CN105012272B - A kind of isotope of redox-sensitive Bone targeting micella that can be used for treating metastatic carcinoma of bone - Google Patents
A kind of isotope of redox-sensitive Bone targeting micella that can be used for treating metastatic carcinoma of bone Download PDFInfo
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Abstract
The invention discloses it is a kind of can be used for treatment metastatic carcinoma of bone isotope of redox-sensitive Bone targeting micella, the micella with Alendronate sodium (ALN) be Bone targeting aglucon, with the glucan (DEX of molecular weight 5000(5K)) it is water wetted material, with tetradecy lamine (MA) for hydrophobic material, with 3,3 two thiodipropionic acids (DPC) are crosslinking agent, with adriamycin (DOX) for model drug, the micella DOX@MA DEX for having active Bone targeting concurrently and having specificly-response to tumour cell microenvironment are prepared(5K)‑ALN.Bone targeting micella DOX@MA DEX(5K)ALN has higher drugloading rate and envelop rate to DOX, adsorbances of the DOX to hydroxyapatite (HA) can substantially be increased, more DOX are delivered at metastatic tumor of bone, so that DOX is enriched with tumor tissues, increase therapeutic actions of the DOX to metastatic carcinoma of bone, mitigate destruction of the tumour to bone；Distributions of the DOX in normal structure is reduced simultaneously, DOX curative effect is improved, toxic side effect is reduced, and the exploitation for treatment metastatic carcinoma of bone delivery system provides new approaches.
Description
Technical field
Prepared the present invention relates to a kind of design of new glucan (DEX) isotope of redox-sensitive Bone targeting micella and application side
Case.
Background technology
Research finds that the phenomenon of Bone tumour occurs at least 50% Advanced Carcinoma Patient.Bone metastaes make a difference
Treatment of the medicine to tumour, adds the pain of patient, reduces the survival rate of patient.Because sclerotin hardness is big, blood vessel point
Cloth is few, the low feature of drug permeability, and convenient administration mode is difficult that medicine is effectively delivered at metastatic tumor of bone.How effectively to pass
Drugs, is to solve the key that metastatic tumor of bone treats problem.The proposition of Bone targeting delivery system, is that the treatment of metastatic tumor of bone is brought
Dawn.
Bisphosphonates (BPs) have very high affinity to the HA of bone.After BPs enters in vivo, BPs will be fast
Speed is removed from blood circulation and is adsorbed onto exposed bone mineral region.Alendronate sodium (ALN) belongs to third generation BPs class medicines
Thing, with very strong close bone, its is simple in construction, chemically modifies, and is widely used as the Bone targeting part in delivery system.Grind
Study carefully and show, the delivery system of environmental response is played a key effect to the controlled release of medicine.Disulfide bond is a kind of to gluathione
The sensitive chemical bond of peptide (GSH), GSH content difference is huge inside and outside tumour cell.Wherein GSH concentration can in tumour cell
2-10mM is reached, and the outer GSH of tumour cell concentration is about 2-20 μM, concentration almost differs 1000 times.Utilize disulfide bond
Delivery system can selectivity release medicine in the high tumour cell of GSH contents, and in blood can stablize deposit
.
Glucan (DEX) has good biocompatibility and water solubility, has been widely used in biomedicine field.Base
The micella delivery system prepared in DEX, because it has, particle diameter is small, carrying the efficacy of a drug, the feature such as strong has been widely studied.Nearest research
Also show that the micella based on DEX circulates the function also with similar PEG " stealth " in vivo.
The content of the invention
, can be with it is an object of the invention to provide a kind of isotope of redox-sensitive Bone targeting micella that can be used for treatment metastatic carcinoma of bone
More DOX are delivered at metastatic tumor of bone, while distributions of the DOX in normal structure is significantly reduced, so as to effectively improve the anti-of DOX
Tumor promotion, reduces its toxic side effect, and the exploitation for treatment metastatic carcinoma of bone delivery system provides new approaches.
A kind of isotope of redox-sensitive Bone targeting micella that can be used for treating metastatic carcinoma of bone, it is characterized in that with Alendronate sodium
(ALN) it is Bone targeting aglucon, with the glucan (DEX of molecular weight 5000(5K)) it is water wetted material, with tetradecy lamine (MA) for hydrophobic material
Material, is that crosslinking agent synthesizes MA-DEX with 3,3 two thiodipropionic acids (DPC)(5K)- ALN, with adriamycin (DOX) for model drug, is prepared
Go out to have concurrently active Bone targeting and there are the nano-micelle DOX@MA-DEX of specificly-response to tumour cell microenvironment(5K)-ALN。
Specific preparation method is as follows：
The synthetic method of (1) two thiodipropionic acids-Alendronate sodium (DPC-ALN)
1. 2.4mmol DPC 501.1mg, 4.8mmol EDCI are added in 20mL Isosorbide-5-Nitrae dioxane
916.8mg, stirs 30min, then adds 5.0mmol NHS 575.2mg and 150 μ L TEA, continues stir-activating 3h；
2. 1.2mmol ALN 325.6mg are added in 20mL distilled water, it is secondary in three batches to be slowly added dropwise into above-mentioned fully after dissolving
Reaction solution, during the course of the reaction, 0.2M NaOH, which are slowly added dropwise, makes the pH stable of reaction solution maintain after 7.0 or so, 2 hours
Continuing dropwise addition 0.2M NaOH makes pH be tuned into 9.0, continues reaction and stays overnight, reaction is spin-dried for solvent, a large amount of dichloromethanes of solid after terminating
Alkane rinse three times repeatedly, methanol rinses three times obtain product；
The synthetic method of (2) two thiodipropionic acids-tetradecy lamine (DPC-MA)
2.4mmol DPC 500mg, 4.8mmol EDCI 916.8mg are added in 20mL Isosorbide-5-Nitrae dioxane, are stirred
30min is mixed, 5.0mmol NHS 575.2mg and 150 μ L TEA is then added, continues stir-activating 3h, then in reaction
1.3mmol MA 217.6mg are added in liquid, 12h is reacted at room temperature, TLC monitoring reactions terminate after reaction, cross post separation, wherein
Solvent using volume basis as：Dichloromethane:Methanol=10:1；
(3) glucan(5K)- 3,3 two thiodipropionic acids-tetradecy lamine (DEX(5K)- DPC-MA) synthetic method
Weigh a certain amount of DPC-MA, EDCI, NHS and TEA to be dissolved in 30mL DMSO successively, fully add one after dissolving
Quantitative DEX(5K), 12h is reacted at room temperature, is terminated after reaction, filtering reacting liquid obtains faint yellow supernatant liquid, filtrate is with a large amount of two
Chloromethanes is precipitated, and cleans precipitation with dichloromethane repeatedly, and methanol rinses are precipitated three times, and precipitation finally is dissolved in into a small amount of distilled water
Middle dialysis is lyophilized, produces DEX(5K)-DPC-OA；
(4) two thiodipropionic acids of tetradecy lamine-3,3-glucan(5K)- 3,3 two thiodipropionic acids-Alendronate sodium (MA-DPC-
DEX(5K)- DPC-ALN) synthetic method
Weigh a certain amount of DPC-ALN, EDCI, NHS and TEA to be dissolved in 40mL DMSO successively, fully added after dissolving
A certain amount of DEX(5K)- DPC-MA, 60 DEG C of reaction 48h of oil bath, reaction dialyses to freeze after terminating produces MA-DPC-DEX(5K)-DPC-
ALN, is abbreviated as MA-DEX(5K)-ALN；
(5)MA-DEX(5K)- ALN carries the preparation of adriamycin (DOX) micella
3mg DOXHCl are weighed in 4mL DMSO, 3 μ L TEA is added, the lucifuge magnetic agitation in 60 DEG C of oil baths
1h makes it fully dissolve, plus 10mg MA-DEX(5K)Distilled water is slowly added dropwise after persistently stirring 2h in preparation solution in-ALN
32mL, continues to stir 12h；Above-mentioned mixed liquor is fitted into the bag filter that molecule interception is 2000, dialysed 48h, and one is changed per 6h
Polymer medicament carrying micelle is freeze-dried to obtain after secondary water, dialysis.
Bone targeting micella DOX@MA-DEX of the present invention(5K)- ALN has higher drugloading rate and envelop rate to DOX, can be obvious
Increase DOX to hydroxyapatite (HA) adsorbance, more DOX are delivered at metastatic tumor of bone, so that DOX is in tumor group
Enrichment is knitted, therapeutic actions of the increase DOX to metastatic carcinoma of bone mitigates destruction of the tumour to bone；DOX is reduced simultaneously in normal group
The distribution knitted, improves DOX curative effect, reduces toxic side effect.
Brief description of the drawings
Fig. 1 is DOX and DOX@MA-DEX(5K)The variation diagram of gross tumor volume after-ALN micellas treatment tumor bearing nude mice.Nude mice shin
Bone ossis injects A549 cell modelings, tail vein administration.A：General camera observes tumor bearing nude mice gross tumor volume；B：Measure lotus knurl
Nude mouse tumor Volume Changes；C：Each administration group gross tumor volume inhibiting rate.N=3,*P<0.05, VS DOX；#P<0.05, VS
Control。
Fig. 2 is DOX and DOX@MA-DEX(5K)The change curve of nude mice body weight after-ALN micellas treatment tumor bearing nude mice.It is naked
Mouse shin bone ossis injects A549 cell modelings, tail vein administration.N=3,*P<0.05, VS DOX.
Fig. 3 is tumor bearing nude mice right hind Micro-CT after DOX and DOX@MA-DEX (5K)-ALN micellas treatment tumor bearing nude mice
Rebuild (A) and sagittal image (B)；Tumor bearing nude mice right hind Micro-CT data analyses (C and D).BV/TV is bone volume/group
Knit volume.N=3,*P<0.05, VS DOX.
Specific implementation method
DOX@MA-DEX(5K)The inside and outside antitumor activity of-ALN micellas
1 purpose：Tested by inside and outside, evaluate DOX@MA-DEX(5K)The antitumor activity of-ALN micellas.
2 research methods：
2.1 envelop rates and drugloading rate are determined
Using fluorescence spectrophotometry DOX concentration, excitation wavelength is 470nm, and launch wavelength is 597nm, uses DMSO
Prepare 100 μ g/mL DOX standard reserving solutions as solvent, be then diluted to 0.1 respectively, 1.0,2.0,5.0,10.0,15.0,
25.0 μ g/mL, fluorescent spectrophotometer assay fluorescence intensity carries out linear fit with fluorescence intensity to concentration, obtains detecting DOX
The regression equation of standard curve is y=20.118x-15.352, R2=0.9976.Wherein DOX in the range of 0.1-25 μ g/mL,
Fluorophotometric value has good linear relationship with concentration.
Weigh 1mg carrier micelle DOX@MA-DEX(5K)- ALN is dissolved in 3mLDMSO, determines DOX fluorescence intensities, often
Individual sample is determined three times.Drugloading rate and envelop rate are calculated by below equation：
Drugloading rate=(amount of medication amount/micella in micella) × 100%
Envelop rate=(medication amount encapsulated in micella/prepare the medicine total amount of micella input) × 100%
2.2 evaluate DOX@MA-DEX(5K)The adsorption dynamics adsorption kinetics of-ALN micellas and HA
Precision weighs 1mg DOX and DOX@MA-DEX(5K)- ALN micellas are dissolved in 10mL PBS, determine the suction of solution
Shading value, record data.Be then respectively adding 100mg HA stirring, at 5,15,30 and 60min, sample in 5000rmp from
Heart 10min, Aspirate supernatant determines absorbance respectively.
After adsorption rate=[(before survey-is surveyed)/survey before] × 100%
2.3 evaluate DOX@MA-DEX(5K)The vitro cytotoxicity of-ALN micellas
DOX and DOX@MA-DEX are determined using mtt assay(5K)- ALN micellas are to A549 cells, PC-3 cells, MDA-MB-
The toxic action of 231 cells and MDA-MB-231/ADR cells.Take the logarithm the tumour cell in growth period, with 0.25% tryptose
Enzymic digestion, is inoculated in 96 orifice plates (cell concentration 1 × 104/ mL, inoculation volume 200 μ L).Culture 24h in incubator (37 DEG C) is placed in,
Discard nutrient solution.Respectively by DOX and DOX@MA-DEX(5K)- ALN micellas are dissolved in the nutrient solution of serum-free, using be not added with medicine as
Negative control group.The concentration that micella converts into DOX is respectively 0.08,0.8,8.0 and 40.0 μ g/mL, 200 μ L medicines is added per hole molten
Liquid, is incubated 24h.20 μ L MTT solution are added per hole, continues to discard nutrient solution after cultivating 4h, 200 μ L DMSO is added per hole.Will
Culture plate is placed at shaking table shaking 10min, ELIASA 490nm and determines absorbance.The cells survival rate %=(extinctions after administration
The absorbance of angle value/negative control) × 100%.
2.4 evaluate DOX@MA-DEX(5K)The internal antitumor activity of-ALN micellas
2.4.1 experiment packet
Male nude mouse is randomly divided into 3 groups：Lotus knurl model group, DOX groups (5mg/kg), DOX@MA-DEX(5K)- ALN micella groups
(5mg/kg)。
2.4.2 the foundation of tumor-bearing model
Take the logarithm the A549 cells in growth period, obtain concentrating cells after scrubbed, digestion, centrifugation, then add serum-free
RPMI 1640 culture medium diluting cells make its concentration reach 1 × 107/ mL, it is stand-by.By 60 ° of nude mice knee joint bending, Ran Houyong
1mL syringe draws 100 μ L above-mentioned cell suspension, and syringe needle tilts in insertion nude mice shin bone ossis, cell is injected, built
Vertical tumor-bearing model.When tumour is accessible, according to packet, intravenous (IV) drug, gives identical dose again respectively after seven days
Measure medicine.
2.4.3 observation index
1. the Volume Changes of tumour are observed：Observation tumour growth situation, gross tumor volume is calculated according to formula daily.
Tumor Volume=L × W2× 0.5 (L, W represent tumour longest diameter and most short diameter respectively)
2. the changes of weight of nude mice is observed.The weight of animals change is recorded, changes of weight curve is drawn, observation medicine is to animal
The influence of body weight.
3. Micro-CT observes the change of sclerotin at metastatic tumor of bone.
3 experimental results：
3.1 envelop rates and drugloading rate
The DOX@MA-DEX of table 1(5K)The drugloading rate and envelop rate of-ALN micellas
As a result showing the micella of this patent design has high drug load and high encapsulation rate characteristic.
3.2 anti tumor activity in vitro
DOX@MA-DEX(5K)- ALN micellas are to A549 cells, PC-3 cells, MDA-MB-231 cells and MDA-MB-231/
The toxicity of ADR cells has obvious concentration dependent, is gradually reduced with the increase cell survival rate of DOX concentration.Compared to
DOX, DOX@MA-DEX(5K)- ALN micellas are thin to A549 cells, PC-3 cells, MDA-MB-231 cells and MDA-MB-231/ADR
The toxicity of born of the same parents is stronger.DOX to MDA-MB-231/ADR cells almost without toxicity, and DOX MA-DEX(5K)- ALN micellas are shown
Stronger cytotoxicity.
Study of cytotoxicity is evaluates the important indicator of vitro Drug antitumor activity, and the above results are shown, DOX@MA-
DEX(5K)- ALN micellas have prominent cytotoxicity to tumour cell, also have good body simultaneously for cells of resistant tumors
Outer antitumous effect.
Antitumor activity in 3.3 bodies
Figure 1A is the growing state of each group tumor bearing nude mice recorded using general camera, and Figure 1B show tumor bearing nude mice tumour
The change of volume.It can be seen that the nude mouse tumor volume rapid development of blank control group.It is empty when the 30th day
The mean tumour volume of white control group has been added to 4168 ± 204mm3.The treatment of DOX groups can suppress tumour to a certain degree
Rapid growth, 2711 ± 372mm is reached in the 30th day gross tumor volume3.And under the conditions of same dose, DOX@MA-DEX(5K)-ALN
Show antitumous effect more more preferable than DOX.The DOX@MA-DEX after administration the 30th(5K)- ALN administration group nude mouse tumor volumes are
789±118mm3.Fig. 1 C are tumor control rate of the different dosing group to tumor bearing nude mice.As can be seen from the figure DOX@MA-DEX
(5K)-ALN has more preferable tumor suppression ability compared to DOX.After experiment terminates, DOX, DOX@MA-DEX(5K)- ALN's is swollen
Knurl inhibiting rate is 38.4%, 67.9% respectively.
Fig. 2 show the changes of weight of nude mice.As can be seen from the figure all nude mices body weight in initial two weeks has
It is slow to rise, but with the extension for the treatment of time, the rapid decline of the body weight appearance of blank control group and DOX administration group nude mices becomes
Gesture.The nude mice body weight of DOX MA-DEX (5K)-ALN administration groups is declined slightly.Changes of weight is to weigh DOX to body toxic side effect
An important indicator, DOX is loaded into MA-DEX(5K)After-ALN micellas, the relatively free DOX of changes of weight is significantly reduced, and poison is secondary to be made
With being decreased obviously.
The bone tissue at metastatic tumor of bone is scanned using Micro-CT.It can be seen that positive right from Fig. 3 A, Fig. 3 B
According to being seriously damaged at the mouse tibia and fibula of group, obvious osteolytic lesion, cortex destruction, most of bone trabecula are showed
Disappear.And moderate damage is showed at the nude mice shin bone and fibula of DOX groups, partial cortical is still completely present, and bone trabecula is also relative
It is more.DOX@MA-DEX(5K)Destruction of-ALN the administration groups to sclerotin is smaller, compared with negative control group, and sclerotin has been kept substantially
Shaping state.Fig. 3 C, Fig. 3 D results are to have done one to the volume and quantity of shin bone bone trabecula using Micro-CT analysis softwares
The analysis of step.As a result DOX@MA-DEX are shown(5K)- ALN administration groups can be obviously improved destruction of the tumour cell to bone trabecula and make
With.The bone density value of proximal tibia is detected using Micro-CT simultaneously, as can be seen from the results DOX@MA-
DEX(5K)- ALN administration group bone density values are all higher than DOX groups, and with significant difference；DOX@MA-DEX(5K)- ALN with it is normal right
Compared according to group, without significant difference.As a result DOX@MA-DEX are illustrated(5K)- ALN can be weakened by energetically antitumor action
Invasion and attack of the tumour to sclerotin, mitigate the reduction to bone density and act on.
4 conclusions：
The anti-tumor experiment result of inside and outside shows, compared with free DOX, DOX@MA-DEX(5K)- ALN micellas can be effective
Enrichments of the DOX in tumor tissues is improved, while substantially reducing distributions of the DOX in normal structure, mitigates toxic side effect, shows aobvious
Enhanced antitumor activity is write, with good DEVELOPMENT PROSPECT.
Claims (1)
1. a kind of isotope of redox-sensitive Bone targeting micella for being used to treat metastatic carcinoma of bone, it is characterized in that with Alendronate sodium (ALN)
For Bone targeting aglucon, with the glucan (DEX of molecular weight 5000(5K)) it is water wetted material, with tetradecy lamine (MA) for hydrophobic material, with
3,3 2 thiodipropionic acids (DPC) are that crosslinking agent synthesizes MA-DEX(5K)- ALN, with adriamycin (DOX) for model drug, is prepared simultaneous
There is active Bone targeting and there are the nano-micelle DOX@MA-DEX of specificly-response to tumour cell microenvironment(5K)-ALN；
Specific preparation method is as follows：
The synthetic method of (1) two thiodipropionic acids-Alendronate sodium (DPC-ALN)
1. 2.4mmol DPC 501.1mg, 4.8mmol EDCI 916.8mg are added in 20mL Isosorbide-5-Nitrae dioxane, are stirred
30min is mixed, 5.0mmol NHS 575.2mg and 150 μ L TEA is then added, continues stir-activating 3h；2. 20mL's
1.2mmol ALN 325.6mg are added in distilled water, it is secondary in three batches to be slowly added dropwise into above-mentioned reaction solution, anti-fully after dissolving
During answering, 0.2M NaOH, which are slowly added dropwise, makes the pH stable of reaction solution maintain continuation dropwise addition 0.2M after 7.0 or so, 2 hours
NaOH makes pH be tuned into 9.0, continues reaction and stays overnight, and reaction is spin-dried for solvent after terminating, and solid is with a large amount of dichloromethane rinse three repeatedly
Secondary, methanol rinses three times obtain product；
The synthetic method of (2) two thiodipropionic acids-tetradecy lamine (DPC-MA)
2.4mmol DPC 500mg, 4.8mmol EDCI 916.8mg, stirring are added in 20mL Isosorbide-5-Nitrae dioxane
30min, then adds 5.0mmol NHS 575.2mg and 150 μ L TEA, continues stir-activating 3h, then in reaction solution
Middle addition 1.3mmol MA 217.6mg, react at room temperature 12h, and TLC monitoring reactions terminate after reaction, post separation crossed, wherein opening up
Open agent using volume basis as：Dichloromethane:Methanol=10:1；
(3) glucan(5K)- 3,3 two thiodipropionic acids-tetradecy lamine (DEX(5K)- DPC-MA) synthetic method
Weigh a certain amount of DPC-MA, EDCI, NHS and TEA to be dissolved in 30mL DMSO successively, fully added after dissolving a certain amount of
DEX(5K), 12h is reacted at room temperature, is terminated after reaction, filtering reacting liquid obtains faint yellow supernatant liquid, and filtrate uses a large amount of dichloromethanes
Alkane is precipitated, and cleans precipitation with dichloromethane repeatedly, and methanol rinses precipitate three times, are finally dissolved in precipitation in a small amount of distilled water thoroughly
Analysis is lyophilized, produces DEX(5K)-DPC-OA；
(4) two thiodipropionic acids of tetradecy lamine-3,3-glucan(5K)- 3,3 two thiodipropionic acids-Alendronate sodium (MA-DPC-DEX(5K)-
DPC-ALN synthetic method)
Weigh a certain amount of DPC-ALN, EDCI, NHS and TEA to be dissolved in 40mL DMSO successively, fully added after dissolving certain
The DEX of amount(5K)- DPC-MA, 60 DEG C of reaction 48h of oil bath, reaction dialyses to freeze after terminating produces MA-DPC-DEX(5K)- DPC-ALN,
It is abbreviated as MA-DEX(5K)-ALN；
(5)MA-DEX(5K)- ALN carries the preparation of adriamycin (DOX) micella
3mg DOXHCl are weighed in 4mL DMSO, 3 μ L TEA is added, lucifuge magnetic agitation 1h makes in 60 DEG C of oil baths
It fully dissolves, plus 10mg MA-DEX(5K)Distilled water 32mL is slowly added dropwise after persistently stirring 2h in preparation solution in-ALN, after
Continuous stirring 12h；Above-mentioned mixed liquor is fitted into the bag filter that molecule interception is 2000, dialyse 48h, changes a water per 6h, thoroughly
Polymer medicament carrying micelle is freeze-dried to obtain after analysis.
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| CN105853357A (en) * | 2016-04-26 | 2016-08-17 | 中国药科大学 | Multifunctional cooperative mixed micelle drug delivery system and preparation method thereof |
| CN106074378A (en) * | 2016-07-06 | 2016-11-09 | 烟台大学 | A kind of Bone targeting micellar material and the curcumin micellar preparation prepared with this material |
| CN107998406B (en) * | 2017-11-30 | 2020-09-01 | 中国科学院苏州纳米技术与纳米仿生研究所 | Cascade targeted drug delivery system and preparation method and application thereof |
| CN108102004B (en) * | 2018-01-03 | 2020-02-14 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | Glucan polymer, polymer micelle and drug carrier system |
| CN110124053B (en) * | 2019-06-13 | 2022-12-02 | 扬州大学 | Synthetic method of heparin alen sodium phosphate conjugate and drug thereof |
| CN110664753B (en) * | 2019-11-04 | 2021-07-02 | 南通大学 | Bone-targeting hypoxia-responsive nano micelle loaded with anticancer drug and preparation method thereof |
| CN111333835B (en) * | 2020-03-06 | 2021-11-05 | 同济大学 | Bone-targeting polymer, bone-targeting polymer vesicle and preparation method and application thereof |
| CN113616593A (en) * | 2021-08-23 | 2021-11-09 | 嘉兴学院 | Application of nano-targeting polymer micelle in preparation of targeting drug delivery system |
| CN114191391B (en) * | 2022-01-18 | 2023-10-03 | 蒋廷旺 | Preparation method of myricetin-loaded nano micelle for reducing ovariectomy-induced bone loss by inhibiting formation of osteoclast |
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