CN106267149A - A kind of apoplexy intellectual drug carrier of ROS response and preparation method thereof - Google Patents
A kind of apoplexy intellectual drug carrier of ROS response and preparation method thereof Download PDFInfo
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Abstract
Apoplexy intellectual drug carrier and preparation method thereof of a kind of ROS response, carrier is to be grafted on bag load neuroprotective NR2B9C in nano vesicle that the amphipathic nature block polymer that hydrophilic dextrans skeleton formed prepared, nano vesicle for carrier material by with hydrophobicity borate.Preparation method is, by borate with glucosan by covalence graft, then by autonomous dress method, the carrier material after graft reaction is prepared as nano vesicle carrier, and is loaded in described nano vesicle carrier by neuroprotective NR2B9C bag.First borate is passed through covalence graft with glucosan, then the material after graft reaction is prepared as nano vesicle by autonomous dress method；Borate is 10:5～25 with the mass ratio of glucosan；This carrier easily in response to the Degradation of ROS mediation, makes medicine quickly discharge at cerebral ischemia lesions position, reduces simultaneously and discharge in non-focal zone, thus in more safely and effectively realizing the brain of neuroprotective, target area delivers.
Description
Technical field
The present invention relates to pharmaceutical technology field, be specifically related to apoplexy intellectual drug carrier and the system thereof of a kind of ROS response
Preparation Method.
Background technology
Continuous progressive along with human society, social senilization's problem is on the rise, cerebrovascular disease incidence rate also by
Year increases, and has become the emphasis of current epidemiology preventing and treating.Wherein apoplexy is serious harm human health and life peace
Complete common refractory disease, also exists obvious three-hypers (sickness rate is high, disability rate height, mortality rate are high) phenomenon, is listed in people
Class is only second to the third-largest killer of cardiovascular disease and malignant tumor.The apoplexy of 87% belongs to cerebral infarction clinically,
So, the study medication of cerebral infarction is had great clinical meaning.In organism, active oxygen (ROS) including:
Hydroxy radical (OH-), hydrogen peroxide, Peroxynitrite (ONOO-) etc., many physiological reactions all can produce a certain amount of low-level
ROS.Research shows: compared to normal physiological conditions, and cerebral tissue is the generation ROS of meeting high level persistence under the conditions of apoplexy,
The ROS of excess can cause the compositions such as DNA, protein and the lipid in oxidative stress and damaging cells, thus causes local
Cell injury.ROS level improves closely related with the partial onset mechanism of cerebral infarction, and the typical damage of apoplexy (lacks
Blood reperfusion injury) persistently a large amount of ROS can be produced, and initial ischemia injury can be increased the weight of simultaneously.Therefore, sick for cerebral ischemia
The characteristic of stove position high level ROS carries out responding the research of sensitive intellectual drug carrier and has the biggest prospect.
NR2B9C is the polypeptide that there is the treatment cerebral infarction of clinical landscapes a kind of current pole, and it is by for nmda receptor
9 amino acid residue compositions of hypotype NR2B c-terminus, specific can be combined with PSD-95, release NMDAR/PSD-95 even
Connection, blocks and causes the downstream signal of nerve excitability toxicity to conduct, but do not affect the normal physiological function of nmda receptor.Grind at present
Study carefully middle NR2B9C to be carried along into blood circulation by the Tat being derived from HIV and can be only achieved corresponding topical therapeutic effect, but Tat exists
Safety aspect there is much controversy, and potential applicability in clinical practice also allows of no optimist.So, the apoplexy intelligence of research and development NR2B9C
Drug delivery system, it appears extremely important.Owing to NR2B9C is the extremely strong micromolecule polypeptide of hydrophilic, common micelle, nanometer
The carrier of the core-shell type structures such as grain is the most undesirable to its envelop rate and drug loading.Polymer vesicle is by amphipathic block polymerization
What thing was constituted has the double-deck drug delivery vehicle of closing, and inside has good hydrophilic environment, has hydrophilic medicament
There is highly desirable encapsulating effect.
Glucosan is that one has preferable biocompatibility, biodegradability, and that easily modifies and easily obtain is poly-
Compound.Research shows, borate can be as having the triggering group of ROS response characteristic, and this group is easier to respond the fall of ROS mediation
Solution effect.Modified by reversible chemical, the hydrophobicity borate with ROS response characteristic is grafted on hydrophilic dextrane bone
Frame so that it is form amphipathic structure and then can independently fill and be scattered in aqueous phase, forming the nano vesicle medicine of great application prospect
Carrier.
Summary of the invention
It is an object of the invention to, pass the defect that the aspects such as drug effect rate and safety exist in view of current NR2B9C, it is provided that one
Planting apoplexy intellectual drug carrier and the preparation method of ROS response, this carrier easily responds the Degradation of ROS mediation, makes medicine
Thing reduces at cerebral ischemia lesions position rapid release simultaneously and discharges in non-focal zone, thus more safely and effectively realizes medicine and deliver.
The present invention is achieved through the following technical solutions: the apoplexy intellectual drug carrier of ROS response, is by with hydrophobicity boron
Acid esters graft on hydrophilic dextrane skeleton formed amphipathic nature block polymer be carrier material prepare nano vesicle, this nanometer
Vesicle is for wrapping the neuroprotective NR2B9C of load.Nano vesicle carrier has regular spherical design, and mean diameter is at 120-
220nm。
Described glucosan weight average molecular weight is 10000-25000.
Described hydrophobicity borate is the stupid pinacol borate of 4-methylol (PBAP), 4-methylol benzene boron one or many
Kind.The aminoacid sequence of described NR2B9C is KLSSIESDV.
Nano vesicle has regular spherical design, and mean diameter is at 120-220nm.
Described borate is 30 ± 5% with the percent grafting of glucosan.
By borate with glucosan by covalence graft, then the carrier material after graft reaction is prepared by autonomous dress method
Become nano vesicle carrier, and neuroprotective NR2B9C bag is loaded in described nano vesicle carrier.
The preparation method of the apoplexy intellectual drug carrier of described ROS response, first passes through borate altogether with glucosan
Valency is grafted, then by autonomous dress method, the material after graft reaction is prepared as nano vesicle；Borate and the mass ratio of glucosan
For 10:5～25；
Described borate comprises the following steps with glucosan covalence graft method: by 4-methylol phenylboric acid pinacol ester
(PBAP) being dissolved in anhydrous methylene chloride with carbonyl dimidazoles (CDI), after reaction 30 ± 10min, magnesium sulfate is dried overnight, and concentrates also
It is vacuum dried to obtain white solid (PBAP-CDI)；Glucosan (dextran, Mw=10000～25000g/mol) is dissolved in formyl
In amine, it is separately added into PBAP-CDI, DMAP DMAP, stirred overnight at room temperature subsequently；Reactant liquor is passed through dialysis
Removing solvent and unreacted PBAP-CDI, lyophilization gained white powder (PHB-Dextran) is borate and gathers with Portugal
Sugar covalence graft product.
Described self-assembly method comprises the following steps: a certain amount of PHB-Dextran is dissolved in methanol molten with the mixing of Methanamide
Appropriate NR2B9C, as organic facies, is dissolved in 0.2M Tris-HCl buffer, is distributed to after joining above-mentioned organic facies by agent
In 0.5% PLURONICS F87 aqueous solution, continuing stirring 1-2h, then dialysis removes organic solvent and free NR2B9C, solution mistake
The microporous filter membrane of 0.45 μm i.e. obtains nano vesicle carrier (NP/NR2B9C).
Mixing the volume ratio of methanol and Methanamide in organic facies when preparing nano vesicle is 1:1～5.
The mass ratio of NR2B9C Yu PHB-Dextran carrier material is 1:10～20.
The method have the benefit that
1, the apoplexy intellectual drug carrier that the present invention synthesizes, has bigger improvement in synthetic route and preparation technology:
And use dialysis to purify carrier material and to remove organic solvent, the material favorable solubility synthesized, entrapped drug ability
Stronger；Using self-assembling technique to prepare nano-carrier, method is simple, low cost.The ROS response that the present invention prepares
Apoplexy intellectual drug carrier can have preferable stability by size controlling at about 165nm.
2, the present invention switchs with ROS for intelligent medicine releasing, and neuroprotective NR2B9C is encapsulated in the brain soldier with ROS response
In middle intellectual drug carrier, it can be made simultaneously to reduce in cerebral ischemia lesions position immediate release drug and to discharge in non-focal zone, thus more
Add and safely and effectively NR2B9C is delivered to apoplexy position, play the therapeutical effect of medicine to greatest extent, reduce complete simultaneously
Body toxic and side effects.
Accompanying drawing illustrates:
Fig. 1 be carrier material (PHB-Dextran) synthesized by the present invention molecular formula (on) with nuclear magnetic resonance map (under).
Fig. 2 is the transmission electron microscope picture of the apoplexy intellectual drug carrier of ROS of the present invention response.
Fig. 3 is conduct hydrolysis figure (the most corresponding 0.01M PBS of the apoplexy intellectual drug carrier of ROS of the present invention response
Buffer system and containing 1mM H2O2The outward appearance photo of nano-carrier solution of 0.01M PBS buffer system shooting；Corresponding 0h
Six time periods of (AB figure) 0.25h (CD figure), 0.5h (EF figure), 1h (HI figure), 2h (JK figure), 4h (LM figure), each time period
Two photos.
Fig. 4 is the release in vitro figure of the apoplexy intellectual drug carrier of ROS of the present invention response.
Fig. 5 is that the internal drug effect of apoplexy intellectual drug carrier of ROS of the present invention response compares photo: be divided into four groups:
Sham operated rats (Sham), model group (MCAO), free (NR2B9C) group, apoplexy intellectual drug carrier (NP/NR2B9C) group, often
Group take optic chiasma before 4mm and thereafter brain do continuous coronal section and respectively take five photos of 5.
Fig. 6,7 it is the internal pharmacodynamics figure of apoplexy intellectual drug carrier of ROS of the present invention response, (the most corresponding * * P <
0.01,***P<0.001)。
Detailed description of the invention:
Below in conjunction with specific embodiments and the drawings, the invention will be further elaborated, and specific embodiment is in the present invention
Carry out under optimum condition.Described method is conventional method if no special instructions, and described raw material the most all can be from
Disclose commercial sources and obtain.
Embodiment 1
The preparation of carrier material PHB-Dextran and sign
By 4-methylol phenylboric acid pinacol ester (PBAP, 7.37g, 31.5mmol) and carbonyl dimidazoles (CDI, 10.20g,
62.9mmol) it is dissolved in anhydrous methylene chloride, reacts 30min.Pure water is washed three times (3 × 10ml), and salt is washed once (1 × 10ml),
Magnesium sulfate is dried overnight, and concentrates and be vacuum dried and to obtain white solid (PBAP-CDI).By glucosan (dextran, Mw=
10000g/mol) it is dissolved in 4ml Methanamide, is separately added into PBAP-CDI, DMAP, stirred overnight at room temperature subsequently.Reactant liquor is used
Bag filter (molecular cut off 500Da, dialysis medium is pure water) dialysis removes Methanamide and free PBAP-CDI, and lyophilization obtains
White powder (PHB-Dextran).Nuclear magnetic resonance analyser detects its nuclear magnetic spectrum, sees Fig. 1.
Embodiment 2
The preparation of ROS response apoplexy intellectual drug carrier and sign
Prepared by employing self-assembly method, weigh 10mg PHB-Dextran and be dissolved in the mixed solvent (V:V=of Methanamide and methanol
1:1) as organic facies, weigh 1mg NR2B9C and be dissolved in 0.2M Tris-HCl buffer, be dropwise distributed to after mixing with organic facies
Being stirred continuously in the 10ml 0.5% PLURONICS F87 aqueous solution of (500rpm, 37 DEG C), continue stirring 1-2h, dialysis (retains point
Son amount 50kDa, dialysis medium is pure water) after 24h, cross 0.45 μm microporous filter membrane and i.e. obtain nano vesicle carrier (NP/NR2B9C), use
Transmission electron microscope characterizes its form and sees Fig. 2.Fig. 2 shows observe under transmission electron microscope this nano vesicle carrier have regular spherical outside
Seeing, size is uniform, and particle diameter is at about 165nm.Laser particle size analysis shows, gained nano vesicle carrier is with 170nm for the most straight
Footpath in normal distribution, polydispersity is 0.018.Envelop rate is 60%, and drug loading is 2.91%.
Embodiment 3
The conduct hydrolysis of ROS response apoplexy intellectual drug carrier
The nano vesicle carrier (NP) prepared is divided into two parts, is respectively placed in 0.01M PBS buffer system and containing 1mM
H2O20.01M PBS buffer system in, hatch for 37 DEG C.Digital camera is respectively at 0, and 0.25,0.5,1,2,4h shooting photograph is investigated
The cosmetic variation of nano-carrier solution, is shown in Fig. 3.As seen from Figure 3,1mM H is added2O2After 15min, nano vesicle carrier is light
Blue-opalescent substantially weakens, opalescence disappearance bleach clarification after 30min, and without H2O2PBS group outward appearance without significant change, this knot
Fruit demonstrates the conduct hydrolysis of nano vesicle carrier and has ROS response characteristic.
Embodiment 4
The release in vitro of ROS response apoplexy intellectual drug carrier
Bag carries NR2B9C (Rhodamine-NR2B9C) the nano vesicle carrier preparation method of rhodamine labelling ibid.Use
Ultrafiltration centrifuging investigates the drug release behavior of NP/Rhodamine-NR2B9C, uses 1mM H2O2The brain simulating the rising of ROS level lacks
The microenvironment of blood lesions position.Release medium is respectively the PBS phosphate buffer of pH7.4 and containing 1mM H2O2PBS phosphoric acid
Salt buffer.In 37 DEG C of waters bath with thermostatic control, 160rpm vibration carries out release experiment, operation repetitive 3 parts.Respectively at 0,0.5,1,2,4,
8h time point timing extracting medium 0.5mL, supplements the fresh dissolution medium of equivalent constant temperature simultaneously.The medium taken out is micro-through 0.45 μm
Hole membrane filtration, is placed in ultra-filtration centrifuge tube (MWCO=30000Da) and is centrifuged with 3500rpm 5min ultrafiltration, and lower floor's stillness of night is dilute
After releasing suitable multiple, spectrofluorophotometer (EX:460nm, EM:525nm) measures and calculates cumulative release percentage rate.By scheming
4 understand, H2O2Group release medicine is very fast, and cumulative release amount during 4h is close to 50%.And PBS group releasing trend is shallower, during 4h
Cumulative release amount be only about 15%.Understand from the above, at H2O2Preparation under existence condition is significantly higher than nothing
H2O2The PBS group existed, demonstrates the ROS response characteristic of nano vesicle carrier drug release behavior, and this is beneficial to it and enters cerebral tissue
After, respond under ROS stimulates in ischemia cell, discharge rapidly medicine, repair the neuron being at death's door.
Embodiment 5
The internal pharmacodynamic study of ROS response apoplexy intellectual drug carrier
Healthy male SD rat, is randomly divided into 4 groups: sham operated rats (Sham), model group (MCAO), free NR2B9C group,
Apoplexy intellectual drug carrier (NP/NR2B9C) group, often group is after brain injury, the corresponding prescription of tail vein injection.Lack at brain
After blood Reperfu-sion 24h, according to Zea-Longa set up neurological functional deficit Pyatyi quartering modular system mark.
After ischemia-reperfusion 24h, rats by intraperitoneal injection chloral hydrate anesthesia, broken end takes brain at once, after transverse section is by forward direction, takes optic chiasma
Front 4mm and thereafter brain do continuous coronal section (thickness 2mm), take 5 altogether.Section is placed in 1% (mass concentration) TTC dyeing
In liquid, in drying baker, 37 DEG C of lucifuges hatch 30min, and perusal normal cerebral tissue is rose, and infarcted region cerebral tissue is white.
Calculating infarct area percentage: place half, Infarct area Sn/ infarcted region brain area S ' n × 100%.Sn represents every single noisy
Infarct size sum in section, S ' n represents the half brain area sum (n=1～5) at place, every single infarcted region.See that Fig. 5, TTC contaminate
In color result brain, rose position is normal cerebral tissue, and white position is infarcted region.Understanding in figure, sham operated rats has no infarction
Region, model group has to be damaged largely, and is obviously reduced seen from the infarct size of NP/NR2B9C group, and NP/NR2B9C is described
Protective effect to brain injury is obvious.Being amassed comparison diagram from infarction of brain cooktop, NP/NR2B9C group relatively MCAO group can be obvious
Reducing ischemic infarction area, significant difference is notable (P < 0.001).By Neuroscore as a result, it is possible to find out NP/NR2B9C
The rat of group has lighter nervous function damage compared with MCAO group, and significant difference is notable (P < 0.01).Result above all shows this
NR2B9C safely and effectively can be delivered to apoplexy position by apoplexy intellectual drug carrier (NP/NR2B9C) of invention,
It is made to play therapeutical effect.
Claims (9)
1. the apoplexy intellectual drug carrier of a ROS response, it is characterised in that: this carrier is to be grafted by with hydrophobicity borate
The amphipathic nature block polymer (PHB-Dextran) formed in hydrophilic dextrane skeleton is nano vesicle prepared by carrier material,
This nano vesicle is used for wrapping load neuroprotective NR2B9C；Nano vesicle has regular spherical design, and mean diameter is at 120-
220nm。
The apoplexy intellectual drug carrier of ROS the most according to claim 1 response, it is characterised in that: above-mentioned glucosan weight
Average molecular weight is 10000～25000, and described borate is 4-methylol phenylboric acid pinacol ester (PBAP), 4-methylol benzene boron
One or more in acid.
ROS the most according to claim 1 response apoplexy intellectual drug carrier, it is characterised in that: described borate with
The percent grafting of glucosan is 30 ± 5%.
The apoplexy intellectual drug carrier of ROS the most according to claim 1 response, it is characterised in that: described NR2B9C's
Aminoacid sequence is KLSSIESDV.
The apoplexy intellectual drug carrier of ROS the most according to claim 1 response, it is characterised in that: by borate and Portugal
Polysaccharide passes through covalence graft, then by autonomous dress method, the carrier material after graft reaction is prepared as nano vesicle carrier, and will
Neuroprotective NR2B9C bag is loaded in described nano vesicle carrier.
The preparation method of the apoplexy intellectual drug carrier of ROS the most according to claim 5 response, it is characterised in that: first
By borate with glucosan by covalence graft, then the material after graft reaction is prepared as nano vesicle by autonomous dress method；
Borate is 10:5～25 with the mass ratio of glucosan；
Described borate comprises the following steps with glucosan covalence graft method: by 4-methylol phenylboric acid pinacol ester (PBAP)
Being dissolved in anhydrous methylene chloride with carbonyl dimidazoles (CDI), after reaction 30 ± 10min, magnesium sulfate is dried overnight, and concentrates and vacuum is done
Dry white solid (PBAP-CDI)；Glucosan dextran, Mw=10000～25000g/mol are dissolved in Methanamide, subsequently
It is separately added into PBAP-CDI, DMAP DMAP, stirred overnight at room temperature；By reactant liquor by dialysis remove solvent and
Unreacted PBAP-CDI, lyophilization gained white powder (PHB-Dextran) is borate and glucosan covalence graft
Product.
The preparation method of the apoplexy intellectual drug carrier of ROS the most according to claim 5 response, it is characterised in that: will
A certain amount of PHB-Dextran is dissolved in the mixed solvent of methanol and Methanamide as organic facies, and appropriate NR2B9C is dissolved in 0.2M
Tris-HCl buffer, is distributed to after joining above-mentioned organic facies in 0.5% PLURONICS F87 aqueous solution, continues stirring 1-2h,
Then dialysis removes organic solvent and free NR2B9C, and solution is crossed the microporous filter membrane of 0.45 μm and i.e. obtained nano vesicle carrier (NP/
NR2B9C)。
The preparation method of the apoplexy intellectual drug carrier of ROS the most according to claim 7 response, it is characterised in that: system
During standby nano vesicle, in mixing organic facies, the volume ratio of methanol and Methanamide is 1:1～5.
The preparation method of the apoplexy intellectual drug carrier of ROS the most according to claim 6 response, it is characterised in that:
The mass ratio of NR2B9C Yu PHB-Dextran carrier material is 1:10～20.
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| CN108102004A (en) * | 2018-01-03 | 2018-06-01 | 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 | A kind of dextran polymer, polymer micelle and medicament carrier system |
| CN108714221A (en) * | 2018-05-04 | 2018-10-30 | 浙江大学 | A kind of monoclonal antibody class drug oral nanometer formulation and preparation method thereof |
| CN109355310A (en) * | 2018-11-06 | 2019-02-19 | 南京工业大学 | The gene delivery vector and its preparation method and application of ROS response |
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| 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 |
| CN108714221A (en) * | 2018-05-04 | 2018-10-30 | 浙江大学 | A kind of monoclonal antibody class drug oral nanometer formulation and preparation method thereof |
| CN108714221B (en) * | 2018-05-04 | 2020-09-08 | 浙江大学 | Oral nano preparation of monoclonal antibody medicine and preparation method thereof |
| CN109355310B (en) * | 2018-11-06 | 2021-09-28 | 南京工业大学 | ROS (reactive oxygen species) -responsive gene delivery vector as well as preparation method and application thereof |
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