tumor cell for medicine, improving the antitumous effect of medicine.The present invention intends adopting IL13 peptide decorated nanometer delivery system, by the IL13R α 2 on selectively targeted glioma cell surface, promotes the picked-up of tumor cell, improves the antitumous effect of chemotherapeutics.
Summary of the invention
The object of the invention is to the deficiency existed for prior art, a kind of nanoscale medicine delivery system for cerebral glioma is provided, be specifically related to the nanoscale medicine delivery system that IL13 peptide is modified.This delivery system, by the mediation of brain glioblastoma cell surface receptor IL13R α 2, promotes the picked-up of tumor cell, improves the antitumous effect of chemotherapeutics.
Specifically, it is characterized in that, comprise target function molecule, medicine and nano-carrier, described target function molecule is the small peptide (IL13) deriving from interleukin-11 3, described medicine is small molecule, anti-tumor drug, and described nano-carrier is surperficial polyethyleneglycol modified liposome, nanoparticle, polymer waterfloocling, polymer micelle or solid lipid nanoparticle; Described medicine is loaded in nano-carrier with parcel or covalently bound mode bag, and described small peptide is connected by the Polyethylene Glycol of covalently bound mode with nanoparticle surface.
In the present invention, the described small peptide aminoacid sequence deriving from IL13 is VDKLLLHLKKLFREGQFNRNFESIIICRDR.
In the present invention, the molecular weight of nano-carrier surface Polyethylene Glycol is 1000-20000Da, preferred 2000-5000Da; Above-mentioned Polyethylene Glycol can be mono methoxy polyethylene glycol, or contains the Polyethylene Glycol of other active group; Above-mentioned active group is selected from the one in maleimide base, sulfydryl, amido, carboxyl, biotin or Avidin.
In the present invention, described targeted nano delivery system particle diameter is 10-300nm, preferred 50-150nm.
In the present invention, small molecule, anti-tumor drug is selected from the one in taxanes, Anthraquinones, camptothecin, vinca.
Object of the present invention is achieved through the following technical solutions:
1, with polyethylene glycol-caprolactone (PEG-PCL) for material, the preparation of emulsifying lyase evaporation is adopted to carry Docetaxel nanoparticle (DTX-NP), IL13 peptide is connected with the carboxyl-PEG covalency on nanoparticle surface and obtains DTX-ILNP, Zeta/ laser particle analyzer measures mean diameter and the current potential of nanoparticle, its form of transmission electron microscope observing;
2, vitro in glioma Apoptosis assay, cellular level evaluates the drug-carrying nanometer particle of IL13 peptide modification to the targeted therapy effect of glioma cell;
3, by vitro in glioma ball Cell suppression test, the drug-carrying nanometer particle of IL13 peptide modification is evaluated to the therapeutic effect of vitro in glioma ball;
4, with after IR dyes Dir marking nano grain, the nanoparticle of IL13 peptide modification is evaluated to the targeting of cerebral glioma by living imaging;
5, by glioma experiment anti-in body, the drug-carrying nanometer particle of ILI3 peptide modification is evaluated to the therapeutic effect of lotus glioma Mus.
Outstanding advantages of the present invention is, this delivery system, by the mediation of brain glioblastoma cell surface Interleukin-13 receptor α 2, promotes the picked-up of brain glioblastoma cell, effectively realizes the targeted therapy of cerebral glioma, improve the anti-cerebral glioma effect of chemotherapeutics.
For the ease of understanding, by by concrete drawings and Examples, the cerebral glioma targeted nano delivery system that IL13R α 2 of the present invention mediates is described in detail below.It needs to be noted, instantiation and accompanying drawing are only to illustrate, those of ordinary skill in the art according to illustrating, can make various correction and change to the present invention herein within the scope of the invention, and these are revised and change and also include in scope of the present invention.
Accompanying drawing explanation
Fig. 1, the structure of nanoparticle and sign, wherein, (A) transmission electron microscope picture; (B) grain size distribution.
Fig. 2, the ILNP carrying DTX suppresses external U87 tumor ball growth figure, wherein, (A) tumor sphere volume-time graph; (B) the shape of tumor figure after drug treatment; DTX concentration 2500ng/mL, Control are non-administration matched group, and DTX is free Docetaxel group, and NP is for carrying a DTX nanoparticle group, and ILNP is year DTX nanoparticle group that IL13 peptide is modified,
ap<0.05 compares with matched group;
bp<0.05 and DTX group compares;
cp<0.05 and NP group compares.
Fig. 3, the live body scattergram of targeted nano granule in lotus glioma nude mouse, wherein, (A) living imaging figure; (B) blood, organ fluorescence imaging figure; (C) brain fluorescence intensity semi-quantitative analysis result figure; (D) organ fluorescence intensity semi-quantitative analysis result figure; (E) cerebral tumor position fluorescence intensity semi-quantitative analysis result figure.
Fig. 4, targeted nano delivery system treatment lotus glioma animal model effect, wherein, the survival curve that (A) is tumor bearing nude mice; (B) (green fluorescence granule represents nucleus apoptosis to TUNEI apoptosis colored graph, and blue markings is nucleus; Experiment divides four groups: normal saline (Saline) group, DTX group, NP group and ILNP group.
Detailed description of the invention
The UV absorber of embodiment 1 IL13 peptide decorated nanometer grain (ILNP)
Emulsifying lyase evaporation is adopted to prepare nanoparticle, precise 1.0mgDTX, 28.0mg methoxyl group-PEG-PCL, 2.0mg carboxyl-PEG-PCL, after being dissolved in 1ml dichloromethane, add the sodium cholate of 5ml0.6 ﹪, under ice-water bath, ultrasonic 5s, stops 5s, totally 20 times, 37 DEG C revolve steaming 15min removal dichloromethane, and 3500rpm4 DEG C of centrifugal ultrafiltration is concentrated into 1mL.The desalination of Hitrap desalting column is crossed and the outer aqueous phase of displacement with MES (MES) buffer (pH6.0), add 4mg1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDC) and 6mgN-N-Hydroxysuccinimide (NHS) activates 20 minutes, crossing the desalination of Hitrap desalting column and replacing outer aqueous phase is 0.01 mol/L phosphate buffer (PBS, pH7.4).Add 20 μ gIL13 peptides, reaction 6h, cross Sepharose CL-4B post and wash punching, remove unconjugated ILl3 peptide, obtain year DTX nanoparticle (ILNP) that ILl3 peptide is modified.Particle size analyzer is adopted to measure particle diameter and the Zete current potential of nanoparticle, after 1% (w/V, pH 7.0) phosphotungstic acid negative staining, transmission electron microscope observing particle shape.As shown in Figure 1, ILNP form rounding, mean diameter 124.5 nm, surperficial Zeta potential is-2.44 mV.
Embodiment 2 vitro in glioma Apoptosis assay
U87 cell is seeded to 6 cm culture plates and cultivates 24 hours, cultivate 24 hours when cell confluency degree reaches the ILNP that to add containing DTX concentration after about 80% be 500ng/mL.By cell dissociation, adopt apoptosis detection kit (containing annexinV-FITC and propidium iodide 50 μ g/mL) to dye to cell, flow cytometry detects morning, the late apoptic rate of cell.It is as shown in table 1 that flow cytometry detects apoptosis result, and matched group U87 cell early, late apoptic is little.Compared with matched group, cell early after NP, ILNP, DTX process, late apoptic rate all has remarkable increase, and the total apoptosis rate of cell significantly increases, and wherein, total apoptosis rate of NP, ILNP group process cell afterwards is all significantly higher than DTX group.Table 1 is U87 apoptosis rate (n=3).
Table 1
*p<0.05, compared with the control;
compared with DTX group.
Embodiment 3 vitro inhibition U87 tumor ball growth test
U87 cell is seeded to bag and is cultivated 7 days by 6 well culture plates of agarose, make it to be grown to serve as without vascular tumor ball.The ILNP that to add containing DTX concentration be 2500ng/mL cultivates 5 days, measures tumor sphere volume every day, with initial tumor sphere volume during administration for reference to the change in volume calculating tumor ball.After treatment terminates, tumor ball 2.5% glutaraldehyde is fixed, the configuration of surface of scanning electron microscopic observation tumor ball.Result as shown in Figure 2 A, the growth of matched group tumor ball is very fast, and compared with matched group, after NP, ILNP, DTX process, the growth of tumor ball is subject to obvious suppression, the tumor sphere volume of ILNP group, significantly lower than NP and DTX group, shows the good Tumor suppression ball growth of ILNP tool.Scanning electron microscope result also shows, and matched group tumor sphere volume is comparatively large, and smooth surface, cellular morphology is complete, clear to be debated.After adopting NP or DTX process, tumor sphere volume diminishes, and surface is comparatively smooth, but cellular morphology is imperfect, has obvious cell rupture as seen.After adopting ILNP process, tumor sphere volume is minimum, rough surface, and cellular morphology is imperfect, has obvious cell rupture, can obviously observe coming off of tumor cell.Prompting ILNP can the apoptosis of inducing tumor cell, the growth of Tumor suppression ball.
Embodiment 4 Brain Glioma Model living imaging is tested
Set up lotus U87 Brain Glioma Model, with nir dye Dir marking nano grain, by after 10 μ g/kg dosage tail intravenously administrables respectively at 2h, 4h, 8h, 12h, 24h detects the picked-up of nanoparticle at cerebral glioma position, thing is put to death after administration 24, get each major organs, fluorescence imaging in living imaging instrument, as shown in Fig. 3 result, the nanoparticle that ILNP modifies is significantly higher than the nanoparticle NP of unmodified in the fluorescence intensity at cerebral glioma position, confirm that being modified with of target function molecule I L13 peptide helps nanoparticle and be distributed to cerebral glioma position in animal level.
The anti-cerebral glioma pharmacodynamic experiment of embodiment 5
The nude mice of lotus cerebral glioma is divided into four groups at random, is labeled as normal saline group (Saline), free Docetaxel group (DTX), carry Docetaxel nanoparticle group (NP), carry Docetaxel targeted nano granule group (ILNP), plant tumor and within 8 days, press DTX 10mg/Kg administration afterwards, within every 3 days, be administered once, totally four times (the 8th, 11,14,17 days), observe the survival curve of animal, calculate the median survival interval of each treatment group, be reference with matched group, calculate the median survival interval rate elongation of each treatment group.Often organize after 20 days in kind of tumor and get 2 animals at random, put to death and get brain, dewater after 10 ﹪ neutral formalins fix 24 hours, frozen section after OCT embedding, TUNEL test kit detects apoptosis situation.
As shown in Fig. 4 and table 2, after administration, the death of matched group mice with tumor is the fastest, and all death (Fig. 4 A) in 30 days after kind tumor, its median survival time is 23.0 days (table 2).Adopt DTX and NP treatment, significantly can delay the death (Fig. 4 A) of mice with tumor, its median survival time is respectively 30.0,35.0 days (table 2).Adopt ILNP treatment significantly can delay the death of mice with tumor, its median survival time is 42.0 days, is significantly higher than DTX and NP group.As shown in Figure 4 B, TUNEL apoptosis dyeing display, the unobservable obvious apoptosis of brain glioblastoma cell of normal saline group, NP and DTX group brain glioblastoma cell has a small amount of apoptosis, and apoptosis of tumor cells degree is significantly higher than NP and DTX group after ILNP treatment, consistent with survival curve result.Above result shows, IL13 peptide can increase DTX specifically and make Suppressive effect obviously be better than other each group in the accumulation at cerebral glioma position.
The median survival time (n=6) of table 2. mice with tumor
ap<0.05 compared with the control,
bp<0.05 and DTX group is compared,
cp<0.05 and NP group is compared.
SEQUENCE LISTING
<110> Fudan University
<120> mono-kind is for the targeted nano delivery system of cerebral glioma
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 30
<212> PRT
<213> derives from the small peptide of interleukin-11 3
<400> 1
Val Asp Lys Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly Gln
1 5 10 15
Phe Asn Arg Asn Phe Glu Ser Ile Ile Ile Cys Arg Asp Arg
20 25 30
Claims (6)
1. the targeted nano delivery system for cerebral glioma, it is characterized in that, comprise target function molecule, medicine and nano-carrier, described target function molecule is the small peptide deriving from interleukin-11 3, and its aminoacid sequence is: VDKLLLHLKKLFREGQFNRNFESIIICRDR; Described medicine is small molecule, anti-tumor drug Docetaxel; With polyethylene glycol-caprolactone (PEG-PCL) for material, adopt the preparation of emulsifying lyase evaporation to carry Docetaxel nanoparticle (DTX-NP), be connected IL13 peptide with the carboxyl-PEG covalency on nanoparticle surface obtained DTX-ILNP.
2., by the described targeted nano delivery system for cerebral glioma of claim 1, it is characterized in that, the molecular weight of described Polyethylene Glycol is 1000-20000Da.
3., by the described targeted nano delivery system for cerebral glioma of claim 1, it is characterized in that, the molecular weight of described Polyethylene Glycol is 2000-5000Da.
4. by the targeted nano delivery system for cerebral glioma of claim 1, it is characterized in that, described Polyethylene Glycol is mono methoxy polyethylene glycol or the Polyethylene Glycol containing other active group.
5., by the targeted nano delivery system for cerebral glioma of claim 4, it is characterized in that, described active group is selected from the one in maleimide base, sulfydryl, amido, carboxyl, biotin or Avidin.
6., by the targeted nano delivery system for cerebral glioma of claim 1, it is characterized in that, described targeted nano delivery system particle diameter is 10-300nm.
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| CN105497922B (en) * | 2014-09-25 | 2018-11-16 | 复旦大学附属华山医院 | For the targeted nano mr contrast agent of brain epileptogenic focus and its preparation and application |
| CN105582539B (en) * | 2014-10-20 | 2019-01-11 | 复旦大学 | It is a kind of for glioma cell and its rely on blood vessel drug delivery system |
| CN105582540A (en) * | 2014-10-20 | 2016-05-18 | 复旦大学 | Brain glioma targeting drug delivery system by aiming at fatty acid-binding protein acceptor |
| CN106619571B (en) * | 2017-01-03 | 2020-04-07 | 西南交通大学 | Polymer nano-carrier for improving endocytosis and cell nucleus targeting and preparation method thereof |
| CN108126189B (en) * | 2018-02-12 | 2021-03-02 | 中国药科大学 | Nano composite carrier drug delivery system assembled in grading manner and application thereof |
| CN110604821A (en) * | 2018-06-14 | 2019-12-24 | 复旦大学 | Brain targeting delivery system mediated by amyloid beta short peptide |
| CN110354096B (en) * | 2019-07-03 | 2020-07-21 | 中国人民解放军第四军医大学 | Brain-targeted drug delivery system capable of improving drug-resistant brain glioma microenvironment and reversing drug resistance |
| CN113480603B (en) * | 2021-07-13 | 2022-03-01 | 四川大学 | Specific short peptide targeting glioma cells, coding gene and application thereof |
| CN113384707A (en) * | 2021-07-16 | 2021-09-14 | 高州市人民医院 | Preparation method of novel nano preparation capable of treating brain glioma |
| CN116869968B (en) * | 2023-09-07 | 2023-11-24 | 四川大学 | Nanoparticulate targeting brain and brain glioma, and synthesis method and application thereof |
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