阅读说明：本技术 一种甘露糖修饰的靶向纳米制剂 (A kind of targeted nano preparation of mannose-modified ) 是由 宋相容 魏于全 于 2019-05-13 设计创作，主要内容包括：本发明涉及医药技术领域,具体涉及一种甘露糖及其衍生物修饰的靶向纳米制剂。本发明所解决的技术问题是采用甘露糖及其衍生物修饰纳米制剂,制备得到的纳米制剂,提高了纳米制剂的靶向性,可用于疫苗递送、肿瘤靶向治疗、动脉硬化治疗及各种炎症性疾病等的治疗。(The present invention relates to pharmaceutical technology fields, and in particular to the targeted nano preparation of a kind of mannose and its Derivatives Modified.Technical problem solved by the invention is using mannose and its Derivatives Modified nanometer formulation, the nanometer formulation being prepared, the targeting for improving nanometer formulation can be used for the treatment of vaccine delivery, neoplasm targeted therapy, artery sclerosis treatment and various diseases associated with inflammation etc..)

1. the targeted nano preparation of a kind of mannose and its Derivatives Modified, which is characterized in that its by targeting ligand mannose and Its derivative, nanometer formulation and main ingredient can be used for vaccine delivery, neoplasm targeted therapy, artery sclerosis treatment and each at being grouped as The treatment of kind diseases associated with inflammation etc..

2. targeted nano preparation according to claim 1, which is characterized in that mannose derivative is mannoside, sweet dew One or more of osamine, mannosan etc..

3. targeted nano preparation according to claim 1, which is characterized in that the nanometer formulation is liposome, emulsion, receives One or more of rice gel, core-shell type nano grain, HDL nanoparticle, solid rouge nanoparticle, polymer micelle etc..

4. targeted nano preparation according to claim 1, which is characterized in that the main ingredient ingredient is small-molecule drug, egg One or more of white polypeptide drug or genomic medicine etc..

5. targeted nano preparation according to claim 1, which is characterized in that the targeting ligand sweet dew carbohydrates and their derivative Content be 0.05%-40%.

6. targeted nano preparation according to claim 1, which is characterized in that the targeting ligand sweet dew carbohydrates and their derivative Content be 1%-10%.

7. targeted nano preparation according to claim 1, which is characterized in that the targeting ligand sweet dew carbohydrates and their derivative Content be 2%-5%.

8. targeted nano preparation according to claim 1, which is characterized in that the targeting ligand sweet dew carbohydrates and their derivative Modification mode are as follows: prepare and sweet dew carbohydrates and their derivative adsorbed or be coupled to nanometer formulation surface again after nanometer formulation；Or Sweet dew carbohydrates and their derivative is first prepared into nanometer formulation with the carrier material coupling for preparing nanometer formulation again later.

9. targeted nano preparation according to claim 8, which is characterized in that the sweet dew carbohydrates and their derivative, which is adsorbed on, to be received The mode of rice dosage surface are as follows: use solvent evaporation method, high pressure homogenization method or micro emulsion method.

10. targeted nano preparation according to claim 1, which is characterized in that it is described modification nanometer formulation mannose and Its derivative is single sweet dew carbohydrates and their derivative or 2~10 sweet dew carbohydrates and their derivatives.

11. targeted nano preparation according to claim 8, which is characterized in that the sweet dew carbohydrates and their derivative and nanometer Preparation or the carrier material coupling mode for preparing nanometer formulation are as follows: be directly coupled or by an interval base coupling.

12. targeted nano preparation according to claim 11, which is characterized in that the interval base be glutaraldehyde, ethylenediamine, One or more of malonic acid, PEG, amino acid, dipeptides, oligopeptides, polypeptide, stearoyl, palmityl etc..

13. targeted nano preparation described in -12 according to claim 1, which is characterized in that prepare nanometer formulation material be with At least one of active amino or hydroxyl, pharmaceutically acceptable prepares micella, emulsion, nanogel, core-shell type nano The carrier material of grain, HDL nanoparticle, solid rouge nanoparticle, liposome, polymer micelle etc., is received using pharmaceutically acceptable Rice formulation preparation method is made.

Technical field

The present invention relates to field of medicaments, and in particular to a kind of targeted nano preparation of mannose-modified.

Background technique

In recent years, the targeted drug delivery system mediated based on drug receptor has been widely studied, targeted drug transmitting system Its specific target tropism can be improved in system, overcomes the problems, such as that drug distribution is wide, toxic side effect is serious.Wherein, agglutinin receptor is One kind is distributed in the glycoprotein, glycolipid or saccharide complex of cell membrane surface, can specific recognition and bound fraction glycosyl.Mannose Receptor is most important efficient endocytosis agglutinin receptor, and function includes removing endogenous molecule, promoting antigen presentation, adjust carefully Born of the same parents' activation and transport, also with the immunologic escape of tumour and shift closely related, be mainly expressed in macrophage, dendritic cells with Tumour cell, can specific recognition mannose glycosyl molecule.Mannose group as most potential targeting group, have it is nontoxic, It many advantages, such as non-immunogenicity, good biocompatibility and biodegradability, can be widely used for drug delivery system It is glycosylation modified.

(Liu R, Li H, Gao X, the et al.mannose-conjugated platinum such as Liu Ran complexes reveals effective tumor targeting mediated by glucose transporter [J] .Biochem Biophys Res Commun, 2017,487 (1): 34-40.) platinum complexes of mannose-modified have been synthesized, It was found that it has stronger inhibiting effect to human colon cancer cell (HT29), the service life of leukemia mouse can be extended, but when administration The compound has apparent toxicity when measuring larger, and the compound is not due to having long linker (such as PEG chain) connection to lead to it Body-internal-circulation is in relative disadvantage.(Zeng Junfen, Huang Ling, Lu Jianwu wait Lung targeting Hydroxycamptothecin liposome to Zeng Junfen etc. Prepare and its in hospital, mouse intracorporal Tissue distribution research [J] state pharmaceutical journal, 2016,36 (16): 1374-1379.) In It is added to D-MANNOSE and octadecylamine during preparing liposome, has obtained Lung targeting Hydroxycamptothecin liposome, although knot Fruit is shown in lung's residence time and significantly extends compared with normal injection agent, opposite uptake ratio 60.72, Lung targeting efficiency 17.57, tool There is certain Lung targeting effect, but this method cannot be guaranteed that mannose is centainly exposed to outside, targeting effect is reached in conjunction with receptor Fruit, and its liposome preparation process is cumbersome, condition is not easy to control, and the liposomal particle size of preparation is bigger than normal, galenic pharmacy property need into One-step optimization.(Su Pengfei, Dan Qiang, Niu Yunqi wait the Brain targeting of sweet dew Derivatives Modified liposome to study [J] to Su Pengfei etc. Qiqihar Medical College's journal, 2015,36 (9): 1249-1251.) mannose-modified DSPE-PEG2000 is used, and lecithin is added Rouge, cholesterol, DSPE-PEG2000 are prepared for the Puerarin liposome of mannose-modified, and in mouse brain capillary Chrotoplast BMVEC establishes external BBB model, establishes internal intraluminal middle cerebral artery occlusion in rats occlusion (MCAO) animal model, that is, first Prepare and glutaraldehyde and mannose be added after liposome, discovery glycosylation Puerarin liposome can enhance to a certain degree drug across BBB is simultaneously enriched with to infarcted region, but this synthetic method can only synthesize a kind of material, cannot guarantee that mannose is centainly exposed to Outside, Targeting Effect is reached in conjunction with receptor, and DSPE is prohibitively expensive, it is difficult to realize extensively and promote.(the Wang such as Wang Ning N,Wang T,Zhang ML,et al.Mannose derivative and lipid A dually decorated cationic liposomes as an effective cold chain free oral mucosal vaccine Adjuvant-delivery system [J] .Eur J Pharm Biopharm, 2014,88 (1): 194-206.) be prepared for it is sweet Reveal sugar-modified cholesterol, the two is connected by PEG1000, can guarantee that mannose group is exposed to outside, in conjunction with receptor, but It is that method does not have versatility, a kind of carrier material can only be synthesized.

Summary of the invention

The object of the present invention is to provide a kind of nanometer formulation, the targeting of specially a kind of mannose and its Derivatives Modified is received The targeting of the nanometer formulation can be improved by the modification of sweet dew carbohydrates and their derivative in metric system agent.

To solve the above problems, the present invention uses following scheme:

A kind of targeted nano preparation of mannose and its Derivatives Modified, by targeting ligand sweet dew carbohydrates and their derivative, Nanometer formulation and main ingredient can be used for vaccine delivery, neoplasm targeted therapy, artery sclerosis treatment and various inflammatory diseases at being grouped as The treatment of disease etc..The targeting ligand sweet dew carbohydrates and their derivative and nanometer formulation have certain distance, it is ensured that mannose and Its derivative can reach better Targeting Effect (as shown in figure 13) fully in conjunction with receptor outside being exposed to.

Further, the targeting ligand sweet dew carbohydrates and their derivative and nanometer formulation are connected by way of absorption, described Main ingredient ingredient is wrapped among nanometer formulation or in nanometer formulation surface or half insertion nanometer formulation.

Further, the mannose derivative is one or more of mannoside, mannosamine, mannosan etc..

Specifically, targeted nano preparation provided by the invention, mannose derivative are methyl-Dmannose glycosides, 1- α formyl Methyl-mannopyrane glucosides, 4- aminophenyl-α-D- mannopyranose glycosides, 4- nitrobenzophenone-α-D- mannopyranose glycosides, 4- Methylumbelliferyl ketone group-α-D- mannopyranose glycosides, Man-6-P, carbamoyl-D-MANNOSE, mannosamine, sweet dew One or more of glycan etc..

Further, the targeted nano preparation be liposome, emulsion, nanogel, core-shell type nano grain, HDL nanoparticle, Gu one or more of rouge nanoparticle, polymer micelle etc..

Further, the main ingredient ingredient be one of small-molecule drug, protein and peptide drugs or genomic medicine etc. or It is several.

Further, the weight ratio of the targeting ligand sweet dew carbohydrates and their derivative and nanometer formulation is 0.05%-40%.

Preferably, the weight ratio of the targeting ligand sweet dew carbohydrates and their derivative and nanometer formulation is 1%-10%.

More preferably, the weight ratio of the targeting ligand sweet dew carbohydrates and their derivative and nanometer formulation is 2%-5%.

Further, the modification mode of the targeting ligand sweet dew carbohydrates and their derivative are as follows: prepare nanometer formulation and again will later Sweet dew carbohydrates and their derivative is adsorbed onto nanometer formulation surface.

Further, the sweet dew carbohydrates and their derivative is adsorbed on the mode on nanometer formulation surface are as follows: using solvent evaporation method, After high pressure homogenization method or micro emulsion method prepare nanometer formulation, the solution of the carbohydrates and their derivative containing sweet dew is added, and is mixed adequately In the process, sweet dew carbohydrates and their derivative is made to be adsorbed on nanometer formulation by modes such as affinity between intermolecular force or group Surface.

The solvent evaporation method is a kind of method for preparing microballoon, and simple process is exactly first to configure the height of suitable concentration Then molecular solution emulsifies Polymer Solution in continuous phase, gradually evaporation of solvent.In this process, the targeting mannose And its derivative can be adsorbed on nanometer formulation surface.

High pressure homogenization method is that material passes through homogenizing valve under high pressure, is sprayed with high flow velocity, hits collision ring, passes through sky Cave, shock, shearing effect make material micronization and dispersion and emulsion.The micronization of material increases the surface area of partial size, institute Surface can be adsorbed in by the affinity between intermolecular active force and group by stating targeting sweet dew carbohydrates and their derivative.

Micro emulsion method: the system for being used to prepare nanoparticle is usually w/o type system, and 4 groups of Chang You, which are grouped as, helps surface living Property agent, surfactant, organic solvent and aqueous solution.Common surfactant has AOT, SDS, CTAB, TritonX.It is used as Cosurfactant be still medium carbochain fatty alcohol, surfactant can be not added in some systems.Organic solvent is mostly C₆-C₈Straight-chain hydrocarbons or cycloalkane.

Micro emulsion method prepares the characteristics of superfine nano particle and is: ion surface is wrapped in layer of surface active agent molecule, makes Interionic is not easy to coalesce, and by selecting different surfactant molecules that can modify the surface of ion, and is controlled The size of particle.The surface area of the partial size of nanoparticle increases in the process, and the targeting sweet dew carbohydrates and their derivative passes through Affinity between intermolecular active force and group can be adsorbed in surface.

Further, the sweet dew carbohydrates and their derivative of the modification nanometer formulation be single sweet dew carbohydrates and their derivative or 2~ 10 sweet dew carbohydrates and their derivatives, the sweet dew carbohydrates and their derivative are adsorbed in the surface of nanometer formulation, specially described single Sweet dew carbohydrates and their derivative or 2~10 sweet dew carbohydrates and their derivatives pass through absorption and nanometer formulation or nanometer formulation material surface Generate certain space distance.

Further, the material for preparing nanometer formulation is at least one of active amino or hydroxyl, pharmaceutically can be with What is received prepares micella, emulsion, nanogel, core-shell type nano grain, HDL nanoparticle, solid rouge nanoparticle, liposome, polymer The carrier material of micella etc. is made using pharmaceutically acceptable nanometer formulation preparation method.

Further, the main ingredient ingredient small-molecule drug is that can be wrapped in nanometer formulation for neoplasm targeted therapy, move Treatment the effect of property small molecule of arteries and veins hardening treating and various diseases associated with inflammation etc..

In some embodiments, the mRNA for encoding particular tumor antigens can be wrapped in targeted nano preparations carrier, then is led Enter in body cell, and pass through the expression system synthetic antigen albumen of host cell, induction host immune system is generated to the tumour The immune response of antigen can realize the function of anti-curing oncoma, and the targeted nano preparation for being loaded with mRNA has better cancer target Property, be conducive to the treatment of tumour.Equally by antitumor chemical drug and biological medicament, the drug for the treatment of artery sclerosis and diseases associated with inflammation It can also be wrapped in targeted nano preparations carrier, play the role of targeted therapy more accurately.

Further, the targeting ligand sweet dew carbohydrates and their derivative and nanometer formulation are connected by way of coupling, described Main ingredient ingredient is wrapped among nanometer formulation or in nanometer formulation surface or half insertion nanometer formulation.

Further, the mannose derivative is one or more of mannoside, mannosamine, mannosan etc..

Specifically, targeted nano preparation provided by the invention, mannose derivative are methyl-Dmannose glycosides, 1- α formyl Methyl-mannopyrane glucosides, 4- aminophenyl-α-D- mannopyranose glycosides, 4- nitrobenzophenone-α-D- mannopyranose glycosides, 4- Methylumbelliferyl ketone group-α-D- mannopyranose glycosides, Man-6-P, carbamoyl-D-MANNOSE, mannosamine, sweet dew One or more of glycan etc..

Further, the targeted nano preparation be liposome, emulsion, nanogel, core-shell type nano grain, HDL nanoparticle, Gu one or more of rouge nanoparticle, polymer micelle etc..

Further, the main ingredient ingredient be one of small-molecule drug, protein and peptide drugs or genomic medicine etc. or It is several.

Further, the weight ratio of the targeting ligand sweet dew carbohydrates and their derivative and nanometer formulation is 0.05%-40%.

Preferably, the weight ratio of the targeting ligand sweet dew carbohydrates and their derivative and nanometer formulation is 1%-10%.

More preferably, the weight ratio of the targeting ligand sweet dew carbohydrates and their derivative and nanometer formulation is 2%-5%.

Further, the modification mode of the targeting ligand sweet dew carbohydrates and their derivative are as follows: prepare nanometer formulation and again will later Sweet dew carbohydrates and their derivative is coupled to nanometer formulation surface；Or first by sweet dew carbohydrates and their derivative and the carrier for preparing nanometer formulation Nanometer formulation is prepared again after material coupling.

Further, the sweet dew carbohydrates and their derivative of the modification nanometer formulation be single sweet dew carbohydrates and their derivative or 2~ 10 sweet dew carbohydrates and their derivatives, or by single sweet dew carbohydrates and their derivative and/or 2~10 sweet dew carbohydrates and their derivatives and It connects and forms every base.

Further, the sweet dew carbohydrates and their derivative and nanometer formulation or the carrier material coupling mode of nanometer formulation is prepared Are as follows: it is directly coupled or by an interval base coupling.

Further, " hydroxyl " or " ammonia of the single sweet dew carbohydrates and their derivative or 2~10 sweet dew carbohydrates and their derivatives Base " end is directly coupled with " hydroxyl " of nanometer formulation or nanometer formulation material end or " carboxyl " end, the specially described single sweet dew Carbohydrates and their derivative or 2~10 sweet dew carbohydrates and their derivatives are by being directly coupled to nanometer formulation or nanometer formulation material surface Generate certain space length.

Further, " hydroxyl " or " ammonia of the single sweet dew carbohydrates and their derivative or 2~10 sweet dew carbohydrates and their derivatives " carboxyl " of base " end and interval base, which is held, to be connected, and " hydroxyl " of interval base and nanometer formulation or nanometer formulation material end or " carboxylic are passed through The coupling of base " end, the specially described single sweet dew carbohydrates and their derivative or 2~10 sweet dew carbohydrates and their derivatives by interval base with Nanometer formulation or the coupling of nanometer formulation material surface generate certain space length.

Further, the interval base be glutaraldehyde, ethylenediamine, malonic acid, short-chain alkyl chain (such as-CH2-CH2-), One or more of PEG, amino acid, dipeptides, oligopeptides, polypeptide, stearoyl, palmityl etc..

Further, the amino acid is arginine, asparagine, aspartic acid, glutamic acid, glutamine, lysine, silk Propylhomoserin, threonine, tyrosine.Dipeptides, few skin, polypeptide two terminal amino acids amino acid composition selected from the following: arginine, asparagus fern Amide, aspartic acid, glutamic acid, glutamine, lysine, serine, threonine, tyrosine；Central amino acid is selected from 20 kinds Arbitrary amino acid (such as RGD).

Further, the main ingredient ingredient small-molecule drug is that can be wrapped in nanometer formulation for neoplasm targeted therapy, move Treatment the effect of property small molecule of arteries and veins hardening treating and various diseases associated with inflammation etc..

In some embodiments, the mRNA for encoding particular tumor antigens can be wrapped in targeted nano preparations carrier, then is led Enter in body cell, and pass through the expression system synthetic antigen albumen of host cell, induction host immune system is generated to the tumour The immune response of antigen can realize the function of anti-curing oncoma, and the targeted nano preparation for being loaded with mRNA has better cancer target Property, be conducive to the treatment of tumour.Equally by antitumor chemical drug and biological medicament, the drug for the treatment of artery sclerosis and diseases associated with inflammation It can also be wrapped in targeted nano preparations carrier, play the role of targeted therapy more accurately.

Further, the material for preparing nanometer formulation is at least one of active amino or hydroxyl, pharmaceutically can be with What is received prepares micella, emulsion, nanogel, core-shell type nano grain, HDL nanoparticle, solid rouge nanoparticle, liposome, polymer The carrier material of micella etc. is made using pharmaceutically acceptable nanometer formulation preparation method.

Specifically, carrier material is lipid, poly lactide-glycolide acid (PLGA), polylactic acid (PLA), gathers in oneself It is ester (PCL), poly-D-lysine (PLL), polyethyleneimine (PEI), hyaluronic acid (HA), chitosan, gelatin, poloxamer, hard One or more of lipidol etc..Specifically, liposome is prepared, the matrix material of core-shell type nano grain is cholesterol, yolk ovum Phosphatide, soybean lecithin, cephalin, sphingomyelins, PC (phosphatidyl choline), EPG (phosphatidylglycerol), SPG (soybean phospholipid phosphatidyl Glycerol), Distearoyl Phosphatidylethanolamine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), two palmityl phosphatidyl gallbladders Alkali (DPPC), Dioleoyl Phosphatidylcholine (DOPC), Distearoyl Phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilinoleoylphosphatidylcholine (DLPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), two nutmeg phosphatidyl cholines (DMPC), dilauroylphosphatidylglycerol (DLPG), cetyl trimethyl bromination Ammonium (CTAB), GERBU Adjuvant 100 (DDAB), 1,2-dioleoyloxy-3-trimethylammonio propane (chloride salt) (DOTAP) etc. one of or a variety of.The solid lipid material for preparing solid rouge nanoparticle is stearic acid, cholesterol, monostearate Glyceride, bi-tristearin, glyceryl tristearate, three Yu acid glycerides, glyceryl laurate ester, glycerol palmitinic acid are stearic Sour rouge, behenic acid monoglyceride, behenic acid double glyceride, behenic acid glyceryl ester, three myristins, Chinese holly One or more of rafter acid glyceride, octadecyl alcolol, palmitinic acid, myristic acid, three Yu acid, lauric acid.

Beneficial effects of the present invention:

1) it is outer can to guarantee that mannose and its mannose derivative are exposed to for the nanometer formulation provided by the invention, can fill Divide ground in conjunction with receptor, reaches better Targeting Effect, can be applied to the preparation of targeted drug；

2) nanometer formulation provided by the invention shows good profile, and size is small, close to spherical shape, has good Serum stability, cytotoxicity is small, is applicable to the targeting drug delivery system of drug (chemical drug and biological medicament), and transfection efficiency is significant Higher than the Lipo 3K of commercialization, it can be used as transfection reagent use, be applied in scientific research and business；

3) synthetic method of the targeting vector is low in cost, is readily synthesized, and can carry out the targeting point of different ligands chain length The synthesis of son, therefore there is versatility, multiple material can be synthesized, and the click-reaction used is conducive to purify and characterize.

Detailed description of the invention

Attached drawing 1 is mannose-PEG₁₀₀- Chol nuclear-magnetism verification result figure.

Attached drawing 2 is the grain-size graph of 1 liposome of prescription.

Attached drawing 3 is the potential diagram of 1 liposome of prescription.

Attached drawing 4 is that the TEM of 1 liposome of prescription schemes.

Attached drawing 5 is liposome transfection result.

Attached drawing 6 is the expression of GFP in fluorescence microscope DC cell.

Attached drawing 7 is that transfection efficiency analyzes histogram.

Attached drawing 8 is mannose-PEG₁₀₀₀The stability analysis of-Chol.

Attached drawing 9 is 4 DEG C and stores lower mannose-PEG₁₀₀₀The transfection efficiency of-Chol.

Attached drawing 10 is mannose-PEG₁₀₀₀Stability analysis of-the Chol in serum.

11 Flow cytometry mannose-PEG of attached drawing₁₀₀₀Toxicity of-the Chol and Lipo 3K for DC cell.

12 Flow cytometry mannose-PEG of attached drawing₁₀₀₀Data of-the Chol and Lipo 3K for the toxicity of DC cell Statistically analyze histogram.

Figure 13 is the structural schematic diagram of targeted nano preparation.

Figure 14 is the research of DC2.4 cellular uptake targeted nano granule.

Figure 15 is the intake situation of mRNA targeting lipids nanocrystal composition in fluorescence microscope BMDCs cell.

Figure 16 is the data point of the intake situation of mRNA targeting lipids nanocrystal composition in fluorescence microscope BMDCs cell Analysis.

Specific embodiment

Following embodiment further describes preparation process and beneficial effect of the invention, and embodiment is only used for the mesh of illustration , do not limit the scope of the invention, while those of ordinary skill in the art made according to the present invention it is obvious change and Modification is also contained within the scope of the invention.

For the deficiency of existing nanometer formulation, the receiving with targeting of a kind of mannose and its Derivatives Modified is designed Metric system agent.

In present embodiment, targeted nano preparation by targeting ligand sweet dew carbohydrates and their derivative, nanometer formulation and main ingredient at It is grouped as.

In present embodiment, targeting ligand is mannose.

In other embodiments, targeting ligand can be mannose derivative, can be above-mentioned mannoside, sweet dew One or more of osamine, mannosan etc..Specifically, mannose derivative is methyl-Dmannose glycosides, 1- α formyl first Base-mannopyrane glucosides, 4- aminophenyl-α-D- mannopyranose glycosides, 4- nitrobenzophenone-α-D- mannopyranose glycosides, 4- first Base umbrella shape ketone group-α-D- mannopyranose glycosides, Man-6-P, carbamoyl-D-MANNOSE, mannosamine, sweet dew are poly- One or more of sugar etc..

In present embodiment, nanometer formulation is liposome, HDL nanoparticle, solid rouge nanoparticle, polymer micelle.

In other embodiments, nanometer formulation can be one of emulsion, nanogel, core-shell type nano grain etc. or It is several.

In present embodiment, the main ingredient ingredient that nanometer formulation contains is small-molecule drug, protein and peptide drugs or gene One or more of drug etc..

In present embodiment, received by single sweet dew carbohydrates and their derivative and/or 2~10 mannoses and its Derivatives Modified Metric system agent.

In present embodiment, after targeting ligand sweet dew carbohydrates and their derivative and the carrier material coupling for preparing nanometer formulation Nanometer formulation is prepared again.

In other embodiments, targeting ligand sweet dew carbohydrates and their derivative can prepare nanometer formulation later again by sweet dew Carbohydrates and their derivative adsorbs or is coupled to nanometer formulation surface.

In present embodiment, between sweet dew carbohydrates and their derivative and nanometer formulation or the carrier material for preparing nanometer formulation pass through It is coupled every base PEG.

In other embodiments, sweet dew carbohydrates and their derivative and nanometer formulation or prepare nanometer formulation carrier material it is straight It connects coupling or is coupled by other interval bases, other interval bases can be above-mentioned glutaraldehyde, ethylenediamine, malonic acid, short alkane One or more of base chain (such as-CH2-CH2-), PEG, amino acid, dipeptides, oligopeptides, polypeptide etc..Specifically, interval base ammonia Base acid is arginine, asparagine, aspartic acid, glutamic acid, glutamine, lysine, serine, threonine, tyrosine.Two Peptide, few skin, polypeptide two terminal amino acids amino acid composition selected from the following: arginine, asparagine, aspartic acid, glutamic acid, Glutamine, lysine, serine, threonine, tyrosine；Central amino acid is selected from 20 kinds of arbitrary amino acids (such as RGD).

In the present embodiment, PEG can be the common PE G that unmodified both-end is hydroxyl, be also possible at least one The one end the PEG of Amino End Group, PEG connects DSPE, cholesterol, palmitinic acid.

In other embodiments, the one end PEG also can connect other above-mentioned active amino or hydroxyl, pharmacy Upper acceptable prepares the carrier material of liposome, HDL nanoparticle, solid rouge nanoparticle, polymer micelle etc..Specifically, institute It states carrier material and is selected from poly lactide-glycolide acid (PLGA), polycaprolactone (PCL), poly-D-lysine (PLL), poly- second Alkene imines (PEI), hyaluronic acid (HA), chitosan, gelatin, poloxamer, stearyl alcohol egg yolk lecithin, soybean lecithin, brain Phosphatide, sphingomyelins, PC (phosphatidyl choline), EPG (phosphatidylglycerol), SPG (soy phosphatidylglycerol), two palmityl phosphatide Acyl ethanol amine (DPPE), dipalmitoylphosphatidylcholine (DPPC), Dioleoyl Phosphatidylcholine (DOPC), distearoylphosphatidyl Choline (DSPC), dimyristoylphosphatidylcholine (DMPC), dilinoleoylphosphatidylcholine (DLPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), two nutmeg phosphatidyl cholines (DMPC), dilauroylphosphatidylglycerol (DLPG), cetyl trimethylammonium bromide (CTAB), GERBU Adjuvant 100 (DDAB), 1,2- dioleoyl- 3- trimethyl ammonium propane (chloride salt) (DOTAP), stearic acid, cholesterol, glycerin monostearate, bi-tristearin, Glyceryl tristearate, three Yu acid glycerides, glyceryl laurate ester, glycerol palmitic, stearic rouge, behenic acid monoglyceride, Behenic acid double glyceride, behenic acid glyceryl ester, three myristins, citron acid glyceride, octadecyl alcolol, cardamom One or more of acid, three Yu acid, lauric acid etc..

In the present embodiment, the nanometer formulation of preparation is sent into vivo using intravenous injection, hypodermic mode.

In other embodiments, the nanometer formulation of preparation can also be sent by the way of intraperitoneal injection, intramuscular injection In vivo.

In embodiment involved mRNA according to normal conditions, such as Molecular Cloning:A Laboratory guide (third edition, J. Sa Nurse Brooker etc. write) described in condition, or according to the normal condition proposed by manufacturer implement obtain.

The following are specific embodiments.