CN102178954B - Recombinant high density lipoprotein (HDL) medicament delivery system with functions of targeted and reverse cholesterol transport (RCT) on vascular wall and application thereof - Google Patents
Recombinant high density lipoprotein (HDL) medicament delivery system with functions of targeted and reverse cholesterol transport (RCT) on vascular wall and application thereof Download PDFInfo
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Abstract
The invention belongs to the medical technical field, and relates to a new function of high density lipoproteins (HDLs) of different structures as a targeted carrier for a liposoluble cardiovascular medicament. The recombinant HDL can be taken as a cholesterol receptor for receiving excess extra-hepatic cellular cholesterol and transporting the cholesterol to liver for metabolism, thus achieving the purpose of treating cardiovascular or arteriosclerotic disease. In the invention, the HDLs or lipid components thereof are recombined into the carrier for the liposoluble medicament in vitro so as to achieve dual functions of medicament delivery to an atherosclerosis focal area on a vascular wall and reverse cholesterol transport (RCT), which provides a new effective way for treating cardiovascular disease.
Description
Technical field
The present invention relates to medical technical field, be specifically related to the preparation of different structure rHDL and the new function as fat-soluble cardiovascular drugs carrier thereof, reach the function of transportation drug targeting blood vessel wall atherosis focus region and antiport cholesterol.
Background technology
Quantity research shows greatly, and generation and the order of severity of plasma high density lipoprotein level (high density lipoprotein, HDL) level and atherosclerosis (atherosclerosis, As) and coronary heart disease are negative correlation.An important mechanisms of the anti-As of HDL is exactly that HDL participates in cholesterol antiport, the superfluous cholesterol of extrahepatic tissue is shifted out and is transported to liver and transform, remove.In addition, HDL also has the expression of anti-lipid oxidation, anticoagulant and adhesion molecule, the propagation that affects cell, protection endothelium and promotes the effects such as vasodilation.HDL has new life's (plate-like) and ripe (spherical) two types, and the former is mainly made up of the Lipid bilayer membranes surrounding containing apolipoprotein A-1 (apolipoproteinA I, apoA-I); The latter is made up of single phospholipid membrane and the apolipoprotein of nonpolar lipid core and periphery.At present, existing research and utilization apoA-I and phospholipid in vitro rHDL (reconstituted HDL, rHDL) are used for the treatment of atherosclerosis, have obtained good curative effect.In addition, HDL uniqueness hydrophilic-hydrophobic structure, larger lipid core (can be used as the storage space of fat-soluble medicine), endogenous can characteristics degradable and that do not identified and remove by reticuloendothelial system, make the carrier of rHDL as medicine, demonstrate unique advantage at aspects such as improving drug targeting distributes, increase drug effect.Foreign patent US5128318 discloses a kind of method that apoA-I of utilization and phospholipid are prepared plate-like HDL, object is to remove unnecessary liposoluble substance in body, and do not use its medicine carrying, foreign patent US6514523B1 discloses the preparation method of a kind of medicine carrying rHDL, be used for improving drug effect, reduce toxicity and reduce engulfing of reticuloendothelial system, and the targeting tissue or the cell that are mediated by apoA-I, but do not relate to rHDL and other machine-processed targeting of different structure, CN1307906A discloses a kind of new drug carrier, utilize rHDL medicine carrying to improve the targeting transhipment of liver or tumor tissues, but liver is as one of target organ maximum in body, the targeting of itself is very remarkable, the application of therefore developing rHDL novel targets will have larger meaning.
In circulating the process changing from new life to maturation, the natural HDL of research finds, cholesteryl esters most in ripe HDL granule can be transferred to rapidly on other apolipoproteins such as very low density lipoprotein (VLDL) (very low density lipoprotein, VLDL).In this process, VLDL can bring cholesteryl ester into the extrahepatic tissue including arterial wall, and HDL is reinvented discoid newborn HDL simultaneously, continues the effect of performance antiport cholesterol, and this process is conducive to antiatherogenic treatment.Cardiovascular drugs bag is written into rHDL; in its metabolic process, be transferred to VLDL; be carried into arterial wall by VLDL receptor acting; this targeting is almost negligible to normal body; but for atherosclerotic patient; VLDL not only participates in the formation of foam cell in Atheromatosis reason process, and the permeability increase of blood vessel endothelium to VLDL, and VLDL is subject to physical ability medicine to be brought into the lesions position of arterial wall by VLDL.Therefore, the object of the invention is to utilize rHDL bag to carry cardiovascular drugs, do not introducing under the condition of exogenous VLDL, both brought into play the targeting of VLDL blood vessel focus, make again rHDL after reconstruct, produce the antiport cholesterol function of similar newborn HDL, improve the therapeutic effect of medicines from increasing target site drug level and antiport cholesterol two aspects.
As everyone knows, cardiovascular drugs especially some Chinese medicine ingredients mostly is fat-soluble, and bioavailability is low, this brings much inconvenience to clinical practice, consider the chronicity of cardiovascular patient medication, at present, existing document and patent report the sustained-release microparticle preparation of cardiovascular drugs, as liposome, solid lipid nanoparticle etc., but the common matrix material that these preparations adopt, multi-source is oils and fats used in intestinal and non-enteral nutrition Emulsion,, can there is potential harm in life-time service or intravenous injection.As glyceryl monostearate is generally used for food additive; Content in blood of triglyceride and cholesterol and hyperlipemia, atherosclerosis are closely related, and long-term a large amount of these ectogenic fat of taking in, will jeopardize human health, for the patient of cardiovascular and cerebrovascular disease, more harm than good especially.Difference of the present invention is its bio-imitability, is to adopt the composition of natural high density lipoprotein and the drug-loading system that approaching ratio is recombinated, and has both avoided the unfavorable factor of common lipid materials, has brought into play again targeting and the physiological function of carrier.
Summary of the invention
The carrier that the present invention is fat-soluble medicine by high density lipoprotein or its lipid components vitro recombination, bring into play its dual function to the atherosis focus of blood vessel wall region transmission medicine and antiport cholesterol, for foregoing invention object, inventor adopts following technical scheme:
A kind of rHDL drug-loading system of plate-like, it is characterized in that comprising fat-soluble medicine, phospholipid, cholesterol, apolipoprotein in surfactant and natural high density lipoprotein, and according to the ratio of each component in natural HDL, in prescription gross weight, the shared percentage ratio of each component is: phosphatidase 13 0%～60%, cholesterol 1%～10%, surfactant 1%～5%, apolipoprotein 20%～60%, fat-soluble medicine 1%～5%, and there is the function of plate-like form and antiport cholesterol.
The preparation method of above-mentioned plate-like rHDL is by Tanshinone I I A (also can select other fat-soluble medicines) and phospholipid, the common mixed dissolution of cholesterol for example, in organic facies (ethanol, acetone, chloroform, methanol) in, remove organic facies, prepare a dry mixture, the buffer medium hydration that use contains surfactant, form liquid mixture, cross 0.22 μ m filter membrane, add apolipoprotein, stirring is fully hatched it, surfactant is removed in dialysis, it is characterized in that one or more surfactants to add in water, improve the combination rate of albumen and lipid, and albumen incubation conditions gentleness, guarantee the biological activity of apolipoprotein.
A kind of spherical rHDL drug-loading system, it is characterized in that comprising fat-soluble medicine, phospholipid, cholesterol, glyceride, cholesteryl ester, apolipoprotein in surfactant and natural high density lipoprotein, according to the ratio of each component in natural HDL, in prescription gross weight, the shared percentage ratio of each component is: phosphatidase 11 0%～30%, cholesterol 1%～10%, glyceride 2%～10%, cholesteryl ester 1%～15%, surfactant 1%～3%, apolipoprotein 20%～60%, fat-soluble medicine 1%～3%, and there is spherical-like morphology, after entering in body, form plate-like HDL through metabolism, should there is the function of antiport cholesterol.
The preparation method of above-mentioned spherical rHDL is by tanshinone ⅡA (also can select other fat-soluble medicines) and phospholipid, cholesterol, glyceride, the common mixed dissolution of cholesteryl ester for example, in organic facies (ethanol, acetone, chloroform, methanol) in, at a certain temperature, organic facies is splashed into the water that contains surfactant, fully stir and form translucent milky liquid, Ultrasonic Pulverization, organic facies is removed in decompression, cross 0.22 μ m filter membrane, add apolipoprotein, stirring is fully hatched it, surfactant is removed in dialysis, it is characterized in that one or more surfactants to add in water, improve the combination rate of albumen and lipid, and albumen incubation conditions gentleness, guarantee the biological activity of apolipoprotein.
The apolipoprotein of above plate-like or spherical rHDL is selected from Genetyping poA I, and on high density lipoprotein other main apolipoprotein as apoAII, apoAIV, apoD, apoE, apoC I, apoCII, any one or more in apoCIII.
Above plate-like or spherical rHDL drug-loading system, wherein fat-soluble medicine can be cardiovascular drugs,
Above plate-like or spherical rHDL drug-loading system, cardiovascular drugs is tanshinone ⅡA, lovastatin.
Above plate-like or spherical rHDL drug-loading system, wherein phospholipid is selected from the natural phospholipid in Semen sojae atricolor, egg yolk, brain or spinal cord.
Spherical rHDL drug-loading system above, wherein the fatty acid in cholesteryl ester and triglyceride is the middle long-chain fatty acid of 6-24 carbon, contain one or more unsaturated bonds, cholesteryl ester can be cholesterol acid ester, cholesterol palm acid ester, cholesterol arachidonate, cholesterol linoleate, cholesterol Semen Myristicae oil acid esters, one or more in cholesterol linolenate; Glyceride can be Lipoid MCT, Labrafac CC, glycerol trioleate, Dynasan114, Miglyol812N, Softisan138, Softisan142, one or more in Mi glyol840.
Above plate-like or spherical rHDL drug-loading system can be used for preparing the carrier of fat-soluble cardiovascular drugs, reach to the function of the atherosis focus of blood vessel wall region transmission medicine and performance carrier antiport cholesterol.
While preparing rHDL at present use single apolipoprotein-apoA-I, but apolipoprotein in HDL there is polytype more, and there is difference in functionality separately, as apoA-I can activate lecithin cholesterol acyltransferase, and can be used as the part of HDL receptor; ApoA-II has HDL Stability Analysis of Structures and the ability with phospholipids incorporate of maintaining; ApoE can determine the binding site of cholesterol, mediates in addition the effects such as cholesterol efflux.Therefore the present invention adopts the mixture of the multiple apolipoprotein including apoA-1 to prepare rHDL drug-loading system, will have higher physiologically active.
The present invention has adopted the method that adds in advance one or more surfactants in the time preparing fat core in water, this adds or does not add compared with the method for single surfactant with previous literature report in the time hatching albumen, there is higher apolipoprotein combination rate, and the rHDL fat core drug loading forming is high, thereby can more effectively realize protein mediated receptor acting, the physiological function of performance carrier and raising curative effect of medication.
The present invention simulates the conventional theory of natural HDL particle diameter while having broken through in the past preparation containing albumen rHDL, adopt comparatively gentle condition to hatch albumen, this is because the three dimensional structure of albumen is to guarantee its bioactive key factor, although the conditions such as acutely ultrasonic can obtain less particle diameter, but can produce cavitation, make albumen local temperature too high or generate free radical and degeneration.The prepared rHDL of the present invention, particle diameter, much larger than natural HDL, has but still retained the physiologically active of natural HDL antiport cholesterol and has had targeting the characteristic of transporting medicine.
Plate-like prepared by the present invention or spherical medicine carrying rHDL are respectively liposome and nanoparticle form before hatching with apolipoprotein, and after hatching with albumen, liposome changes the plate-like of accumulation into, and nanoparticle is still the spherical and surperficial brush border that occurred, Electronic Speculum figure is shown in Fig. 1.Mean diameter～160nm, envelop rate > 90%, drug loading > 4%, Zeta potential <-16mV.
Due to the rHDL of spherical medicine carrying will be after biotransformationin vivo be discoid the effect of competence exertion mediation Cholesterol Efflux, therefore can only investigate in vitro this function of plate-like medicine carrying rHDL.Cholesterol Efflux experiment (seeing Fig. 2) shows, negative control bovine serum albumin is at each time point, cell inner cholesterol does not have significant difference, and plate-like medicine carrying rHDL can flow out by mediated cell inner cholesterol, content lowers as 50.1% of cell inner cholesterol primary quantity, ability similar (56.0%) to natural HDL reduction cholesterol, prove that the prepared plate-like medicine carrying rHDL of the present invention has the ability of mediation Cholesterol Efflux, lay a good foundation for further bringing into play antiatherogenic effect in body.
With atherosis focus district in Foam cell analogue body; vitro data shows that the foam cell amount of engulfing of plate-like and spherical HDL medicine carrying rHDL has increased respectively 10.3 and 5.0 times than macrophage; prove that two kinds of medicine carrying rHDL all have good targeting; and phagocytosis depends on very low density lipoprotein (VLDL) (VLDL) and cholesterol ester transfer protein (CETP); in addition; plate-like medicine carrying rHDL targeting is greater than spherical medicine carrying rHDL, can produce higher targeting efficiency adding after Lecithin-cholesterol acyltransferase. (LCAT).
Accompanying drawing explanation
Fig. 1 is the transmission electron microscope picture of albumen rHDL.In figure, show in prescription and add after cholesteryl ester and glyceride, the fat core forming is nanoparticle structure (A), and while not using this two kinds of lipids, the fat core forming is liposome structure (B), and the fat core of nanoparticle structure and apolipoprotein after hatching still for nanoparticle structure (C), liposome structure become plate-like (D).
Fig. 2 is the result that plate-like rHDL mediated cell inner cholesterol flows out, and shows that plate-like rHDL can reduce the content of cell inner cholesterol compared with negative control bovine serum albumin in figure.
The specific embodiment
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative completely, and they are only used for the present invention to be specifically described, and not should be understood to limitation of the present invention.
Embodiment 1:
Preparation technology: by the medicine of recipe quantity, egg phosphatide, cholesterol is placed in cillin bottle, add appropriate chloroform, ultrasonicly make its dissolving, be transferred in eggplant-shape bottle, be placed in Rotary Evaporators, organic facies is removed in decompression, vacuum drying 2h, add the hydration medium that is dissolved with in right amount sodium cholate, ultrasonicly be uniformly dispersed into translucent suspension, re-using Probe Ultrasonic Searching pulverizes, become the transparent liquid that has opalescence, cross 0.22 μ m filter membrane, add apolipoprotein, dissolving is placed on 4 ℃ of refrigerators, 300rpm magnetic agitation 3-6h, the Tris-HCl buffer dialysed overnight that uses 2L to contain NaCI and EDETATE SODIUM, obtain rHDL.
In employing transmission electron microscope observing embodiment 1, rHDL and albumen are hatched the form of front and back, see B, D in accompanying drawing 1, before hatching, are liposome structure, after hatching, are plate-like packed structures, and mean diameter is 158.5nm, and envelop rate is 60.12%, and protein binding rate is 60.8%.
Embodiment 2:
Preparation technology is with embodiment 1, and the mean diameter after prepared rHDL and albumen are hatched is 211.5nm, and envelop rate is 89.12%, and protein binding rate is 44.1%.
In vitro cell experiment: adopt Mus source cell strain RAW264.7 macrophage, oxidized low-density lipoprotein stimulation copies Foam cell, in two kinds of cells, add respectively plate-like rHDL, investigate at very low density lipoprotein (VLDL) (VLDL), Lecithin-cholesterol acyltransferase. (LCAT), under the effect of cholesterol ester transfer protein (CETP), the targeting of rHDL, result shows that the engulf amount of plate-like rHDL in foam cell is a 0.19 μ g/1000000 cell, the intake of macrophage is a 0.084 μ g/1000000 cell, there is significant difference in the two, and phagocytosis depends on VLDL and CETP, the amount of engulfing of foam cell after LCAT that adds increases to a 0.505 μ g/1000000 cell, show that plate-like rHDL can issue the structure that changes in the effect of LCAT, bring into play more significant targeting, when apolipoprotein content is increased to 0.55g by 0.16g, foam cell is increased to a 0.58 μ g/1000000 cell to the intake of rHDL by 0.13, illustrates that the amount of apolipoprotein in rHDL and cellular uptake amount are proportionate.
Cellular cholesterol flows out experiment: adopt Mus source cell strain RAW264.7 macrophage, after hatching, be inoculated in 24 porocyte plates, go down to posterity after 2～3 times, do the experiment of cell Cholesterol Efflux, rHDL and bovine serum albumin are added respectively in cell culture medium, in incubator, hatch after 9 hours, taking-up discards supernatant liquid, and repeatedly rinse cell plates with cold PBS, add dissolve with methanol attached cell, HPLC detects the content of cell inner cholesterol, and with the comparison of bovine serum albumin negative control group, the reduction of calculating cell inner cholesterol is primary quantity 63.5%.Illustrate that rHDL has the ability of mediation Cholesterol Efflux.
Embodiment 3:
Preparation technology is with embodiment 1, and the mean diameter after prepared rHDL and albumen are hatched is 173.4nm, and envelop rate is 88.12%, and protein binding rate is 61.3%.
Cell in vitro test: with embodiment 2, the intake of plate-like rHDL foam cell is a 0.21 μ g/1000000 cell, and the intake of macrophage is a 0.087 μ g/1000000 cell.
Cellular cholesterol flows out experiment: with embodiment 2, rHDL mediated cell inner cholesterol flows out, content is reduced to 41.2% of cell inner cholesterol primary quantity, and the ability that uses the rHDL building with natural HDL apolipoprotein same composition to have higher mediation Cholesterol Efflux than the rHDL that contains an apoA-I is described.
Embodiment 4:
Preparation technology is same: by the medicine of recipe quantity, egg phosphatide, cholesterol, cholesterol Semen Myristicae oil acid esters, Miglyol812N is placed in cillin bottle, add appropriate ethanol, ultrasonicly make its dissolving, be heated to 60 ℃, splash in the water that contains sodium cholate, magnetic agitation, Probe Ultrasonic Searching disperses, then be placed in Rotary Evaporators, organic facies is removed in decompression, and be concentrated into certain volume, cooling, cross 0.22 μ m filter membrane, add apolipoprotein, after dissolving in 37 ℃ of magnetic agitation 8-12h, the Tris-HCl buffer dialysed overnight that uses 2L to contain NaCI and EDETATE SODIUM, obtain rHDL.
In employing transmission electron microscope observing embodiment 4, rHDL and albumen are hatched the form of front and back, see A, C in accompanying drawing 1, are nanoparticle structure before and after hatching, and its particle surface of hatching has brush border, mean diameter is 162.3nm, and envelop rate is 72.37%, and protein binding rate is 48.7%.
Embodiment 5:
Preparation technology is with embodiment 4, and the mean diameter after prepared rHDL and albumen are hatched is 158.5nm, and envelop rate is 90.3%, and protein binding rate is 54.1%.
In vitro cell experiment: adopt Mus source cell strain RAW264.7 macrophage, OxLDL ELISA stimulation copies Foam cell, in two kinds of cells, add respectively spherical rHDL, investigate at VLDL, under the effect of CETP, the targeting of rHDL, result shows that the engulf amount of spherical rHDL in foam cell is a 0.057 μ g/1000000 cell, significantly be greater than the intake of macrophage (0.013 μ g/1000000), and phagocytosis depends on VLDL and CETP, but be less than the targeting of plate-like rHDL.
Embodiment 6:
Preparation technology is with embodiment 4, and it is 155.1nm that prepared rHDL and albumen are hatched rear mean diameter, and envelop rate is 92.7%.
Cell in vitro test: with embodiment 5, the intake of spherical rHDL is a 0.05 μ g/1000000 cell, significantly be greater than the intake of macrophage (0.011 μ g/1000000), when apolipoprotein content is increased to 0.26g by 0.06g, the intake of foam cell is increased to a 0.13 μ g/1000000 cell by 0.03, illustrates that the amount of apolipoprotein in rHDL and cellular uptake amount are proportionate.
Claims (10)
1. the rHDL drug-loading system of a plate-like, it is characterized in that comprising fat-soluble medicine, phospholipid, cholesterol, apolipoprotein in surfactant and natural high density lipoprotein, and according to the ratio of each component in natural HDL, in prescription gross weight, the shared percentage ratio of each component is: phosphatidase 13 0%～60%, cholesterol 1%～10%, surfactant 1%～5%, apolipoprotein 20%～60%, fat-soluble medicine 1%～5%, and there is the function of plate-like form and antiport cholesterol.
2. drug-loading system according to claim 1, its preparation method is a) by fat-soluble medicine and phospholipid, the common mixed dissolution of cholesterol is in organic facies, b) remove organic facies, prepare a dry mixture, c) use the buffer medium hydration that contains surfactant, form liquid mixture, cross 0.22 μ m filter membrane, d) add apolipoprotein, stirring is fully hatched it, e) surfactant is removed in dialysis, it is characterized in that one or more surfactants to add in water, improve the combination rate of albumen and lipid, and albumen incubation conditions gentleness, guarantee the biological activity of apolipoprotein.
3. a spherical rHDL drug-loading system, it is characterized in that comprising fat-soluble medicine, phospholipid, cholesterol, glyceride, cholesteryl ester, apolipoprotein in surfactant and natural high density lipoprotein, according to the ratio of each component in natural HDL, in prescription gross weight, the shared percentage ratio of each component is: phosphatidase 11 0%～30%, cholesterol 1%～10%, glyceride 2%～10%, cholesteryl ester 1%～15%, surfactant 1%～3%, apolipoprotein 20%～60%, fat-soluble medicine 1%～3%, and there is spherical-like morphology, after entering in body, form plate-like HDL through metabolism, should there is the function of antiport cholesterol.
4. drug-loading system according to claim 3, its preparation method is a) by fat-soluble medicine and phospholipid, cholesterol, glyceride, the common mixed dissolution of cholesteryl ester is in organic facies, b) at a certain temperature, organic facies is splashed into the water that contains surfactant, fully stir and form translucent milky liquid, c) Ultrasonic Pulverization, d) organic facies is removed in decompression, cross 0.22 μ m filter membrane, e) add apolipoprotein, stirring is fully hatched it, f) surfactant is removed in dialysis, it is characterized in that one or more surfactants to add in water, improve the combination rate of albumen and lipid, and albumen incubation conditions gentleness, guarantee the biological activity of apolipoprotein.
5. according to the drug-loading system described in claim 1～4, wherein apolipoprotein is selected from Genetyping poA I, and other main Genetyping poA II on high density lipoprotein, apoAIV, apoD, apoE, apoC I, apoC II, any one or more in apoCIII.
6. according to the drug-loading system described in claim 1～4, wherein fat-soluble medicine is cardiovascular drugs.
7. according to the drug-loading system described in claim 1～4, cardiovascular drugs is tanshinone ⅡA, lovastatin.
8. according to the drug-loading system described in claim 1～4, wherein phospholipid is selected from the natural phospholipid in Semen sojae atricolor, egg yolk, brain or spinal cord.
9. according to the drug-loading system described in claim 3～4, wherein the fatty acid of cholesteryl ester is the middle long-chain fatty acid of 6～24 carbon, contain one or more unsaturated bonds, formed by one or more cholesteryl esters, wherein glyceride is selected from one or more in list or two or the triglyceride of fatty acid, wherein fatty acid is 6～24 carbon, the middle long-chain fatty acid that contains one or more unsaturated bonds.
According to the rHDL drug-loading system described in arbitrary claim in claim 1～9 in the application of preparing aspect fat-soluble medicine blood vessel wall targeting vector.
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| CN102846551A (en) * | 2011-06-28 | 2013-01-02 | 复旦大学 | Liver-targeting high-density lipoprotein analogue nano-particles, preparation method thereof, and application thereof |
| CN102614515A (en) * | 2012-04-16 | 2012-08-01 | 中国药科大学 | Novel chemical restructuring high-density lipoprotein drug carrying system with targeted and double anti-tumor effects and application |
| CN103505720A (en) * | 2012-06-30 | 2014-01-15 | 复旦大学 | Application of apolipoprotein A-I in preparation of medicine used for preventing and treating liver disease metabolic syndrome |
| CN104324007B (en) * | 2014-09-15 | 2017-04-12 | 中国药科大学 | Preparation technology and application of natural recombinant nanostructured lipid carrier |
| CN104784188A (en) * | 2015-03-26 | 2015-07-22 | 辽宁中医药大学 | Application of tanshinone IIA in preparing medicine for regulating blood serum HDL subclass distribution |
| AU2018370237A1 (en) * | 2017-11-20 | 2020-06-04 | Icahn School Of Medicine At Mount Sinai | Inhibiting trained immunity with a therapeutic nanobilogic composition |
| CN108144070A (en) * | 2017-12-06 | 2018-06-12 | 常州朋悦纺织品有限公司 | A kind of preparation method of lipoprotein cladding hydridization gadolinium oxide micelle contrast agent |
| CN108404139A (en) * | 2018-01-29 | 2018-08-17 | 南昌大学 | The preparation method and applications of the recombination lipoprotein of low concentration Monostalotetrahexosylgangliside modification |
| CN108508102A (en) * | 2018-02-05 | 2018-09-07 | 贵州医科大学 | The assay method of nine kinds of effect components plasma protein binding rates in Sheepear Inula Herb extract |
| CN111973759A (en) * | 2020-09-10 | 2020-11-24 | 吉林大学 | Preparation method of diagnosis and treatment integrated recombinant high-density lipoprotein |
| CN112999351B (en) * | 2021-03-11 | 2022-06-10 | 华中农业大学 | Preparation method and application of artificial lipid drops and freeze-dried preparation thereof |
| JP2024511067A (en) | 2021-03-19 | 2024-03-12 | トレインド セラピューティクス ディスカバリー，インコーポレーテッド | Compounds and methods of use for modulating trained immunity |
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