CN105687159A - Preparation and application of silymarin lipid nanoparticles - Google Patents
Preparation and application of silymarin lipid nanoparticles Download PDFInfo
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Abstract
The invention provides silymarin lipid nanoparticles.The silymarin lipid nanoparticles are prepared, infantile autism experimental animal models are combined, pharmacodynamics indicators of the silymarin lipid nanoparticles are evaluated from the total animal level, it is proved that the silymarin lipid nanoparticles have good targeting for the brain inflammation focus area, medicine can be enriched within the inflammation area, bioavailability of the medicine is improved, and medicine dosage is lowered.The preparation and application of silymarin lipid nanoparticles can provide a new experiment basis and thought for clinically treating infantile autism, and the silymarin lipid nanoparticles can serve as a drug-loading system which is higher in efficiency and low in toxicity and be applied to preparation of infantile autism intervention medicine.
Description
Technical field
The invention belongs to biomedicine technical field, relate to targeting drug delivery system, be specifically related to a kind of brain targeting drug delivery system for treating infantile autism, the preparation method and application of especially a kind of silymarin lipid nanoparticle。
Background technology
Infantile autism is a kind of brain pervasive developmental disorders that nervous system development imbalance causes。Infantile autism affects development and the interpersonal communication ability of people social and communication skill, fall ill before being everlasting 3 years old。Its cause of disease is various, but concrete pathogenesis is unclear。It is now recognized that this disease is probably environmental factors and the coefficient result of genetic predisposition。Research finds, the generation of infantile autism has certain dependency with oxidative stress and inflammatory reaction, the phenomenon that inflammatory reaction is abnormal is there is in infantile autism patient's brain, show as proinflammatory cytokine to increase, these pro-inflammatory cytokines and infantile autism patient lack social competence, and opposing new things and the symptom such as sleep disordered are relevant。In brain, inflammatory reaction and oxidative stress increase may result in inflammation, activate microglia。Thus, it may be possible to inflammatory reaction causes Activated Microglia thus promoting brain lesions and clinical symptoms。
Thus, anti-inflammatory drug treatment infantile autism is utilized to receive the concern of people, and Chinese medicine anti-inflammatory agent, because its good drug efficacy, untoward reaction are few and the advantage such as abundance, increasingly it is subject to people's attention, researches and develops the new Chinese medicine with anti-inflammatory active ingredient and be increasingly becoming focus。Silymarin is traditional Chinese medicine, recently studies discovery, and it has good antiphlogistic effects。
Owing to small-molecule drug passes through the limited in one's ability of blood brain barrier, many researchs think that blood brain barrier is the bottleneck of brain diseases treatment。Therefore by designing novel Brain targeting drug-loading system, overcome the obstruction of blood brain barrier, improve the curative effect of conventional medicament, increase treatment window。
Nanoparticle is that a class that at present research is more passs drug carrier system for brain targeted therapy, including following advantage: have specificity, targeting, quantitatively accurately, easily absorb, has suitable particle diameter and grain type, and granule is little；Drug degradation can be reduced, improve medicine stability；There is higher drug loading, there is the ability in target site location, reduce dosage, reduce or avoid the toxic and side effects of medicine further；There is longer circulation time in vivo, increase Brain targeting efficiency。
Based on background above, we mainly study the infantile autism pathogenesis based on inflammatory reaction, and utilize infantile autism animal model to give the treatment of Chinese medicine anti-inflammatory agent, the intervention effect that infantile autism Ii _ i_iLLci _ i_ is reacted by detection medicine。Concrete grammar is with BTBRT+tf/J Mus for infantile autism animal model, and with silymarin and nanoparticle thereof, BTBRT+tf/J Mus inflammatory reaction being carried out pharmacologic intervention respectively, the neurobiochemistry molecular marker of this infantile autism model mice brain hippocampus and cortex is changed by primary evaluation medicine。
Summary of the invention
It is an object of the present invention to provide silymarin lipid nanoparticle, be prepared by step and realize:
Take stearic acid 270mg, medium chain triglyceride (MCT) 90mg, silymarin 40mg, add in 2mL dehydrated alcohol, at water-bath 60 DEG C, heated and stirred makes it dissolve, while hot above-mentioned solution is slowly injected in the 18mL pure water containing 0.1% (mass percent) Tween 80,60 DEG C of magnetic agitation 5min, it is stirred at room temperature and is cooled to room temperature, in milk yellow, both obtained 2mg/mL silymarin lipid nanoparticle solution。
Wherein the material of lipid nanoparticle is not limited to glyceryl monostearate, medium chain triglyceride etc., it is possible to be the fatty glyceride that other are conventional。
It is a further object to provide the application in preparing infantile autism inflammation intervention medicine of the described silymarin lipid nanoparticle。Described lipid nanoparticle is as drug administration carrier application in preparing infantile autism medicine。
Application of the present invention is realized by following steps:
Utilize BTBRT+tf/J Mus for infantile autism animal model。Experiment packet: Normal group, infantile autism model group, silymarin administration group (100mg/kg), silymarin nanoparticle group (20mg/kg), Dexamethasone group (0.125mg/kg, positive drug group)。Each group mice gastric infusion every day, successive administration 30 days。Mice carries out the evaluation to inflammation intervention effect after being administered 30 days。
Evaluation index:
(1) Nao Nei inflammation foci district drug accumulation imaging: mouse stomach is administered the lipid nanoparticle adding fluorescent material, observes the brain fluorescence distribution situation of each administration mice respectively after administration 2h, 4h, 6h, 8h。Fluorescent lipid nanoparticle is in the timeliness accumulation fluorescence intensity imaging of mouse brain, such as Fig. 1。
Result shows, lipid nanoparticle has good brain targeting, the effective break-through blood brain barrier of energy, and during 2h, accumulation fluorescence intensity is maximum, slowly weakens subsequently, almost without seeing fluorescence during to 8h, the nanoparticle in brain is entered maximum when administration 2h is described, subsequently along with the metabolism of internal nanoparticle and elimination, its content lowers gradually, almost disappears after 8h。
(2) immune-blotting method: successive administration is after 30 days, take brain Hippocampus and the cortical area of each group of mice, the expression change of inflammation related proteins Caspase-1, CathepsinB, IL-1 β and NLRP3 in cortex and Hippocampus is investigated with immunoblotting, characterize inflammation and intervene degree, immunoblotting and quantitatively see Fig. 2-Fig. 9。
Result shows, the testing result of inflammation related proteins finds BTBR group inflammation corpusculum signal activation, CathepsinB protein expression raises, the Caspase-1 causing downstream also raises therewith, but be in the NLRP3 on another path of downstream and be not affected, the IL-1 β in Caspase-1 downstream is owing to being secreted protein, and we do not find that this protein expression raises。And the Caspase-1 down-regulated expression in the CathepsinB of administration group and downstream, illustrate that silymarin and nanoparticle thereof have all reached certain antiphlogistic effects, and owing to the dosage of silymarin nanoparticle group is the 1/5 of silymarin group, it can be deduced that the drug effect of silymarin nanoparticle strengthens。
(3) Immunofluorescence test: successive administration, after 30 days, takes each group of mice Brain slices containing Hippocampus and cortical area, investigates the morphologic change expressing change and microglia of inflammation related proteins IL-1 β by immunofluorescence。
Result is such as shown in Figure 10-Figure 17, and compared to matched group, the up-regulated of IL-1 β in model group BTBR hippocampus of mice and cortex, being further characterized by BTBR has inflammation corpusculum signal activation really。Observing under Laser Scanning Confocal Microscope that model group microglia metamorphosis is obvious, cell space increases relatively simultaneously, and projection bounces back, and presents state of activation。And compared to model group, the down-regulated expression of IL-1 β in silymarin and nanoparticle group BTBR hippocampus of mice thereof and cortex, the cell space of microglia reduces, projection stretches elongates, recover quiescent condition, illustrate that silymarin and nanoparticle thereof have effectively intervened inflammation, and owing to the dosage of silymarin nanoparticle group is the 1/5 of silymarin group, it can be deduced that the drug effect of silymarin nanoparticle strengthens。
Silymarin lipid nanoparticle provided by the invention has good brain targeting, many particularly in inflammation foci district abundance, produces obvious inflammation intervention effect under less dosage, advantageously reduces the medicine toxic and side effects in non-focal zone；Containing medicine to discharge from carrier and have slow releasing function, carrier material is nontoxic, biodegradable and good biocompatibility, can be applicable to treatment infantile autism and relevant disease。
The pharmacodynamic index of silymarin lipid nanoparticle by preparing silymarin nanoparticle, in conjunction with infantile autism experimental animal model, from whole animal level, is evaluated by the present invention, it was demonstrated that its good brain targeting and to the obvious intervention effect of brain inflammation。The indexs such as activation are deformed from inflammation corpusculum signal activation and microglia, prove that this lipid nanoparticle can the inflammation of Effective Regulation infantile autism, thus provide new experimental basis and thinking for clinical treatment infantile autism, and provide drug-loading system more efficient, low toxicity。
Usefulness of the present invention is: (1) adopts nanotechnology, it is possible to be effectively improved the dissolubility of insoluble medicine carrying, strengthens drug effect。(2) after silymarin being made nanoparticle, it is possible to improve in inflammation foci district abundance, produce obvious improvement result under less dosage, advantageously reduce the medicine toxic and side effects in non-focal zone。(3) lipid nanoparticle drug-loading system has slow releasing function, extends action time。
The present invention has the prominent advantages that, adopts the infantile autism brain inflammation focal zone targeted system silymarin lipid nanoparticle with clinical practice potentiality innovatively, it is achieved the brain active targeting transmission of Chinese medicine anti-inflammatory drug；Silymarin lipid nanoparticle, increases long circulating in vivo, finally makes medicine be enriched with in inflammation foci district, improves the bioavailability of medicine, reduces drug dose, and significantly reduces the injury of normal tissue organ。
Accompanying drawing explanation
Fig. 1: fluorescent lipid nanoparticle brain timeliness accumulation fluorogram。Be divided into five groups, from left to right respectively non-administered group, administration 2h group, be administered 4h group, be administered 6h group, be administered 8h group。
Fig. 2: after silymarin and nanoparticle thereof are administered, the western blot figure of inflammation related protein Caspase-1。
Fig. 3: after silymarin and nanoparticle thereof are administered, the immunoblotting of inflammation related protein Caspase-1 is quantitatively schemed。Result is represented by meansigma methods ± S.E.M (n=6),#p<0.05,##P < 0.01 and matched group ratio, * p < 0.05, * * * p < 0.001 and model group ratio。
Fig. 4: after silymarin and nanoparticle thereof are administered, the western blot figure of inflammation related protein CathepsinB。
Fig. 5: after silymarin and nanoparticle thereof are administered, the immunoblotting of inflammation related protein CathepsinB is quantitatively schemed。Result is represented by meansigma methods ± S.E.M (n=6),#p<0.05,##P < 0.01 and matched group ratio, * p < 0.05, * * p < 0.01, * * * p < 0.001 and model group ratio。
Fig. 6: after silymarin and nanoparticle thereof are administered, the western blot figure of inflammation related protein IL-1 β。
Fig. 7: after silymarin and nanoparticle thereof are administered, the immunoblotting of inflammation related protein IL-1 β is quantitatively schemed。
Fig. 8: after silymarin and nanoparticle thereof are administered, the western blot figure of inflammation related protein NLRP3。
Fig. 9: after silymarin and nanoparticle thereof are administered, the immunoblotting of inflammation related protein NLRP3 is quantitatively schemed。
Figure 10-Figure 13: silymarin and cortex and hippocampus immunofluorescence figure after nanoparticle administration, is followed successively by cortical area, Hippocampus DG, CA1, CA3 district；In figure respectively labelling be IL-1 β albumen (proinflammatory factor), ED1 albumen (activated microglia mark thing), DAPI (labeled cell core)。
Figure 14-Figure 17: silymarin and cortex and hippocampus immunofluorescence figure after nanoparticle administration, is followed successively by cortical area, Hippocampus DG, CA1, CA3 district。In figure respectively labelling be Iba1 albumen (label of microglia), NeuN albumen (nucleus of labeled neurons), DAPI (labeled cell core)；The cell space of microglia increases relatively, and projection bounces back, and presents state of activation；Cell space reduces, and projection stretches elongates, in quiescent condition。
Detailed description of the invention
By the concrete drawings and Examples silymarin to the present invention and nanoparticle thereof, the intervention effect of infantile autism inflammatory reaction will be described in detail in order to make it easy to understand, following。It needs to be noted, instantiation and accompanying drawing are merely to explanation, the present invention according to illustrating herein, can be made various correction and change by obvious those skilled in the art within the scope of the invention, and these are revised and change and also include in the scope of the present invention。
The following is experiment material used by embodiment: glyceryl monostearate (Solution on Chemical Reagents in Shanghai company limited); Tween 80 (Shanghai Shen Yu medication chemistry company limited); medium chain triglyceride (mediumchaintriglycerides; MCT); silymarin (Sigma Co., USA); dehydrated alcohol (ethanol, Chemical Reagent Co., Ltd., Sinopharm Group)。
The structure of embodiment one silymarin lipid nanoparticle
The synthesis of 1.1 silymarin lipid nanoparticles
Take stearic acid 270mg, medium chain triglyceride (MCT) 90mg, silymarin (SM) 40mg, add in 2mL ethanol, to be heated melted after constant speed under its disposable liquid is injected in the 18mL pure water containing 0.1% (mass percent) Tween 80,60 DEG C of magnetic agitation 5min, it is stirred at room temperature and is cooled to room temperature, in milk yellow, obtain finished product, 4 DEG C of cryopreservations are standby, ultrasonic mixing before every time using, matching while using best (finished product is unstable, places and needs preparation again two days later)。
1.2 silymarin lipid nanoparticle grain diameter measurements
Take the silymarin nanoparticle (SM of above-mentioned synthesisSLN) 0.5mL, deionized water dilutes 10 times, then with Zetasizer particle size measurer, its particle diameter is measured, and needs ultrasonic mixing, record particle diameter 80 ran before mensuration。
1.3 silymarin lipid nanoparticles penetrate the fluorescence of blood brain barrier and follow the trail of
Change the medicine silymarin (SM) in above-mentioned building-up process into fluorescent material DiR (lipophilic cell membrane fluorescent dye), consumption is 10 μ g/mL, all the other materials are constant, and experimentation need to carry out when lucifuge, makes fluorescent lipid nanoparticle。Mouse stomach is administered by fluorescent lipid nanoparticle with the dosage of 100mg/kg, then after 2h, 4h, 6h and 8h, mice perfusion is taken brain respectively, at whole body optical imaging system (MaestroTM2MaestroTMEX-RRO) location mouse brain fluorescent places in。Fluorescent lipid nanoparticle brain timeliness accumulation fluorogram is shown in Fig. 1, is divided into five groups, from left to right respectively non-administered group, administration 2h group, be administered 4h group, be administered 6h group, be administered 8h group。
Embodiment two silymarin and nanoparticle thereof are to the intervention of infantile autism inflammatory reaction and pharmacodynamic study
Laboratory animal is grouped: matched group (C57BL/6NJ), model group (BTBR), three administration groups: silymarin (100mg/kg) group, silymarin lipid nanoparticle (20mg/kg) group, dexamethasone (0.125mg/kg, positive drug) group, often 8 mices of group。Take the mode of gastric infusion, successive administration 30 days, every day gavage 1 time；Matched group (con) and model group (BTBR) such as give at the normal saline of body weight ratio。
Evaluation index:
A. immune-blotting method: after each group experiment mice is administered 30 days, broken end takes brain, collect cerebral tissue sample, and crack tissue extraction albumen with lysate homogenate, the Expression change of Western-blotting method examination inflammation related protein Caspase-1, CathepsinB, IL-1 β, NLRP3, characterize inflammation and intervene degree, immunoblotting and quantitatively see Fig. 2-Fig. 9。
Western-blotting method step: extract albumen, contains the total protein of same concentrations in sample, the SDS-polyacrylamide acrylamide gel (SDS-PAGE) at 10-15% separates。Immunoblotting assay uses following primary antibodie: Caspase-1 antibody (mousemonoclonalantibody, 1:1000, SantaCruzBiotechnology)；CathepsinB antibody (mousemonoclonalantibody, 1:1000, ABcam)；IL-1 β antibody (rabbitpolyclonalantibody, 1:1000, SantaCruzBiotechnology)；NLRP3 antibody (Ratmonoclonalantibody, 1:1000, R&DSystems)。Use the chemiluminescence detection system ECL (AmershamLifeScience) strengthened that immunoreactive protein is visualized。
Result shows, the testing result of inflammation related proteins finds BTBR group inflammation corpusculum signal activation, CathepsinB protein expression raises, the Caspase-1 causing downstream also raises therewith, but be in the NLRP3 on another path of downstream and be not affected, the IL-1 β in Caspase-1 downstream is owing to being secreted protein, and we do not find that this protein expression raises。And the Caspase-1 down-regulated expression in the CathepsinB of administration group and downstream, illustrate that silymarin and nanoparticle thereof have all reached certain antiphlogistic effects, and owing to the dosage of silymarin nanoparticle group is the 1/5 of silymarin group, it can be deduced that silymarin nanometer is passed the drug effect of grain and is strengthened。
B. Immunofluorescence test: after each group experiment mice is administered 30 days, perfusion takes brain, chooses containing Hippocampus, skin portion, by the crown serial section being cut into 45 μ m thick of vibratome, with PFA4 DEG C of preservation, to be ready for use on Immunofluorescence test。Investigating the morphologic change expressing change and microglia of inflammation related proteins IL-1 β, fluorescence results is Figure 10-Figure 17 such as。
Immunofluorescence step: often group chooses the brain sheet of same position, with containing 0.01%TritonTMThe PBS permeable membrane of-X100, then closes with under TSA room temperature, adds corresponding antibody: IL-1 β antibody (rabbitpolyclonalantibody, 1:100, SantaCruzBiotechnology)；NeuN antibody (mousemonoclonalantibody, 1:500, MILLIPORE)；ED1 antibody (mousemonoclonalantibody, 1:100, ABcam)；Iba1 antibody (rabbitpolyclonalantibody, 1:500, ABcam)。It is subsequently adding and resists with the AlexaFluor488 (Anti-rabbitIgG, lifetechnologies) and AlexaFluor594 (Anti-mouseIgG, lifetechnologies) two of TSA dilution, mounting after last DAPI dyeing。Utilize the fluorescence of ZeissLSM510 confocal microscopy brain sheet Taking Pictures recording。
Result shows, compared to matched group, the up-regulated of IL-1 β in model group BTBR hippocampus of mice and cortex, being further characterized by BTBR has inflammation corpusculum signal activation really。Observing under Laser Scanning Confocal Microscope that model group microglia metamorphosis is obvious, cell space increases relatively simultaneously, and projection bounces back, and presents state of activation。And compared to model group, the down-regulated expression of IL-1 β in Stigma Croci crude extract and silymarin and nanoparticle group BTBR hippocampus of mice thereof and cortex, the cell space of microglia reduces, projection stretches elongates, recover quiescent condition, illustrate that silymarin and nanoparticle thereof have effectively intervened inflammation, and owing to the dosage of silymarin nanoparticle group is the 1/5 of silymarin group, it can be deduced that the drug effect of silymarin nanoparticle strengthens。
Claims (3)
1. a silymarin lipid nanoparticle, it is characterised in that prepared by following steps:
Take stearic acid 270mg, medium chain triglyceride 90mg, silymarin 40mg, add in 2mL dehydrated alcohol, at water-bath 60 DEG C, heated and stirred makes it dissolve, while hot above-mentioned solution is slowly injected in the 18mL pure water containing 0.1% Tween 80,60 DEG C of magnetic agitation 5min, it is stirred at room temperature and is cooled to room temperature, in milk yellow, both obtained 2mg/mL silymarin lipid nanoparticle solution。
2. the lipid nanoparticle that according to claim 1 prepared by method application in preparing infantile autism inflammation intervention medicine。
3. application according to claim 2, it is characterised in that described lipid nanoparticle is as drug administration carrier application in preparing infantile autism medicine。
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Citations (2)
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| CN104224808A (en) * | 2014-09-05 | 2014-12-24 | 电子科技大学 | Protective function of minocycline for offspring neuropsychiatric injury caused by stress during pregnancy |
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| CN101669904A (en) * | 2009-09-29 | 2010-03-17 | 北京中海康医药科技发展有限公司 | Epoprostanol lipid nanoparticle and preparation method thereof |
| CN104224808A (en) * | 2014-09-05 | 2014-12-24 | 电子科技大学 | Protective function of minocycline for offspring neuropsychiatric injury caused by stress during pregnancy |
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| R.L. BLAYLOCK: "Immune-Glutamatergic Dysfunction as a Central Mechanism of the Autism Spectrum Disorders", 《CURRENT MEDICINAL CHEMISTRY》 * |
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