CN105582539B - It is a kind of for glioma cell and its rely on blood vessel drug delivery system - Google Patents
It is a kind of for glioma cell and its rely on blood vessel drug delivery system Download PDFInfo
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- CN105582539B CN105582539B CN201410557645.5A CN201410557645A CN105582539B CN 105582539 B CN105582539 B CN 105582539B CN 201410557645 A CN201410557645 A CN 201410557645A CN 105582539 B CN105582539 B CN 105582539B
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Abstract
The invention belongs to field of pharmaceutical preparations, are related to a kind of targeted drug delivery system and preparation method thereof for brain colloid primary tumor.The present invention, which constructs one kind, can target the drug-loading system that glioma passs medicine.This delivery system is with biodegradable, the internal good polylactic acid of compatibility is that nanometer formulation (NP) is made in raw material, by extending circulation time in vivo in its surface modification polyethylene glycol, simultaneously by the way of being covalently attached, achieve the purpose that targeting drug delivery in its surface modification target function molecule, show through inside and outside experiment, this delivery system energy specificity is assembled in tumor locus, pharmacodynamic results show it with significant antitumous effect, it is shown that its vast prospect in clinical application.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, are related to targeted delivery of drugs system, and in particular to a kind of by chemicals packet
It is loaded in inside delivery system, the targeting drug delivery system that specificity passs medicine is reached by the functional targeted molecular of surface modification.
Background technique
It is the common malignant disease of central nervous system prior art discloses brain tumor, and wherein glioma is hair
Sick most wide, grade malignancy highest, treatment difficulty maximum and postoperative brain tumor easy to recur.According to statistics, glioma (brain glue
Cell plastid tumor) account for about the 46% of intracranial tumors.The World Health Organization announces and ranks by death rate sequence for 1998, glioblastoma
It is the 2nd cause of death of 34 years old or less tumor patient, is the 3rd cause of death of 35~54 years old patient.Spongiocytoma is inclined
Benign person's slow growth, the course of disease is longer, and it is 2 years average to consultation time to occur symptom certainly；Pernicious person's knurl growth is fast, and the course of disease is short,
From occur symptom to it is medical when majority within 3 months, more than 70%~80% within half a year.It is clinically directed to brain colloid at present
The primary treatments of tumor are still based on operation excision, chemotherapy and radiotherapy.Although these methods can be to a certain degree
Patients in remission, but excision of performing the operation often has Neoplasm residual, and causes the surging recurrence of tumour in a short time, and chemistry treatment
Method and radiotherapy also have very big damage while killing to tumor locus to normal portions.Therefore, one kind is sought
Safely and effectively therapeutic modality reduces the side effect because of caused by treatment while obtaining good therapeutic effect, becomes colloid
The hot spot of tumor treatment.
Nano-carrier on the basis of biodegradable material is established, have many advantages, such as: good biocompatibility, partial size are small
Make it that can make full use of tumor vascular high osmosis and retention effect assembling in tumor locus to selectivity, drugloading rate is high
And it can recycle for a long time in vivo.In addition, can be reached by having the molecule of targeting in the connection of nanoparticle surface
The purpose of targeting drug delivery has been greatly reduced toxicity while increasing curative effect.People's Sonic hedgehog is a kind of wide expression
In kinds of tumor cells (glioma etc.) and a small amount of expression new vessels cell receptor, and it is several in normal tissue cell
It does not express.Peptide C VNHPAFAC (C peptide) is the specific polypeptide obtained using phage technology, can efficient target tumor
Highly expressed people's Sonic hedgehog on cell.Vascular endothelial growth factor receptor -2 (VEGFR-2) is that one kind is known and wide expression
In the receptor of neovascular endothelium cell, the HTMYYHHYQHHL (K237 peptide) found therewith has shown that have very by a variety of researchs
Good tumor vascular targeting.Some researches show that in lower series glioma, in addition to new vessels, together in recent years
When have the presence of more mimicry blood vessel (Vasculogenic Mimicry, VM), different from new vessels, VM is not by endothelial cell
It constitutes, but is directly differentiated to form by tumour cell.Therefore, although the drug of general anti-new vessels can destroy and inhibit swollen
New vessels and formation in tumor, but the presence of VM can continue to nutrition needed for supplying tumour, to reduce antitumor effect, very
To the recurrence for causing tumour.Existing research shows that VEGFR-2 plays crucial work in the formation and growth course of mimicry blood vessel
With, thus, K237 peptide can play VM targeting.There is research and utilization amino acid sequence GYG to connect CVNHPAFAC and K237 peptide
It is connected into as a kind of new function targeted molecular CK peptide, which can not only be simultaneously in targets neoplastic cells and tumor neogenetic blood vessels
Chrotoplast, while capableing of the mimicry vascular delivery chemotherapeutics of specificity being directed in tumour, this is existing a variety of targeting drug deliveries
Not available for system.
Present inventor is quasi- to provide a kind of nanoscale medicine delivery system of novel polypeptide modification load taxol, to reach targeting
The purpose of brain glioblastoma cell and its new vessels and mimicry blood vessel.
Summary of the invention
The purpose of the present invention is constructing a kind of nanoscale medicine delivery system of novel polypeptide modification load taxol, passes through targeting and kill
Brain glioblastoma cell and induction glioma grow relied on blood vessel apoptosis and are finally reached the purpose of anti-glioma.
For the present invention using degradable and good biocompatibility polylactic acid as material, broad spectrum activity antineoplastic taxol is mould
Type medicine is prepared into uniform nano medicament carrying system, while CK peptide is modified by way of covalent linkage on its surface, to reach
To the purpose of targeting brain glioblastoma cell and its new vessels and mimicry blood vessel.
Model drug of the present invention is broad spectrum activity anti-cancer medicine paclitaxel (PTX), can be obtained by market channel；
The taxol keeps tubulin to stablize, inhibits cell mitogen by promoting tubulin polymerization to inhibit depolymerization.
Polypeptide of the present invention is the combination of two kinds of not homopolypeptides, one of which using people's Sonic hedgehog as receptor,
Its sequence is CVNHPAFAC (C peptide)；The receptor of another polypeptide is vascular endothelial growth factor receptor -2 (VEGFR-2), sequence
It is classified as HTMYYHHYQHHL-NH2 (K237 peptide).
Sonic hedgehog according to the present invention plays an important role in the generating process of kinds of tumors, thin in tumour
Largely exist in born of the same parents and is distributed in endothelial cells in tumor neogenetic blood vessels on a small quantity；VEGFR-2 is in endothelial cells in tumor neogenetic blood vessels
With a large amount of expression, while existing in mimicry blood vessel；By the connection of GYG, by K237 peptide in conjunction with C peptide after modification exist
The surface of nanoscale medicine delivery system can not only play C peptide to the target function of glioma cell and enhancing in glioma
New vessels targeting, and can specificity target tumor in mimicry blood vessel.
The present invention through internal Vitro Experimental Results show preparation delivery system have very strong targeting characteristic and significantly
Antitumous effect.
In the present invention, using source of people mother's glioma cell U87 as tumor models, Human umbilical vein endothelial cells HUVEC is
Neovascular endothelium cell model, this two kinds of cells are recognized by this field and known.
More specifically, the drug delivery system provided by the invention that blood vessel is relied on for tumour cell and tumour, feature
It is, is that material is prepared into drug-loading system of the same size, surface with carboxy polyethylene glycol polylactic acid (COOH-PEG-PLA)
Polyethylene glycol increase delivery system circulation time in vivo, by target function molecule by way of covalent linkage with carry medicine
The carboxyl of system surfaces is connected, and achievees the purpose that targeting drug delivery.
In the present invention, target function molecule is that a kind of pair of glioma has the polypeptide of strong compatibility (with CK peptide life in text
Name), amino acid sequence is as follows:
CVNHPAFACGYGHTMYYHHYQHHL-NH2
The receptor of the target function molecule is distributed widely in brain glioblastoma cell and tumor neogenetic blood vessels cell and intends
State blood vessel.
In the present invention, the molecular weight of the carboxy polyethylene glycol (COOH-PEG) is 2000-8000Da；The poly- second of carboxyl
The molecular weight of glycol polylactic acid (COOH-PEG-PLA) is 20000-50000Da；In one embodiment of the present of invention, using single first
Oxygroup polyethylene glycol polylactic acid (MPEG-PLA), molecular weight 20000-50000Da.
The present invention provides the preparation methods of the delivery system comprising, it is originally passed using the preparation of emulsified vehicles evaporation
The consistent nanometer formulation of medicine system size, wherein aqueous media used includes, molten for the sodium taurocholate of 1:100 with mass volume ratio
Liquid as in emulsifier water phase and mass volume ratio be 0.5:100 water phase of the cholic acid sodium water solution as decentralized medium；
Ultrasound condition are as follows: ultrasonic time 2.4min is spaced 2s, and power 240W is carried out under the conditions of ice-water bath, this delivery system obtained
Partial size between 100-200nm, with good particle diameter distribution.
The present invention provides the results of system inside and outside qualitative, quantitative expression with the evaluation of pharmacodynamics.
The present invention by cell-specific absorb, internal pharmacodynamics test show the delivery system be capable of specificity
Assemble in glioma cell and neovascular endothelium cell, and has the lethal effect of specificity to targeting cell；Living imaging skill
Art and pharmacodynamic evaluation are also shown, which has good in-vivo tumour targeting and apparent antitumor effect
Fruit.
Its administration mode of targeting drug delivery system obtained by the present invention is intravenous injection.
For the present invention according to tumor vascular infiltration and retention effect and on the basis of existing research, constructing one kind can target
The drug-loading system of medicine is passed to glioma.For this delivery system with biodegradable, the good polylactic acid of internal compatibility is raw material system
At nanometer formulation (NP), by extending circulation time in vivo in its surface modification polyethylene glycol, while using covalently connecting
The mode connect achievees the purpose that targeting drug delivery in its surface modification target function molecule；Show originally to pass medicine system through inside and outside experiment
System can specificity assemble in tumor locus, there is significant antitumous effect, it is shown that before its vast in clinical application
Scape.
Detailed description of the invention
Fig. 1 is the grain size distribution of delivery system,
Figure A, B are respectively the grain size distribution of NP and CK-NP.
Fig. 2 is qualitative and quantitative result of the HUVEC cell to load cumarin nanoparticle intake,
Figure A is qualitative intake picture of the HUVEC cell to NP and bis- kinds of CK-NP load cumarin nanoparticles, and figure B is quantitative knot
Fruit.
Fig. 3 is qualitative and quantitative result of the U87 cell to load cumarin nanoparticle intake,
Figure A is qualitative intake picture of the U87 cell to NP and bis- kinds of CK-NP load cumarin nanoparticles, and figure B is quantitative knot
Fruit.
Fig. 4 is the qualitative and quantitative result for carrying effect of nano-paclitaxel extracorporeal anti-tumor mimicry blood vessel,
Scheme the qualitative photo that A is light field shooting, figure B is by calculating resulting quantitative suppression result.
Fig. 5 is to use the Tissue distribution figure that DIR nanoparticle is carried captured by bioluminescence imaging technology,
Scheming A, B is respectively NP and CK-NP in the intracorporal distribution map of tumor-bearing mice.
Fig. 6 is to carry taxol targeting drug delivery system to the pharmacodynamic evaluation result of tumor animal.
Specific embodiment
The preparation and characterization of the load taxol targeting drug delivery system of embodiment 1
Nanoparticle is prepared using emulsified vehicles method: by the COOH-PEG-PLA 1mL of the MPEG-PLA of 22.5mg and 2.5mg
Methylene chloride dissolution, and PTX is added makes its concentration 0.5mg/mL, the then sodium cholate solution of addition 2mL 1%；Ice-water bath punching
Ultrasonic 2.4min (interval time 2s, power 240W), 0.5% sodium cholate solution of 10mL disperse 5min.Rotary evaporation removes two
After chloromethanes, under the conditions of 4 DEG C, 14500rpm is centrifuged 1h to get common drug-carrying nanometer particle (NP-PTX)；
Preparation has target function delivery system: on the basis of common nanoparticle, passing through the NH2- and nanometer in polypeptide
- COOH the covalent linkage on grain surface is made with target function delivery system comprising: N is first used, N '-dicyclohexyl carbon two is sub-
Amine (EDC) and N- hydroxy-succinimide (NHS) are protected from light-COOH 0.5h on activation nanoparticle surface；14500rpm centrifugation
After 45min, distilled water is resuspended, and then functional polypeptide solution is added in 1:1 in molar ratio, is protected from light 4h and is obtained required delivery system
(CK-NP-PTX)；
The characterization of nanoparticle: using its form of transmission electron microscope observation, is received using the measurement of Malvern particle size determination instrument
The partial size of the grain of rice, as the result is shown: the partial size of NP and CK-NP is respectively 104.6nm and 119.9nm, shows functional polypeptide
Introducing conspicuousness do not generated on the partial size of nanoparticle influence, qualitative figure shows that two kinds of equal sizes of nano-carrier are uniform, form circle
It is whole.
Intake of the embodiment 2HUVEC cell to cumarin nanoparticle is carried
HUVEC cell is inoculated on 96 orifice plates with the density in 5000, every hole, for 24 hours after, respectively not with 50-400 μ g/mL
With 37 DEG C of load cumarin NPs and CK-NPs common incubation 1h of concentration gradient, PBS (phosphate buffered saline solution, PH are then used
7.4) it cleans 3 times, after the fixed 15min of 4% paraformaldehyde, the qualitative results of fluorescence microscopy microscopic observation cellular uptake；It is quantitative real
When testing, after the fixed 15min of above-mentioned 4% paraformaldehyde, core 10min is contaminated with 2 μ g/mL Hochest 33258, is eventually adding 200
μ L PBS, quantitative result are read by high intension and are obtained, the results showed that and CK-NP has stronger intake effect compared to NP,
Significantly enhance the intake effect of HUVEC cell.
Intake of the embodiment 3U87 cell to cumarin nanoparticle is carried
U87 cell is inoculated on 96 orifice plates with the density in 5000, every hole, for 24 hours after, it is different from 50-400 μ g/mL respectively
37 DEG C of load cumarin NPs and CK-NPs of concentration gradient are common to be incubated for 1h, is then cleaned 3 times with PBS, 4% paraformaldehyde is fixed
After 15min, in the qualitative results of fluorescence microscopy microscopic observation cellular uptake；When quantitative experiment, fixed in above-mentioned 4% paraformaldehyde
After 15min, core 10min is contaminated with 2 μ g/mL Hochest 33258, is eventually adding 200 μ L PBS, quantitative result passes through in height
Contain to read and obtain, the load cumarin nanoparticle after the modification of CK peptide has preferably intake effect, print in U87 cell as the result is shown
Its targeting to glioma cell is demonstrate,proved.
The external mimicry vascularization Inhibition test of embodiment 4
50 μ L matrigels are added in 96 orifice plates being pre-chilled, are taken out after 37 DEG C of incubation 1h, then by logarithmic growth phase
U87 cell pancreatin digest and be centrifuged, then with (paclitaxel solution agent Taxol, NP-PTX, C-NP-PTX containing different PTX preparations
And CK-NP-PTX, and it is diluted to following concentration respectively: cell is resuspended in cell culture fluid 1,5and10nM), with every hole 2-3
×104A density is inoculated on orifice plate, and light field is shot after cell incubator is incubated for 10h；
As the result is shown: Taxol and NP-PTX has a faint toxic effect to mimicry blood vessel, and with CK-NP incubation group altogether
Mimicry vascularization receives apparent antagonism, shows that the delivery system of CK peptide modification can be for mimicry vascularization poison
Property effect.And with the raising of concentration, inhibitory effect is become apparent.
5 nanoscale medicine delivery system of embodiment is in the intracorporal distribution experiments of tumor animal
The foundation of lotus original position glioma animal model: the U87 cell of logarithmic growth phase is centrifuged after pancreatin digestion, with suitable
Amount PBS resuspension makes concentration 5 × 108cells/mL；4~6 weeks, 20g or so male BALB/c nude mice are taken, with 5% chloraldurate
Anesthesia, is placed on stereotaxic instrument, on the right side of the bregma at 1.8mm, depth 3mm 5 μ L of injection cell suspension, the withdraw of the needle is simultaneously after 10min
Pin hole is sealed with bone wax；
The brain tumor targeting of delivery system is investigated using living imaging: cell inoculation the 10th day, nude mice distinguished tail vein
It injects 2mg/kg and carries DiR iodide (1 '-dioctadecyl-3,3,3 ', 3 '-tetramethyl
Indotricarbocyanine Iodide) NPs or CK-NPs；Nude mice abdominal cavity injects 5% chloral hydrate anesthesia of 0.2mL, sets
In in living imaging instrument, certain time progress fluorescent scanning (600~900nm) after injection for 24 hours anaesthetizes nude mice after injection, presses
Conventional treatment carries out fluorescent scanning (600~900nm) to the nude mice heart, liver, spleen, lung, kidney and lotus tumour brain, investigates nanoparticle
In the distribution respectively organized；
As the result is shown: compared with NP group, CK-NP group can significantly increase the aggregation in glioma, and organ distribution is shown,
CK peptide modification after delivery system can not only integrated distribution in glioma, in addition, it is bright in the distribution of normal tissue site
It is aobvious to be less than NP group, it is shown that good targeting characteristic.
The internal pharmacodynamic evaluation of 6 drug-carrying nanometer particle of embodiment
By establishing lotus original position glioma animal model in embodiment 5, and only it is divided into 5 groups with every group 6, with every in two weeks
Three days difference tail vein injection Taxol, NP-PTX, CK-NP-PTX (concentration of PTX is 5mg/kg) and physiological saline, and remember
Record the existence death condition of each group；Experimental result is shown: the median survival interval of each administration group is respectively (22 days) Taxol, NP-
PTX (27 days) and CK-NP-PTX (55 days), and the median survival interval for giving physiological saline group is then 18.5 days；In NP group
Position life cycle is apparently higher than physiological saline and Taxol group, shows that the nanoscale medicine delivery system can be entered on a small quantity by passive target
Tumor tissues, and after injecting the nanoscale medicine delivery system of CK peptide modification, mouse median survival interval extends 36.5 days, as a result table
Bright, CK-NP can largely enter tumor locus, as a result confirm that CK peptide has stronger cancer target characteristic.
Claims (5)
1. it is a kind of for glioma cell and its rely on blood vessel drug delivery system, which is characterized in that with carboxy polyethylene glycol
Polylactic acid (COOH-PEG-PLA) be material drug-loading system is made, by target function molecule by way of covalent linkage with carry medicine
The carboxyl of system surfaces is connected, and the drug delivery system that blood vessel is relied on for tumour cell and tumour is made；
The target function molecule is CK peptide, and amino acid sequence is as follows:
CVNHPAFACGYGHTMYYHHYQHHL-NH2；
The molecular weight of the carboxy polyethylene glycol (COOH-PEG) is 2000-8000Da；The carboxy polyethylene glycol polylactic acid
(COOH-PEG-PLA) molecular weight is 20000-50000Da.
2. the drug delivery system according to claim 1 for being directed to glioma cell and its relying on blood vessel, which is characterized in that institute
Stating drug model used by drug delivery system is broad spectrum activity antineoplastic taxol (PTX).
3. the drug delivery system according to claim 1 for being directed to glioma cell and its relying on blood vessel, which is characterized in that institute
The partial size for the drug delivery system stated is between 100-200nm.
4. the drug delivery system according to claim 1 for being directed to glioma cell and its relying on blood vessel, which is characterized in that adopt
It is prepared with emulsified vehicles evaporation, including it is the sodium cholate solution of 1:100 with mass volume ratio that aqueous media used, which is,
As in emulsifier water phase and mass volume ratio be 0.5:100 water phase of the cholic acid sodium water solution as decentralized medium；It is super
Sound condition are as follows: ultrasonic time 2.4min is spaced 2s, and power 240W is carried out under the conditions of ice-water bath.
5. the drug delivery system for being directed to glioma cell and its relying on blood vessel of claim 1 is in preparing targeting drug delivery system
Purposes.
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| CN201410557645.5A CN105582539B (en) | 2014-10-20 | 2014-10-20 | It is a kind of for glioma cell and its rely on blood vessel drug delivery system |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106265598A (en) * | 2016-08-25 | 2017-01-04 | 广东工业大学 | A kind of based on biological functionalized nano silver paclitaxel loaded or the targeted delivery systems of its analog |
| CN107875140A (en) * | 2016-09-30 | 2018-04-06 | 复旦大学 | A kind of double targeted drug delivery systems and its application in oncotherapy preparation is prepared |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101822642A (en) * | 2009-03-04 | 2010-09-08 | 上海交通大学医学院 | Peptide modified invisible nano particle loaded with anti-tumor angiogenesis drug and application thereof |
| CN103622915A (en) * | 2012-08-24 | 2014-03-12 | 复旦大学 | Targeting nanometer drug delivery system aiming at glioma |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101822642A (en) * | 2009-03-04 | 2010-09-08 | 上海交通大学医学院 | Peptide modified invisible nano particle loaded with anti-tumor angiogenesis drug and application thereof |
| CN103622915A (en) * | 2012-08-24 | 2014-03-12 | 复旦大学 | Targeting nanometer drug delivery system aiming at glioma |
Non-Patent Citations (3)
| Title |
|---|
| "A New Phage-Display Tumor-Homing Peptide Fused to Antiangiogenic Peptide Generates a Novel Bioactive Molecule with Antimelanoma Activity";Alisson L. Matsuo et al.;《Molecular Cancer Research》;20110907;第9卷(第11期);第1471-1478页 |
| "LDLR-mediated peptide-22-conjugated nanoparticles for dualtargeting therapy of brain glioma";Bo Zhang et al.;《Biomaterials》;20130903;第34卷(第36期);第9171-9182页 |
| "Multi-targeting Peptide-Functionalized Nanoparticles Recognized Vasculogenic Mimicry, Tumor Neovasculature, and Glioma Cells for Enhanced Anti-glioma Therapy";Xingye Feng et al.;《ACS Applied Materials & Interfaces》;20151130;第7卷(第50期);第27885-27899页 |
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